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Preview: Chemical Biology & Drug Design

Chemical Biology & Drug Design



Wiley Online Library : Chemical Biology & Drug Design



Published: 2018-02-01T00:00:00-05:00

 



Computational studies on horseshoe shape pocket of human orexin receptor type 2 and boat conformation of suvorexant by molecular dynamics simulations

2018-02-16T02:12:59.14015-05:00

The FDA approved drug suvorexant binds to the horseshoe shape pocket of OX2R with the boat conformation. The horseshoe shape pocket plays an important role on the biological activity of OX2R in the cell membrane. To study the binding mechanism between the horseshoe shape pocket of OX2R and boat conformation of suvorexant, the crystal structures of wild type and N324A mutant of OX2R in complex with antagonist suvorexant are chosen to perform molecular dynamics (MD) simulations, QM/MM and MMGBSA calculations. By comparison with the wild type of OX2R, the results show the 1,2,3-triazole and p-toluamide groups of suvorexant are changed in the N324A mutant of OX2R during 200 ns MD simulations. The QM/MM and weak interaction analysis are employed to calculate the noncovalent bonds interaction between suvorexant and key residues in the wild type and N324A mutant of OX2R. The MMGBSA calculations indicate the entropy energy is an important influence factor for suvorexant affinity in the distorted horseshoe shape pocket of OX2R. Our results not only show the horseshoe shape pocket of OX2R is the necessary conformation for the binding of antagonist suvorexant, but also give the important sites and structural features for antagonist design of OX2R. This article is protected by copyright. All rights reserved. Binding mechanism between boat conformation of suvorexant and horseshoe shape pocket of OX2R is studied. The results show the change mechanism of boat conformational suvorexant in the horseshoe shape pocket of OX2R. It supplies the structural feature information for further drug design of OX2R.



99mTc-HYNIC-(Ser)3-J18 peptide: A radiotracer for non-small-cell lung cancer targeting

2018-02-14T03:05:37.985518-05:00

Radiolabeled peptide could be a useful tool for the diagnosis of non-small-cell lung cancer (NSCLC). In this study, HYNIC-(Ser)3-J18 peptide was labeled with 99mTc using EDDA/tricine as co-ligands. The in vitro and in vivo studies of this radiolabeled peptide were performed for cellular specific binding and tumor targeting in A-549 cells and tumor bearing mice, respectively. The high radiochemical purity was obtained and this radiolabeled peptide exhibited high stability in buffer and serum. The radiolabeled peptide showed high affinity for the A-549 cells with a dissociation constant value (KD) of 4.4 ± 0.8 nM. The tumor-muscles ratios were 2.7 and 4.4 at 1 and 2 h after injection of 99mTc-(EDDA/tricine)-HYNIC-(Ser)3-J18 in tumor bearing mice. The tumor uptake was decreased after pre-injection with non-labeled peptide for this radiolabeled peptide in blocking experiment. The results of this study showed the 99mTc-(EDDA/tricine)-(Ser)3-HYNIC-J18 peptide might be a promising radiolabeled peptide for NSCLC targeting. This article is protected by copyright. All rights reserved. This study described the preparation and radiolabeling of HYNIC-J18 peptide with 99mTc and EDDA/tricine as co-ligand. The 99mTc-J18 peptide was evaluated for specific binding to non-small cell lung cancer. Results of this study showed that 99mTc-(EDDA/tricine)-(Ser)3-HYNIC-J18 peptide might be a promising radiolabeled peptide for NSCLC targeting.



Novel 3-substituted N-methylcarbazole–imidazolium salt derivatives: Synthesis and cytotoxic activity

2018-02-11T05:50:27.07393-05:00

A series of novel 3-substituted N-methylcarbazole–imidazolium salt derivatives has been prepared and evaluated in vitro against a panel of tumor cell lines (Hep G-2, Hela and PC12). The results suggest that the presence of substituted 2-methyl-imidazole or imidazole ring and substitution of the imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group were important for improving cytotoxic activity. Compounds 17, 18, 27 and 28 with 4-bromophenacyl and naphthylacyl groups displayed good activities with IC50 values of 0.09–7.20 μM against three tumor cell lines investigated and more active than DDP. Compound 35 exhibited cytotoxic activity selectively against Hela cell. This article is protected by copyright. All rights reserved. A series of novel 3-substituted N-methylcarbazole–imidazolium salt derivatives were synthesized and their cytotoxic structure-activity relationship studies were reported. Compounds 17, 18 and 28 displayed good activities with IC50 values of 0.09–7.20 μM against three tumor cell lines investigated. Compound 35 exhibited cytotoxic activity selectively against Hela cell.



New Thiophene-Acridine Compounds: Synthesis, Antileishmanial Activity, DNA Binding, Chemometric and Molecular Docking Studies

2018-02-07T15:45:39.484965-05:00

In the present study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT01 and ACS01-ACS07). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS01 and ACS02 derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC50 values of 9.60±3.19 and 10.95±3.96 μM. Additionally, these two derivatives were effective against antimony-resistant L. (L.) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS01 is not associated to DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 104 M−1. In partial least-squares (PLS) studies, it was observed that the most active compounds (ACS01 and ACS02) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene-acridine derivatives are promising molecules as potential drug candidates. This article is protected by copyright. All rights reserved. The new compounds presented antileishmanial activity, with better performance than the reference drugs (ACS01 and ACS02), without to present human erythrocyte cytotoxicity.The best compound ACS01 interacted with DNA. However, the antileishmanial activity of ACS01 is not associated to DNA fragmentation of the promastigote forms.Theoretical studies showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. In addition, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme.



Synthesis and Evaluation of Pyridinium-Hydrazone Derivatives as Potential Antitumoral Agents

2018-02-07T15:45:28.311953-05:00

The hydrazones of 4-hydrazinylpyridinium bearing alkylphenyl groups on pyridinium nitrogen were synthesized and evaluated for their cytotoxic activity against MCF-7, PC3, U2OS and HEK293 cell lines by Wst1 cell proliferation assay. Cytotoxic activity results indicated that d derivatives having butylene chain; 4 and 5 series having naphthalene and anthracene ring systems, showed high cytotoxic activity (IC50= 3.27-8.54 μM) on cancer cells. 3d (4-(2-(4-hydroxybenzylidene)hydrazinyl)-1-(4-phenylbutyl)pyridinium bromide) was the most cytotoxic compound with IC50 value of 3.27 μM against MCF-7. The most active derivatives (1d, 2d, 3d, 4 and 5 series) were selected to investigate for the effects on autophagy by analyzing the expression of autophagy marker proteins. The conversion of LC3-I to its lipidated form LC3-II is essential for autophagy and related to autophagosomes. According to our results, all tested compounds except for 3d, induced lipidated form LC3-II accumulation. Then, the effects of the compounds on p62 protein level were also analyzed by the immunoblotting since the autophagy inhibition results in accumulation of p62. Further molecular mechanistic studies including morphological analysis and live death assays indicated that all tested compounds (1d, 2d, 3d, 4 and 5 series) are potent antitumoral molecules and all except for 3d have potential to inhibit autophagic flux. This article is protected by copyright. All rights reserved. A series of pyridinium-hydrazones was evaluated for their cytotoxic activity. Among the tested compounds, derivatives with the highest cytotoxicity (1d, 2d, 3d, 4 and 5 series) were found to have potent antitumoral activity and all except for 3d have potential to inhibit autophagic flux.



1,2,3,4-tetrahydroisoquinolines as inhibitors of HIV-1 integrase and human LEDGF/p75 interaction

2018-02-06T02:55:22.478536-05:00

Alkaloids are a class of organic compounds with a wide range of biological properties, including anti-HIV activity. The 1,2,3,4-tetrahydroisoquinoline is a ubiquitous structural motif of many alkaloids. Using a short and an efficient route for synthesis, a series of 1,2,3,4-tetrahydroisoquinolines/isoquinolines was developed. These compounds have been analysed for their ability to inhibit an important interaction between HIV-1 integrase enzyme (IN) and human LEDGF/p75 protein (p75) which assists in the viral integration into the active genes. A lead compound 6d is found to inhibit the LEDGF/p75-IN interaction in vitro with an IC50 of ~10 μM. Molecular docking analysis of the isoquinoline 6d reveals its interactions with the LEDGF/p75-binding residues of IN. Based on an order of addition experiment, the binding of 6d or LEDGF/p75 to IN is shown to be mutually exclusive. Also, the activity of 6d in vitro is found to be unaffected by the presence of a non-specific DNA. As reported earlier for the inhibitors of LEDGF/p75-IN interaction, 6d exhibits a potent inhibition of both the early and late stages of HIV-1 replication. Compound 6d differing from the known inhibitors in the chemical moieties and interactions with CCD could potentially be explored further for developing small molecule inhibitors of LEDGF/p75-IN interaction having a higher potency. This article is protected by copyright. All rights reserved. An isoquinoline compound 6d (ethyl-1-benzyl-7-methoxyisoquinoline-4-carboxylate, shown as a stick model) has been identified as a lead molecule for inhibiting the interaction between human LEDGF/p75 and HIV-1 integrase (IN). Compound 6d inhibits formation of a LEDGF/p75-IN complex with an IC50 of 10.4±3.8 μM in vitro. Similar to LEDGINs identified earlier, the activity of 6d has been characterized at both the early and late stages of HIV-1 replication. Molecular docking analysis reveals that 6d occupies the LEDGF/p75 binding site on a IN dimer (the monomers are shown in red and green ribbons). The in vitro order-of-addition experiment supports an overlap in the binding site for LEDGF/p75 and 6d on IN.



Discovery of novel 5-methyl-1H-pyrazole derivatives as potential anti-prostate cancer agents: design, synthesis, molecular modeling and biological evaluation

2018-02-01T03:10:26.032211-05:00

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability comparing with 10e in human liver microsomes. This article is protected by copyright. All rights reserved. Structure optimization via a fragments splicing strategy led to the discovery of a series of 5-methyl-1H-pyrazole derivatives. Part of the compounds showed strong growth inhibition in prostate cancer LNCap cells. AR luciferase reporter gene assay revealed compounds A13 and A14 as potent AR antagonists.



A novel class of human 15-LOX-1 inhibitors based on 3-hydroxycoumarin

2018-02-01T00:05:33.694112-05:00

Inflammations, sensitivities, and some cancers in mammals are intimately linked to the activity of lipoxygenase enzymes. Owing to the importance of these enzymes, mechanistic studies, product analysis, and synthesis of inhibitors have expanded. In this study, a series of hydroxycoumarins, methoxy-3-hydroxy coumarins and 7-alkoxy-3-hydroxy coumarins were synthesized and evaluated as potential inhibitors of human 15-LOX-1. Among the synthetic coumarins, 7-methoxy-3-hydroxycoumarin (7-M3HC) derivative demonstrated potent inhibitory activity and the compound, 5f, showed the best result. Radical scavenging assessment, IC50, HNMR, and DPPH bleaching results indicate that the electronic properties are the major factors for the lipoxygenase inhibition potency of the synthetic coumarins. Based on the theoretical studies, it was suggested that the mesomeric effect of the substituent at the 7th position of the benzene ring is one of the major factors in the stability of the oxy radical intermediate. This article is protected by copyright. All rights reserved. In this study, a series of hydroxycoumarins, methoxy-3-hydroxy coumarins and 7-alkoxy-3-hydroxy coumarins were synthesized and evaluated as potential inhibitors of human 15-LOX-1. Among the synthetic coumarins, 7-methoxy-3-hydroxycoumarin (7-M3HC) derivative demonstrated potent inhibitory activity and the compound, 5f, showed the best result



Discovery of a novel class of pyridine derivatives that selectively inhibits mutant Isocitrate dehydrogenase 2

2017-11-09T10:50:20.023381-05:00

Current paper presents synthesis and Structure-Activity Relationship of pyridine derivatives as inhibitors of mutant isocitrate dehydrogenase 2 (IDH2). A series of 2,4,6-trisubsitituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC50 of 54.6 nM, which is approximately 1-fold improvement compared to drug candidate AG-221 (Enasidenib) that is in Phase III trial. Exquisite selectivity of 14n for IDH2 R140Q mutant isoform was demonstrated by the poor activity against the wild-type IDH1 and IDH2. This article is protected by copyright. All rights reserved. Thirty-six 2,4,6-trisubsitituted pyridine derivatives have been prepared and evaluated in vitro. Among these compounds, 14n exhibited excellent inhibition activity with the IC50 of 54.6 nM, which is approximately 1-fold improvement compared to drug candidate AG-221 (Enasidenib) that is in Phase III trial.



Design, synthesis of 9H-fluorenone based 1,2,3-triazole analogues as Mycobacterium tuberculosis InhA inhibitors

2017-10-24T03:20:19.506943-05:00

We prepared fifty various 9H-fluorenone based 1,2,3-triazole analogues varied with NH, -S- and -SO2- groups using click chemistry. The target compounds were characterized by routine analytical techniques, 1H, 13CNMR, Mass, Elemental, single crystal XRD (8a) and screened for in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain and two ‘wild’ strains Spec. 210 and Spec. 192 and MIC50 was determined. Further, the compounds were evaluated for MTB InhA inhibition study as well. The final analogues exhibited minimum inhibitory concentration (MIC) ranging from 52.35 - > 295 μM. Among the -NH- analogues one compound 5p (MIC 58.34 μM), amongst -S- containing analogues four compounds 8e (MIC 66.94 μM), 8f (MIC 74.20 μM), 8g (MIC 57.55 μM) & 8q (MIC 56.11 μM), among -SO2- containing compounds one compound 10p (MIC 52.35 μM) showed less than MTB MIC 74.20 μM: Compound 4-(((9H-fluoren-9-yl)sulfonyl)methyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (10p), was found to be the most active compound with 73% InhA inhibition at 50 μM; it inhibited MTB with MIC 52.35 μM. Further, 10f & 10p were docked to crystal structure of InhA to know binding interaction pattern. Most active compounds were found to be non cytotoxic against HEK 293 cell lines at 50 μM. This article is protected by copyright. All rights reserved. Fifty novel compounds are synthesized and evaluated for their MTB activity and MTB InhA inhibition study. in vitro cytotoxicity studies of the most active compounds was analysed.10p emerged as most active compound inhibition 73% at 50 µM against MTB InhA and inhibited MTB with MIC 52.35 µM.



Design and fabrication of dual-targeted delivery system based on gemcitabine conjugated human serum albumin nanoparticles

2017-06-22T10:25:18.497293-05:00

Dual-targeted drug delivery system has established their reputation as potent vehicles for cancer chemotherapies. Herein, gemcitabine (Gem) was conjugated to human serum albumin (HSA) via dithiodipropionic anhydride (DTDPA) to fabricate Gem-HSA nanoparticles. It was hypothesized that this system can enhance the low stability of Gem and can improve its intracellular delivery. Furthermore, folate was applied as targeting agent on HSA nanoparticles for increasing the tumor selectivity of Gem. In order to evaluate the structural properties of synthesized products, 1H NMR and FT-IR were performed. Moreover, HPLC was implemented for confirming the conjugation between HSA and Gem. Nanoparticles have shown spherical shape with negative charge. The release rate of Gem was dependent to the concentration of glutathione and pH. Folate-targeted HSA nanoparticles have shown higher cytotoxicity, cellular uptake and apoptosis induction on folate receptor overexpressing MDA-MB-231 cells in comparison to non-targeted nanoparticles. Finally, it is considered that the developed dual-targeted nanoparticles would be potent in improving the stability and efficacy of intracellular delivery of Gem and its selective delivery to cancer cells. This article is protected by copyright. All rights reserved. In the present study, we prepared folate targeted Gem-HSA nanoparticles. Dithiodipropionic anhydride disulfide linker was used to conjugate Gem with HSA. Nanoparticles had spherical shape and negative charge. Release rate of Gem from nanoparticles was accelerated under reductive and acidic pH. Folate targeting of nanoparticles improved the cytotoxicity, cellular uptake and apoptosis induction of nanoparticles. The dual- targeted nanoparticles enhanced the stability and efficacy of Gem by intracellular release and selective delivery to cancer cells.



Synthesis and Biological Evaluation of Novel Substituted 4-Anilinoquinazolines as Antitumor Agents

2015-12-21T23:06:51.135159-05:00

Eleven novel 4-anilinoquinazoline derivatives were synthesized and evaluated for their in vitro antiproliferative activity. Among them, compound 9a exhibited the best potency, with IC50 values of 25−682 nM against various types of cancer cell lines. In addition, 9a was confirmed that it could arrest the cell cycle at G2/M phase and trigger apoptosis. Indirect immunofluorescence staining revealed its anti-tubulin property. Importantly, 9a significantly inhibited tumor growths in SM-7721 xenograft models (57.0% tumor mass change) without causing significant loss of body weight, suggesting that 9a is a promising new anticancer agent to be developed. This article is protected by copyright. All rights reserved. Eleven novel 4-anilinoquinazoline derivatives were synthesized and evaluated for their antiproliferative activities in vitro and anti-tumor effects in vivo.



Synthesis and biological evaluation of tricyclic guanidine analogues of batzelladine K for antimalarial, antileishmanial, antibacterial, antifungal and anti-HIV activities

2012-06-15T11:37:34.311362-05:00

Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC50 1.25 and 0.88 μM and chloroquine-resistant W2 strain with IC50 1.64 and 1.07 μM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC50 2.39 and 2.78 μM and IC90 11.27 and 12.76 μM respectively. Three analogues 12c, 14c and 14i were the most active against various pathogenic bacteria and fungi with IC50 <3.02 μM and MIC/MBC/MFC <6 μM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structral class for broad spectrum activity.© 2012 John Wiley & Sons A/S



Virtual and In vitro bioassay screening of phytochemical inhibitors from flavonoids and isoflavones against Xanthine oxidase and Cyclooxygenase-2 for gout treatment

2011-10-03T15:42:15.873122-05:00

Synthetic drugs such as allopurinol and benzbroarone are commonly used to treat the complex pathogenesis of gout, a metabolic disease that results from an inflammation of the joints caused by precipitation of uric acid. We seek to discover novel phytochemicals that could treat gout, by targeting the xanthine oxidase (XO) and cyclooxygenase 2 (COX-2) enzymes. In this study, we report the screening of 9 compounds of flavonoids from the ZINC and PubChem databases (containing 2,092 flavonoids) using the iGEMDOCK software tool against the XO and COX-2 3D protein structures. Each compound was also evaluated by an in vitro bioassay testing the inhibition of XO and COX-2. Myricetin and luteolin were found to be the potential dual inhibitors of XO and COX-2 as demonstrated by IC50: 62.7 and 3.29μg/mL (XO) / 70.8 and 16.38μg/mL (COX-2), respectively. In addition, structure activity relationships and other important factors of the flavonoids binding to the active site of XO and COX-2 were discussed, which is expected for further rational drug design.



In silico identification, synthesis and biological evaluation of novel tetrazole inhibitors of MurB

2018-02-12T23:36:04.307766-05:00

In the context of antibacterial drug discovery resurgence, novel therapeutic targets and new compounds with alternative mechanisms of action are of paramount importance. We focused on UDP-N-acetylenolpyruvylglucosamine reductase (i.e. MurB), an underexploited target enzyme that is involved in early steps of bacterial peptidoglycan biosynthesis. On the basis of the recently reported crystal structure of MurB in complex with NADP+, a pharmacophore model was generated and used in a virtual screening campaign with combined structure-based and ligand-based approaches. To explore chemical space around hit compounds, further similarity search and organic synthesis were employed to obtain several compounds with micromolar IC50 values on MurB. The best inhibitors in the reported series of 5-substituted tetrazol-2-yl acetamides were compounds 13, 26 and 30 with IC50 values of 34, 28 and 25 μm, respectively. None of the reported compounds possessed in vitro antimicrobial activity against Staphylococcus aureus and Escherichia coli. Combined ligand-based and structure-based approaches were used in MurB inhibitor design. Model based on crystal structure of MurB in complex with NADP+ was used in a virtual screening campaign to identify a tetrazole hit compound. Chemical space around the hit compound was further explored to encompass novel inhibitors of Escherichia coli MurB displaying IC50 values from 25 to 34 μm.



Insight into the inhibitor discrimination by FLT3 F691L

2018-02-12T23:15:58.026889-05:00

Fms-like tyrosine kinase 3 (FLT3) belongs to the receptor tyrosine kinase family and expressed in hematopoietic progenitor cells. FLT3 gene mutations are reported in ~30% of acute myeloid leukemia cases. FLT3 kinase domain mutation F691L is one of the common causes of acquired resistance to the FLT3 inhibitors including quizartinib. MZH29 and crenolanib were previously reported to inhibit FLT3 F691L. However, crenolanib was reported for the moderate inhibition. We found that Glu661and Asp829 were the most significant residues to target the FLT3 F691L which contribute most significantly to the binding energy with MZH29 and crenolanib. These interactions were found absent with quizartinib. Further free energy landscape analysis revealed that FLT3 F691L bound to MZH29 and crenolanib was more stable as compared to quizartinib. FLT3 kinase domain mutation F691L is one of the common cause of acquired resistance to the FLT3 inhibitors including quizartinib. MZH29 and crenolanib were previously reported to inhibit FLT3F691L. However, crenolanib was reported for the moderate inhibition. We found that Glu661 and Asp829 were the critical residues to target FLT3F691L, as they contribute significantly to the binding energy with MZH29 and crenolanib. These interactions were found absent with quizartinib.



Preparation and evaluation of effect on Escherichia coli and Staphylococcus aureus of radiolabeled ampicillin-loaded graphene oxide nanoflakes

2018-02-10T05:10:35.449685-05:00

Ampicillin is a one of effective antibiotics against Gram-positive and Gram-negative bacteria. This study aimed to label ampicillin-loaded graphene oxide nanoflake (AMP-GO) with 99mTc and evaluate of its in vitro binding to Staphylococcus aureus and Escherichia coli. Firstly, ampicillin was loaded into graphene oxide nanoflake prepared. AMP-GO was characterized by Fourier transform infrared spectroscopy (FTIR) and scanning electron microscope (SEM) techniques, and the amount of loaded ampicillin onto GO was determined by UV-Vis absorption spectroscopy. AMP and AMP-GO were labeled with 99mTc using stannous chloride reducing agent. Labeling efficiency of 99mTc-AMP-GO was found to be 97.66 ± 2.06%. 99mTc-AMP-GO has higher binding efficiencies to both S. aureus and E. coli than 99mTc-AMP. 99mTc-AMP-GO could be promising candidate as agent infection nuclear imaging. Furthermore, in vivo studies of 99mTc-AMP-GO with infected rats are planned to be performed. Ampicillin-Graphene oxide (AMP-GO) nanoparticles by evaluating their in vitro binding in Staphylococcus aureus and Escherichia coli for infection nuclear imaging.



Remarkable similarity in Plasmodium falciparum and Plasmodium vivax geranylgeranyl diphosphate synthase dynamics and its implication for antimalarial drug design

2018-02-04T20:01:00.722522-05:00

Malaria, mainly caused by Plasmodium falciparum and Plasmodium vivax, has been a growing cause of morbidity and mortality. P. falciparum is more lethal than is P. vivax, but there is a vital need for effective drugs against both species. Geranylgeranyl diphosphate synthase (GGPPS) is an enzyme involved in the biosynthesis of quinones and in protein prenylation and has been proposed to be a malaria drug target. However, the structure of P. falciparumGGPPS (PfGGPPS) has not been determined, due to difficulties in crystallization. Here, we created a PfGGPPS model using the homologous P.vivaxGGPPS X-ray structure as a template. We simulated the modeled PfGGPPS as well as PvGGPPS using conventional and Gaussian accelerated molecular dynamics in both apo- and GGPP-bound states. The MD simulations revealed a striking similarity in the dynamics of both enzymes with loop 9-10 controlling access to the active site. We also found that GGPP stabilizes PfGGPPS and PvGGPPS into closed conformations and via similar mechanisms. Shape-based analysis of the binding sites throughout the simulations suggests that the two enzymes will be readily targeted by the same inhibitors. Finally, we produced three MD-validated conformations of PfGGPPS to be used in future virtual screenings for potential new antimalarial drugs acting on both PvGGPPS and PfGGPPS. We create the first atomistic model for Plasmodium falciparum (Pf)GGPPS, a malaria drug target, based on the homologous Plasmodium vivax protein (PvGGPPS). Extensive conventional and Gaussian accelerated molecular dynamics simulations reveal a striking similarity between the dynamics of the two enzymes, with loop 9-10 controlling the access to the active site and the product, GGPP, preventing the enzyme to adopt fully open conformations. A shape-based analysis of the binding pocket throughout the simulations suggests that the two enzymes will be easily targeted by the same inhibitors and provides three clusters of relevant conformations to be used in future virtual screenings for potential antimalarial drugs acting on both Pv and PfGGPPS.



Effects of serum, enzyme, thiol, and forced degradation on the stabilities of αO-Conotoxin GeXIVA[1,2] and GeXIVA [1,4]

2018-01-30T20:20:37.360386-05:00

αO-conotoxin GeXIVA, which is a potent antagonist of α9α10 nicotinic acetylcholine receptor (nAChR), is of great interest as a potential analgesic for chronic neuropathic pain. It has three isomers, of which both GeXIVA[1,2] and GeXIVA[1,4] showed similar low nanomolar IC50s in potent blocking rat α9α10 nAChRs. Here, we first reported stabilities of GeXIVA[1,2] and GeXIVA[1,4] in various biochemical circumstances, including human serum, enzymatic degradation, and thiol, which would be the key factors to affect stabilities of the two isomers in vivo. Simultaneously, forced degradation was carried out to evaluate stabilities of the two isomers. GeXIVA[1,2] and GeXIVA[1,4] were unstable when they were incubated in serum and digestive enzymes at 37°C. Their disulfide bond frameworks were easy to be scrambled in GSH and HSA. For different stress conditions, their stabilities were impacted greatly by oxidation, temperature, and alkaline conditions. The results may provide a foundation for storage conditions, structural modification, and pharmaceutical preparation of GeXIVA[1,2] and GeXIVA[1,4]. αO-conotoxin GeXIVA is of great interest as a potential analgesic for chronic neuropathic pain. The stabilities of GeXIVA were evaluated at the first time, which may provide a foundation for storage conditions, structural modification, and pharmaceutical preparation of GeXIVA.



An overview on Vadimezan (DMXAA): The vascular disrupting agent

2018-01-24T00:15:39.659867-05:00

Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical trials. The reason for this surprising discrepancy, among others, was discovered to be STING receptor variations between mice and humans. In this review, the development, the mechanisms of DMXAA action, the clinical trials, the combination therapy, and the future of this drug will be discussed. This review highlights the characteristics of clinically used vascular disrupting agent drug, vadimezan, DMXAA (ASA404). Also development, and mechanisms of DMXAA action, and also the clinical trials, the combination therapy and the future of this drug is discussed.



Modulation of lateral and longitudinal interdimeric interactions in microtubule models by Laulimalide and Peloruside A association: A molecular modeling approach on the mechanism of microtubule stabilizing agents

2018-01-23T04:51:06.350775-05:00

Laulimalide (LAU) and Peloruside A (PLA) are non-taxane microtubule stabilizing agents with promising antimitotic properties. These ligands promote the assembly of microtubules (MTs) by targeting a unique binding site on β-tubulin. The X-ray structure for LAU/PLA-tubulin association was recently elucidated, but little information is available regarding the role of these ligands as modulators of interdimeric interactions across MTs. Herein, we report the use of molecular dynamics (MD), principal component analysis (PCA), MM/GBSA-binding free energy calculations, and computational alanine scanning mutagenesis (ASM) to examine effect of LAU/PLA association on lateral and longitudinal contacts between tubulin dimers in reduced MT models. MD and PCA results revealed that LAU/PLA exerts a strong restriction of lateral and longitudinal interdimeric motions, thus enabling the stabilization of the MT lattice. Besides structural effects, LAU/PLA induces a substantial strengthening of longitudinal interdimeric interactions, whereas lateral contacts are less affected by these ligands, as revealed by MM/GBSA and ASM calculations. These results are valuable to increase understanding about the molecular features involved in MT stabilization by LAU/PLA, and to design novel compounds capable of emulating the mode of action of these ligands. Molecular dynamics simulations revealed that Laulimalide and Peloruside A association induce a strong restriction in the lateral and longitudinal interdimeric motion between tubulin dimers in reduced microtubule models, which can be related to the stabilization of the microtubule lattice. According to MM/GBSA calculations, Laulimalide and Peloruside A strengthen the longitudinal interdimeric association, whereas lateral interactions are less affected by these ligands.



Synthesis of novel norsufentanil analogs via a four-component Ugi reaction and in vivo, docking, and QSAR studies of their analgesic activity

2018-01-23T04:46:02.355604-05:00

Novel substituted amino acid tethered norsufentanil derivatives were synthesized by the four-component Ugi reaction. Norsufentanil was reacted with succinic anhydride to produce the corresponding carboxylic acid. The resulting carboxylic acid has undergone a multicomponent reaction with different aldehydes, amines, and isocyanides to produce a library of the desired compounds. In all cases, amide bond rotation was observed in the NMR spectra. In vivo analgesic activity of the synthesized compounds was evaluated by a tail flick test. Very encouraging results were obtained for a number of the synthesized products. Some of the synthesized compounds such as 5a, 5b, 5h, 5j, and 5r were found to be more potent than sufentanil, sufentanil citrate, and norsufentanil. Binding modes between the compounds and mu and delta-opioid receptors were studied by molecular docking method. The relationship between the molecular structural features and the analgesic activity was investigated by a quantitative structure–activity relationship model. The results of the molecular modeling studies and the in vivo analgesic activity suggested that the majority of the synthesized compounds were more potent than sufentanil and norsufentanil. In this study, eighteen novel bivalent opioid ligands were prepared by a multicomponent reaction. The in vivo evaluation of the synthesized compounds showed that many of them were most potent than sufentanil as a commercial analgesic drug. The experimental data were supported by the QSAR and docking studies.



Interaction of antivirals with a heptameric bundle model of the p7 protein of hepatitis C virus

2018-01-23T02:10:50.83968-05:00

A series of ligands are known experimentally to affect the infectivity cycle of the hepatitis C virus. The target protein for the ligands is proposed to be p7, a 63 amino acid polytopic channel-forming protein, with possibly two transmembrane domains. Protein p7 is found to assemble into functional oligomers of various sizes, depending on the genotype (GT). Nine ligands are docked to various sites of a computationally derived heptameric bundle of p7 of GT1a. The energy of interaction, here binding energy, is calculated using three different docking programs (Autodock, MOE, LeadIT). Three protein regions are defined to which the ligands are placed, the loop region and the site with the termini as well as the mid-region which is supposed to track poses inside the putative pore. A common feature is that the loop sites and poses either within the pore or at the intermonomer space of the bundle are preferred for all ligands with proposed binding energies smaller than −10 kJ/mol. BIT225, benzamine, amantadine, and NN-DNJ show good overall scoring. Nine ligands are docked with three programs to p7 (genotype 1a) of hepatitis C virus. Binding at the loops and either within bundle or between its monomers is best scored with binding energies smaller than −10 kJ/mol. BIT225, benzamine, amantadine, and NN-DNJ show good overall scoring.



Design, synthesis, and cytotoxic evaluation of novel furo[2,3-b]quinoline derivatives

2018-01-20T05:09:30.941923-05:00

A number of novel furo[2,3-b]quinoline derivatives were designed and synthesized by introducing benzyl ether, benzoate, and benzenesulfonate to 6-position of furo[2,3-b]quinoline and their chemical structures were confirmed by ESI-MS, 1H NMR, and 13C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (HCT-116, MCF-7, U2OS, and A549) by MTT method. Cytotoxic assay showed that compounds 8a, 8e, 10a, 10b, and 10c exhibited more potent cytotoxicities compared to 2-bromine-6-hydroxy-furo-[2,3-b]quinoline (7). Compound 10c exhibited higher antiproliferative activity (IC50 values ranging from 4.32 to 24.96 μm) against four human cancer cell lines (HCT-116, MCF-7, U2OS, and A549) and weak cytotoxicity on normal cell HL-7702, which suggested that 10c might be an ideal anticancer candidate. Compounds 8a, 10a, 10b showed good selectivities to MCF-7 and HCT-116, which could be considered as ideal selective candidates for further study. The SARs showed that the introduction of the benzyl ether and benzenesulfonate could significantly improve cytotoxicities, while the benzoate failed to enhance potency obviously. A number of novel furo[2,3-b]quinoline derivatives were designed and synthesized and screened for cytotoxic activities against four human cancer cell lines.



ALLO: A tool to discriminate and prioritize allosteric pockets

2018-01-19T20:45:42.830363-05:00

Allosteric proteins make up a substantial proportion of human drug targets. Thus, rational design of small molecule binders that target these proteins requires the identification of putative allosteric pockets and an understanding of their potential activity. Here, we characterized allosteric pockets using a set of physicochemical descriptors and compared them to pockets that are found on the surface of a protein. Further, we trained predictive models capable of discriminating allosteric pockets from orthosteric pockets and models capable of prioritizing allosteric pockets in a set of pockets found on a given protein. Such models might be useful for identifying novel allosteric sites and in turn, potentially new allosteric drug targets. Datasets along with a Python program encapsulating the predictive models are available at http://github.com/fibonaccirabbits/allo. In this work, we characterized allosteric pockets using a set of physicochemical descriptors and compared them to pockets that are found on the surface of a protein. Further, we trained predictive models capable of discriminating allosteric pockets from orthosteric pockets and models capable of prioritizing allosteric pockets in a set of pockets found on a given protein.



Discovery of novel negletein derivatives as potent anticancer agents for acute myeloid leukemia

2018-01-17T21:31:20.799829-05:00

Baicalin and its aglycone baicalein derived from Scutellaria baicalensis exhibited potent anticancer effects in various types of cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for their potential clinical development. With the aim of development of novel anticancer agents based on the skeleton of baicalin, a series of novel negletein derivatives were designed and synthesized. Among them, compound 8 (FZU-02,006) with an N,N-dimethylamino ethoxyl moiety at the C-6 position exhibited significant enhanced antiproliferative effect against HL-60 cells in vitro through regulating multisignaling pathways. These results revealed that compound 8 with the improved aqueous solubility (as HCl salt, >1 mg/ml) and enhanced antileukemia potency might serve as a promising lead for further development. FZU-02,006 with an N,N-dimethylamino ethoxyl moiety at the C-6 position exhibited significant enhanced antiproliferative effect against HL-60 cells in vitro through regulating multisignaling pathways. These results revealed that compound 8 with the improved aqueous solubility (as HCl salt, >1 mg/ml) and enhanced antileukemia potency might serve as a promising lead for further development.



Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives

2018-01-17T21:26:14.897166-05:00

A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to-antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence. A new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthrolines was synthesized and screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed good antiparasitic activity with IC50 values in the μm range.



Antibacterial activities and molecular mechanism of amino-terminal fragments from pig nematode antimicrobial peptide CP-1

2018-01-17T00:15:39.396594-05:00

High manufacturing costs and weak cell selectivity have limited the clinical application of naturally occurring peptides when faced with an outbreak of drug resistance. To overcome these limitations, a set of antimicrobial peptides was synthesized with the general sequence of (WL)n, where n = 1, 2, 3, and WL was truncated from the N-terminus of Cecropin P1 without initial serine residues. The antimicrobial peptide WL3 exhibited stronger antimicrobial activity against both Gram-negative and Gram-positive microbes than the parental peptide CP-1. WL3 showed no hemolysis even at the highest test concentrations compared to the parental peptide CP-1. The condition sensitivity assays (salts, serum, and trypsin) demonstrated that WL3 had high stability in vitro. Fluorescence spectroscopy and electron microscopy indicated that WL3 killed microbes by means of penetrating the membrane and causing cell lysis. In a mouse model, WL3 was able to significantly reduce the bacteria load in major organs and cytokines (TNF-α, IL-6, and IL-1β) levels in serum. In summary, these findings suggest that WL3, which was modified from a natural antimicrobial peptide, has enormous potential for application as a novel antibacterial agent. High manufacturing costs and weak antimicrobial activity have limited the application of naturally occurring peptides. In this study, we combined the advantage of peptide truncation and tandem repeat units to generate short Cecropin P1-derived peptides and investigated their antimicrobial activity and model of action. Antimicrobial peptide WL3 has enormous potential for application as a novel antimicrobial agent.



Proteochemometric modeling of the origin of thymidylate synthase inhibition

2018-01-16T23:00:55.481897-05:00

Due to its crucial role in DNA synthesis, thymidylate synthase (TS) has been considered as a potential therapeutic target. Inhibition of the enzyme is a promising strategy for the treatment of some hyperproliferative diseases, including infections. As TS species-specific inhibitors would be able to distinguish between the host and the pathogens, developing highly selective inhibitors is of great clinical importance. TS is among the most highly conserved enzymes over evolutionary history, making the design of its species-selective inhibitor significantly challenging. The chemical interaction space, governed by a set of non-selective TS inhibitors, has been explored for human TS and its homologous proteins in both Toxoplasma gondii and Escherichia coli using proteochemometrics modeling (PCM). Validity, robustness, and prediction power of the PCM model have been assessed applying a diverse set of internal/external validation approaches. Our PCM model has provided major structural information, which is indeed of great help to design new TS species-specific inhibitors with the simultaneous inhibition ability toward both T. gondii and E. coli. To show applicability of the PCM model, new compounds have been designed based on structural information provided by the constructed model. Final results have been very promising with regard to selectivity ratios of the designed compounds for different TS isoforms, confirming the applicability of the PCM model. Proteochemometrics analysis has shed a light on major structural features, suggesting that implementation of specific dual moieties such as HBD/HBA in certain distances can affect the selectivity of a compound for different isoforms of thymidylate synthase.



Cucurbitacin-B attenuates CCl4-induced hepatic fibrosis in mice through inhibition of STAT-3

2018-01-11T07:35:43.85377-05:00

Liver fibrosis is a major health concern worldwide. Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3) have been reported to attenuate experimental liver fibrosis. Therefore, the aim of this study was to investigate the potential ameliorative effect of cucurbitacin-B (Cucu-B) against CCl4-induced liver fibrosis in mice. Treatment with Cucu-B (5 mg/kg) preserved hepatocellular membrane integrity and amended the metabolic function as indicated by preventing the rise of serum liver function markers. This was confirmed histologically. CCl4-induced oxidative stress was improved by Cucu-B treatment (1 and 5 mg/kg). Furthermore, Cucu-B treatment ameliorated the fibrotic state as evidenced by inhibiting the rise of hydroxyproline liver content and mitigating the overexpressions of collagen-1α, α-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-β) as well as the downexpression of matrix metalloproteinase-2 (MMP-2) mRNA. Importantly, STAT3 activity was inhibited by Cucu-B as confirmed by decreased phosphorylation of STAT3 without changing total STAT3 expression. This was substantiated by the reduced Bcl-2 together with increased Bax mRNA expressions with subsequent elevation of Bax/Bcl-2 ratio. In conclusion, Cucu-B hampers CCl4-induced liver fibrosis in mice. This can be attributed—at least partly—to inhibition of oxidative stress, inflammation and STAT3 signalling. Cucurbitacin-B protected against CCl4-induced liver injury and fibrosis in mice. This was confirmed histologically and biochemically. Fibrosis-related markers were also improved by cucurbitacin-B treatment. These actions can be attributed, at least partly, to inhibition of oxidative stress, inflammation and STAT3 signalling.



Design, synthesis, and molecular docking studies of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives as xanthine oxidase inhibitors

2018-01-08T02:31:56.525075-05:00

A series of N-(9,10-anthraquinone-2-carbonyl)amino acid derivatives (1a–j) was designed and synthesized as novel xanthine oxidase inhibitors. Among them, the L/D-phenylalanine derivatives (1d and 1i) and the L/D-tryptophan derivatives (1e and 1j) were effective with micromolar level potency. In particular, the L-phenylalanine derivative 1d (IC50 = 3.0 μm) and the D-phenylalanine derivative 1i (IC50 = 2.9 μm) presented the highest potency and were both more potent than the positive control allopurinol (IC50 = 8.1 μm). Preliminary SAR analysis pointed that an aromatic amino acid fragment, for example, phenylalanine or tryptophan, was essential for the inhibition; the D-amino acid derivative presented equal or greater potency compared to its L-enantiomer; and the 9,10-anthraquinone moiety was welcome for the inhibition. Molecular simulations provided rational binding models for compounds 1d and 1i in the xanthine oxidase active pocket. As a result, compounds 1d and 1i could be promising lead compounds for further investigation. The title compounds (1a–j) were designed, synthesized and identified as novel XO inhibitors. Among them, the L-phenylalanine derivative 1d (IC50 = 3.0 µm) and the D-phenylalanine derivative 1i (IC50 = 2.9 µm) presented the highest potency, and were both more potent than the positive control allopurinol (IC50 = 8.1 µm). Molecular simulations provided rational binding models for compounds 1d and 1i.



New hydrazide–hydrazones of isonicotinic acid: synthesis, lipophilicity and in vitro antimicrobial screening

2018-01-05T20:30:25.638411-05:00

This study describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide–hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed-phase thin-layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram-positive bacteria, Gram-negative bacteria and fungi belonging to Candida spp. Some of the synthesized hydrazide–hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents. This study describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide–hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed-phase thin-layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram-positive bacteria, Gram-negative bacteria and fungi belonging to Candida spp. Some of the synthesized hydrazide–hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents.



Synthesis, adenosine receptor binding and molecular modelling studies of novel thieno[2,3-d]pyrimidine derivatives

2017-12-22T06:33:55.574013-05:00

A series of new molecules containing a thieno[2,3-d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2-position as well as an oxo-group, imidazole or 1,2,4-triazole ring at 4-position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17–19 with a free amino group at 2-position along with the presence of an imidazole/1,2,4-triazole ring at 4-position of the scaffold showed selective binding affinities for hA2A AR, whereas carbamoylation of the amino group at 2-position (in the presence of an oxo-group at 4-position of the scaffold) increased the affinity and selectivity of certain compounds (7–10) for hA3 AR. Molecular dynamic simulation study of one of the most active compound 8 (Ki hA1 > 30 μm, hA2A = 0.65 μm, and hA3 = 0.124 μm) revealed the role of important amino acid residues for imparting good affinity towards hA3 and hA2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA2A AR and a homology model of hA3 AR to rationalize their structure–activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs. A new series of thieno[2,3-d]pyrimidine derivatives have been synthesized and evaluated in vitro for their binding affinities towards adenosine receptors (ARs) and in silico to gain insight into their molecular binding interactions with the hA2A and hA3 ARs.



Characterization of the interaction forces in a drug carrier complex of doxorubicin with a drug-binding peptide

2017-12-21T00:03:51.57527-05:00

Polypeptide-based materials are used as building blocks for drug delivery systems aimed at toxicity decrease in chemotherapeutics. A molecular-level approach is adopted for investigating the non-covalent interactions between doxorubicin and a recently synthesized drug-binging peptide as a key part of a system for delivery to neoplastic cells. Molecular dynamics simulations in aqueous solution at room and body temperature are applied to investigate the structure and the binding modes within the drug–peptide complex. The tryptophans are outlined as the main chemotherapeutic adsorption sites, and the importance of their placement in the peptide sequence is highlighted. The drug–peptide binging energy is evaluated by density functional theory calculations. Principal component analysis reveals comparable importance of several types of interaction for the binding strength. π-Stacking is dominant, but other factors are also significant: intercalation, peptide backbone stacking, electrostatics, dispersion, and solvation. Intra- and intermolecular H-bonding also stabilizes the complexes. The influence of solvent molecules on the binding energy is mild. The obtained data characterize the drug-to-peptide attachment as a mainly attractive collective process with interactions spanning a broad range of values. These results explain with atomistic detail the experimentally registered doxorubicin-binging ability of the peptide and outline the complex as a prospective carrying unit that can be employed in design of drug delivery systems. The study reports the results from molecular modeling of a hydrated drug–peptide complex, in which a chemotherapeutic is non-covalently adsorbed onto a drug-binding peptide. The probable structures of the complex are identified and thoroughly characterized. The feasible peptide adsorption sites and patterns of the drug association are outlined, and an essential structural factor for strong binding is suggested. The forces that keep the molecule of the pharmaceutic attached to the carrier surface are elucidated, and their relative importance is quantified.



Octyl ester of ginsenoside compound K as novel anti-hepatoma compound: Synthesis and evaluation on murine H22 cells in vitro and in vivo

2017-12-18T06:18:52.548301-05:00

Ginsenoside compound K (M1) is the active form of major ginsenosides deglycosylated by intestinal bacteria after oral administration. However, M1 was reported to selectively accumulate in liver and transform to fatty acid esters. Ester of M1 was not excreted by bile as M1 was, which means it was accumulated in the liver longer than M1. This study reported a synthetic method of M1-O, a mono-octyl ester of M1, and evaluated the anticancer property against murine H22 cell both in vitro and in vivo. As a result, both M1 and M1-O showed a dose-dependent manner in cytotoxicity assay in vitro. At lower dose of 12.5 μm, M1-O showed moderate detoxification. Instead, M1-O exhibited significantly higher inhibition in H22-bearing mice than M1. M1-O induced murine H22 tumor cellular apoptosis in caspase-dependent pathway given that pan-caspase inhibitor, Z-VAD-FMK, could reverse the cytotoxicity induced by M1-O. Additionally, pro- and anti-apoptosis proteins, Bcl-2 and Bax, altered and consequently induced increased expression of cleaved caspase-3. Interestingly, cyclophosphamide regimen significantly induced atrophy of spleen and thymus, main immune organs, while M1-O treatment greatly alleviated this atrophy. Collectively, we propose M1-O as a candidate for live cancer treatment. The mono-octyl ester of M1 (M1-O) was synthesized and identified in vitro. M1-O shows detoxification compared with M1 in vitro and inhibits tumor growth of H22-bearing mice by regulating Bax, Bcl-2, and cleaved caspase-3. Intriguingly, M1-O improves the index of spleen and thymus of H22-bearing mice.



Enhanced cytotoxicity and apoptosis by raloxifene in combination with estrogen and methotrexate in human endometrial stromal cells

2017-12-15T05:31:01.546241-05:00

Endometrial hyperplasia is a condition that may lead to the development of endometrial carcinoma. Initially, changes of the endometrium are caused by the estrogen's hyperstimulation that may lead to the development of an irregular bleeding and the infertility problems. Therapy of endometrial hyperplasia is limited to medical and surgical approaches. During the past decade, the new types of drugs were developed for the treatment of the endometrial hyperplasia. Here, for the first time, we investigated the cytotoxic effects of the various combinations of estrogen, raloxifene, and methotrexate in human ThESC cell line as a possible potential treatment of the endometrial hyperplasia. Our aim was to investigate and to determine the most efficient combination of investigated drugs in ThESC cells during 24-hr period using MTT assay, FACS analysis, and immunofluorescence staining. Our results demonstrated that the combination of raloxifene with methotrexate efficiently induced both the cytotoxicity and apoptosis in ThESC cells when compared to their single effect, as well as to the effect of combined treatment of raloxifene with estrogen. The application of the low doses of methotrexate combined with raloxifene offers all advantages of a potential beneficial antitumor match in cancer chemoprevention and therapy. Our results demonstrated that the combination of raloxifene with methotrexate more efficiently induced both the cytotoxicity and apoptosis in ThESC cells when compared to their single effect, as well as to the effect of combined treatment of raloxifene with estrogen. The application of the low doses of methotrexate combined with raloxifene offers all advantages of a potential beneficial antitumor match in cancer chemoprevention and therapy.



Exhaustive sampling of the fragment space associated to a molecule leading to the generation of conserved fragments

2017-12-12T07:07:18.78278-05:00

The first step in hit optimization is the identification of the pharmacophore, which is normally achieved by deconstruction of the hit molecule to generate “deletion analogues.” In silico fragmentation approaches often focus on the generation of small fragments that do not describe properly the fragment space associated to the deletion analogues. We present significant modifications to the molecular fragmentation programme molBLOCKS, which allows the exhaustive sampling of the fragment space associated with a molecule to generate all possible molecular fragments. This generates larger fragments, by combining the smallest fragments. Additionally, it has been modified to deal with the problem of changing pharmacophoric properties through fragmentation, by highlighting bond cuts. The modified molBLOCKS programme was used on a set of drug compounds, where it generated more unique fragments than standard fragmentation approaches by increasing the number of fragments derived per compound. This fragment set was found to be more diverse than those generated by standard fragmentation programmes and was relevant to drug discovery as it contains the key fragments representing the pharmacophoric elements associated with ligand recognition. The use of dummy atoms to highlight bond cuts further increases the information content of fragments by visualizing their previous bonding pattern. We report the modification of the programme molBLOCKS to allow exhaustive fragmentation of molecules to generate all possible molecular fragments, including larger fragments and to cope with fragmentation occurring through key pharmacophoric groups. The programme was used to fragment a set of drug compounds, leading to an increased number of unique fragments per molecule, compared to standard algorithms.



In silico ligand-based modeling of hBACE-1 inhibitors

2017-12-10T23:51:54.893209-05:00

Alzheimer's disease is a chronic neurodegenerative disease affecting more than 30 million people worldwide. Development of small molecule inhibitors of human β-secretase 1 (hBACE-1) is being the focus of pharmaceutical industry for the past 15–20 years. Here, we successfully applied multiple ligand-based in silico modeling techniques to understand the inhibitory activities of a diverse set of small molecule hBACE-1 inhibitors reported in the scientific literature. Strikingly, the use of only a small subset of 230 (13%) molecules allowed us to develop quality models that performed reasonably well on the validation set of 1,476 (87%) inhibitors. Varying the descriptor sets and the complexity of the modeling techniques resulted in only minor improvements to the model's performance. The current results demonstrate that predictive models can be built by choosing appropriate modeling techniques in spite of using small datasets consisting of diverse chemical classes, a scenario typical in triaging of high-throughput screening results to identify false negatives. We hope that these encouraging results will help the community to develop more predictive models that would support research efforts for the debilitating Alzheimer's disease. Additionally, the integrated diversity of the techniques employed will stimulate scientists in the field to use in silico statistical modeling techniques like these to derive better models to help advance the drug discovery projects faster. Multiple ligand-based QSAR approaches with increasing modeling sophistication and descriptor information content were used to develop qualitative classification, and quantitative regression models using experimental IC50's reported for hBACE-1 small molecule inhibitors. The statistical modeling outcome and analysis provide a framework for extending this workflow for other therapeutic targets as well as avenues to further the lead identification and lead optimization of small molecule hBACE-1 inhibitors.



A theoretical insight into selectivity of inhibitors toward two domains of bromodomain-containing protein 4 using molecular dynamics simulations

2017-12-10T23:36:41.711896-05:00

Bromodomains (BRDs) have been an attractive candidate for development of efficient inhibitors toward gene transcription. Molecular dynamics (MD) simulations followed by principal component (PC) analysis were performed to investigate binding selectivity of inhibitors RVX297, BSP, JQ1, SF2523, and CPD2 toward two domains (BD1 and BD2) of bromodomain-containing protein 4 (BRD4). The results show that inhibitor bindings exert different effect on motions of the BC-loops in BD1 and BD2. The rank of binding free energies calculated using molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) method agrees with the one determined by experiment. The results also suggest that the binding ability of RVX297, BSP, and JQ1 to BD2 is stronger than that of them to BD1, while the binding ability of SF2523 to BD2 is obviously weaker than that of SF2523 to BD1. Alanine mutation calculations and the calculated inhibitor–residue interaction spectrum prove that the current five inhibitors have obvious binding selectivity toward BD1 and BD2. This study is not only helpful for further understanding the differences in internal dynamics of BD1 and BD2 caused by inhibitor bindings, but also can theoretically contribute significant guidance to designs of effective and high selective anticancer drugs targeting BD1 and BD2 in BRD4. According to the cross-correlation analysis and PC analysis, the inhibitor bindings generate different influence on motions of the BC-loop in the two domains BD1 and BD2 of BRD4. Alanine mutation calculations and the calculated inhibitor–residue interaction spectrum prove that the current five inhibitors have obvious binding selectivity toward BD1 and BD2.



A structure-based strategy toward the development of novel candidates for antimycobacterial activity: Synthesis, biological evaluation, and docking study

2017-12-07T23:41:31.106482-05:00

Bacterial resistance to most of the available antibiotics has stimulated the discovery of novel efficacious antibacterial agents. Bedaquiline is first of its type that has been specifically introduced for the management of MDR-TB in combination with other drugs. In this study, a series of isoniazid/ethambutol/pyrazinamide/-quinoline conjugates based on the structures of bedaquiline were designed and synthesized. Biological activity tests revealed that some of isoniazid/ethambutol/quinoline conjugates have useful antibiotic activity against MTB H37Rv (MIC: 2.0–8.0 μg/ml). Furthermore, molecular docking calculations were performed for the most potent inhibitor to show its binding interactions within the active site of the possible target protein. Overall, these compounds represent novel valuable starting point with potent antimycobacterial activity and deserve further structural modifications. In this study, a series of isoniazid/ethambutol/pyrazinamide/quinoline conjugates based on the structures of bedaquiline were designed and synthesized. Biological evaluation indicated that some of isoniazid/ethambutol/quinoline conjugates have useful activity against MTB H37Rv (MIC: 2.0–8.0 μg/ml).



Peptides derived from histidine and methionine-rich regions of copper transporter 1 exhibit anti-angiogenic property by chelating extracellular Cu

2017-12-06T23:42:15.233963-05:00

Angiogenesis is a process of synthesis of new blood vessels from preexisting vasculature. Copper (Cu) as a micronutrient is important to many proteins for their physiological roles. Cu is transported by ceruloplasmin from liver to other parts of the body. Copper transporter 1 (CTR1) is a transmembrane protein which participate in Cu transport across the cell. It is also known to be involved in angiogenesis. In this study, we have designed three peptides from copper-binding regions of CTR1 which are rich in histidine and methionine. These peptides were screened for their inhibitory effect on angiogenesis in the HUVEC model. Mass spectroscopy studies revealed that all the three peptides derived from CTR 1 (Pep 1, 2, and 3) bound to Cu. The intracellular Cu levels estimated by atomic absorption spectroscopy showed decreased levels of copper in peptide-treated cells as compared to control. These peptides inhibited proliferation, migration, and tube formation in HUVEC by sequestering copper, preventing its entry into the cell and thereby inhibiting angiogenesis. Schematic representation of the design of CTR1 derived peptides and their role in copper mediated angiogenesis.



Comparative evaluation of 68Ga-labeled NODAGA, DOTAGA, and HBED-CC-conjugated cNGR peptide chelates as tumor-targeted molecular imaging probes

2017-12-06T23:41:01.885561-05:00

The biological behavior of 68Ga-based radiopharmaceuticals can be significantly affected by the chelators’ attributes (size, charge, lipophilicity). Thus, this study aimed at examining the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on the distribution pattern of 68Ga-labeled NGR peptides targeting CD13 receptors. 68Ga-DOTAGA-c(NGR), 68Ga-NODAGA-c(NGR), and 68Ga-HBED-CC-c(NGR) were observed to be hydrophilic with respective log p values being −3.5 ± 0.2, −3.3 ± 0.08, and −2.8 ± 0.14. The three radiotracers exhibited nearly similar uptake in human fibrosarcoma HT-1080 tumor cells with 86%, 63%, and 33% reduction during blocking studies with unlabeled cNGR peptide for 68Ga-DOTAGA-c(NGR), 68Ga-NODAGA-c(NGR), and 68Ga-HBED-CC-c(NGR), respectively, indicating higher receptor specificity of the first two radiotracers. The neutral radiotracer 68Ga-NODAGA-c(NGR) demonstrated better target-to-non-target ratios during in vivo studies compared to its negatively charged counterparts, 68Ga-DOTAGA-c(NGR) and 68Ga-HBED-CC-c(NGR). The three radiotracers had similar HT-1080 tumor uptake and being hydrophilic exhibited renal excretion with minimal uptake in non-target organs. Significant reduction (p < .005) in HT-1080 tumor uptake of the radiotracers was observed during blocking studies. It may be inferred from these studies that the three radiotracers are promising probes for in vivo imaging of CD13 receptor expressing cancer sites; however, 68Ga-NODAGA-c(NGR) is a better candidate. The goal of this study was to determine the influence of three different chelators, DOTAGA, NODAGA, and HBED-CC on pharmacokinetics and biodistribution pattern of 68Ga-labeled NGR peptides targeting CD13 receptors.



Photodynamic therapy and nuclear imaging activities of zinc phthalocyanine-integrated TiO2 nanoparticles in breast and cervical tumors

2017-12-06T23:37:22.340201-05:00

In recent years, phthalocyanines (Pcs) have been widely used as photosensitizer in photodynamic therapy applications. Because of their strong absorptions in the near-infrared region (640–700 nm). The integration of phthalocyanine derivatives to a nanoparticle is expected to be efficient way to improve the activity of the photosensitizer on the targeted tissue. It is known that the integrated molecules not only show better accumulation on tumor tissue but also reduce toxicity in healthy tissues. In this study, the ZnPc molecule was synthesized and integrated to the TiO2 nanoparticle, to investigate the potential of PDT and its cytotoxicity. Additionally, ZnPc and ZnPc-TiO2 molecules were labeled with 131I and it was aimed to put forth the nuclear imaging/therapy potentials of 131I labeled ZnPc/ZnPc-TiO2 by determining in vitro uptakes in mouse mammary carcinoma (EMT6), human cervical adenocarcinoma (HeLa). In result of our study, it was observed that the radiolabeling yields of the synthesized ZnPc and ZnPc-TiO2 with 131I were quite high. In vitro uptake studies shown that 131I-ZnPc-TiO2 could be a potential agent for nuclear imaging/treatment of breast and cervical cancers. According to PDT results, ZnPc-TiO2 might have as to be a potential PDT agent in the treatment of cervical tumor. ZnPc and ZnPc-TiO2 might be used as theranostic agents. New phthalocyanine and TiO2 integrated phthalocyanine were synthesized and their nuclear imaging and PDT potentials were evaluated in tumor cell lines.



Synthesis, molecular modeling, and biological evaluation of 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides toward acetylcholinesterase, carbonic anhydrase I and II enzymes

2017-12-04T03:37:49.796297-05:00

In this study, 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides were synthesized, and inhibition effects on AChE, hCA I, and hCA II were evaluated. Ki values of the compounds toward hCA I were in the range of 24.2 ± 4.6-49.8 ± 12.8 nm, while they were in the range of 37.3 ± 9.0-65.3 ± 16.7 nm toward hCA II. Ki values of the acetazolamide were 282.1 ± 19.7 nm and 103.60 ± 27.6 nm toward both isoenzymes, respectively. The compounds inhibited AChE with Ki in the range of 22.7 ± 10.3-109.1 ± 27.0 nm, whereas the tacrine had Ki value of 66.5 ± 13.8 nm. Electronic structure calculations at M06-L/6-31 + G(d,p)//AM1 level and molecular docking studies were also performed to enlighten inhibition mechanism and to support experimental findings. Results obtained from calculations of molecular properties showed that the compounds obey drug-likeness properties. The experimental and computational findings obtained in this study might be useful in the design of novel inhibitors against hCA I, hCA II, and AChE. 4-[5-aryl-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-1-yl] benzenesulfonamides TP1–10 were synthesized, and biological activities were evaluated on AChE, hCA I, and hCA II enzymes. The compounds had demonstrated their inhibitory activities at nanomolar concentrations on AChE, hCA I, and hCA II enzymes. The experimental and computational findings obtained in this study might be useful in the design of novel inhibitors against hCA I, hCA II, and AChE.



Allosteric mechanism of quinoline inhibitors for HIV RT-associated RNase with MD simulation and dynamics fluctuation network

2017-12-04T03:37:35.922588-05:00

The human immunodeficiency virus (HIV) is a retrovirus which infects T lymphocyte of human body and causes immunodeficiency. Reverse transcriptase inhibitors (RTIs) can inhibit some functions of RT, preventing virus synthesis (double-stranded DNA), so that HIV virus replication can be reduced. Experimental results indicate a series of benzimidazole-based inhibitors which target HIV RT-associated RNase to inhibit the reverse transcription of HIV virus. However, the allosteric mechanism is still unclear. Here, molecular dynamics simulations and dynamics fluctuation network analysis were used to reveal the binding mode between the inhibitors and RT-associated RNase. The most active molecule has more hydrophobic and electrostatic interactions than the less active inhibitor. Dynamics correlation network analysis indicates that the most active inhibitor perturbs the network of RT-associated RNase and decreases the correlation of nodes. 3D-QSAR model suggests that two robust and reliable models were constructed and validated by independent test set. 3D-QSAR model also shows that bulky negatively charged or hydrophilic substituent is favorable to bioactivity. These results reveal the allosteric mechanism of quinoline inhibitors and help to improve the bioactivity. Dynamic correlation networks for bound RTNR suggest that allosteric information is freely transferred within the network.



Predictive QSAR modeling study on berberine derivatives with hypolipidemic activity

2017-12-04T03:36:10.13005-05:00

Berberine (BBR), isolated from a Chinese herb, is identified as a new cholesterol-lowering small molecule, and hundreds of berberine derivatives have been obtained for optimization of their hypolipidemic activities in recent years. However, so far there is no available quantitative structure–activity relationship (QSAR) model used for the development of novel BBR analogues with hypolipidemic activities, mainly due to lack of lipid-lowering molecular mechanisms and target identification of BBR. In this paper, the tactics using ligand efficiency indice instead of pIC50 as the activity could be adopted for the development of BBR QSAR models. A series of 59 BBR derivatives with hypolipidemic activities have been studied and split randomly into three sets of training and test sets. Statistical quality of most building models shows obviously robust. Best calculated model that employs LLE indice as the activity (Model 6) has the following statistical parameters: for training set R2 = .984, Q2 = 0.981, RMSE = 0.1160, and for test set R2 = .989, RMSE = 0.0067. This model would be used for the development of novel BBR analogues with lipid-lowering activities as a hit discovery tool. A total of 59 berberine (BBR) derivatives with hypolipidemic activity were split into three training and test sets. Four ligand efficiency indice (BEI, LLE, SEI, and LELP) instead of the negative logarithm of ten of half maximal inhibitory concentration (pIC50) as the activity could be adopted for the development of BBR quantitative structure–activity relationship (QSAR) models. The predictive potency of most built models was robust.



Design, synthesis, biological evaluation, and docking study of 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors (part II)

2017-12-01T06:36:25.482561-05:00

A series of novel 4-isochromanone compounds bearing N-benzyl pyridinium moiety were designed and synthesized as acetylcholinesterase (AChE) inhibitors. The biological evaluation showed that most of the target compounds exhibited potent inhibitory activities against AChE. Among them, compound 1q possessed the strongest anti-AChE activity with an IC50 value of 0.15 nm and high AChE/BuChE selectivity (SI > 5,000). Moreover, compound 1q had low toxicity in normal nerve cells and was relatively stable in rat plasma. Together, the current finding may provide a new approach for the discovery of novel anti-Alzheimer's disease agents. Twenty-two 4-isochromanone hybrids bearing N-benzyl pyridinium moiety as dual binding site acetylcholinesterase inhibitors were designed and synthesized, their biological activities were evaluated, and molecular docking study was carried out.



Naphthoquinones: A continuing source for discovery of therapeutic antineoplastic agents

2017-11-28T06:20:31.041625-05:00

Naturally occurring naphthoquinones, usually in forms of botanical extracts, have been implicated with human life since ancient time, far earlier than their isolation and identification in modern era. The long use history of naphthoquinones has witnessed their functional shift from the original purposes as dyes and ornaments toward medicinal benefits. Hitherto, numerous studies have been carried out to elucidate the pharmacological profile of both natural and artificial naphthoquinones. A number of entities have been identified with promising therapeutic potential. Apart from the traditional effects of wound healing, anti-inflammatory, hemostatic, antifertility, insecticidal and antimicrobial, etc., the anticancer potential of naphthoquinones either in combination with other treatment approaches or on their own is being more and more realized. The molecular mechanisms of naphthoquinones in cells mainly fall into two categories as inducing oxidant stress by ROS (reactive oxygen species) generation and directly interacting with traditional therapeutic targets in a non-oxidant mechanism. Based on this knowledge, optimized agents with naphthoquinones scaffold have been acquired and further tested. Hereby, we summarize the explored biological mechanisms of naphthoquinones in cells and review the application perspective of promising naphthoquinones in cancer therapies. The explored biological mechanisms of naphthoquinones in cellular and the application perspective of promising naphthoquinones in cancer therapies were reviewed.



Identification of chlamydial T3SS inhibitors through virtual screening against T3SS ATPase

2017-11-27T00:52:46.598924-05:00

Chlamydia trachomatis is a widespread sexually transmitted pathogen that resides within a special vacuole inside host cells. Although acute infection can be treated with antibiotics, chlamydia can enter persistent state, leading to chronic infection that is difficult to cure. Thus, novel anti-chlamydial compounds active against persistent chlamydia are required. Chlamydiae rely upon type III secretion system (T3SS) to inject effector proteins into host cell cytoplasm, and T3SS inhibitors are viewed as promising compounds for treatment of chlamydial infections. C. trachomatis ATPase SctN is an important T3SS component and has not been targeted before. We thus used virtual screening against homology modeled SctN structure to search for SctN inhibitors. Selected compounds were tested for their ability to inhibit chlamydial survival and development within eukaryotic cells, and for the ability to suppress normal T3SS functioning. We identified two compounds that were able to block normal protein translocation through T3SS and inhibit chlamydial survival within eukaryotic cells in 50–100 μm concentrations. These two novel T3SS inhibitors also possessed relatively low toxicity toward eukaryotic cells. A small series of derivatives was further synthesized for the most active of two inhibitors to probe SAR properties. Virtual screening was performed against a homology model of Chlamydia trachomatis type III secretion system (T3SS) ATPase. As a result, a series of N-arylbenzylamines was identified as compounds that were able to inhibit effector protein export by C. trachomatis T3SS and suppress chlamydial development inside eukaryotic cells.



Synthetic piperine amide analogs with antimycobacterial activity

2017-11-27T00:45:51.472991-05:00

Piperine amide analogs are synthesized by replacement of the piperidine moiety with different types of cyclic amines, including adamantyl and monoterpene-derived fragments. The compounds are screened for activity against Mycobacterium tuberculosis H37Rv. The most potent compounds are the 1-adamantyl and the monoterpene-derived hybrids, which combine nanomolar antimycobacterial activity with low cytotoxicity against human cells. The presence of quaternary carbon atom as main structural requirement for anti-TB activity is pointed out by a QSAR study. The most promising compound is the (+)-isopinocampheylamine-derived amide which is characterized with selectivity index of 1387.8. A series of Piperine amide analogues are synthesized by replacing piperidine moiety with different types of cyclic amines, including cyclohexyl, bicyclo[2.2.1]heptyl, adamantyl, and monoterpene-derived fragments. The hybrid analogues with 1-adamantyl and the monoterpene fragments displayed nanomolar antimycobacterial activity with low cytotoxicity against human cells. A QSAR study pointed out the presence of quaternary carbon atom as main structural requirement for the activity. The most promising compound is the (+)-isopinocampheylamine-derived amide, with selectivity index of 1387.8.



Derivatizations of Sgc8-c aptamer to prepare metallic radiopharmaceuticals as imaging diagnostic agents: Syntheses, isolations, and physicochemical characterizations

2017-11-24T07:00:41.506396-05:00

Aptamers, oligonucleotides with the capability to bind to a target through non-covalent bonds with high affinity and specificity, have a great number of advantages as scaffold to prepare molecular imaging agents. In this sense, we have performed post-SELEX modifications of a truncated aptamer, Sgc8-c, which bind to protein tyrosine kinase 7 to obtain a specific molecular targeting probe for in vivo diagnosis and in vivo therapy. Herein, we describe the synthetic efforts to prepare conjugates between Sgc8-c and different metallic ions chelator moieties in short times, high purities, and adequate yields. The selected chelator moieties, derived from 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 2-benzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid, and 6-hydrazinonicotinic acid, were covalently attached at the 5′-aptamer position yielding the expected products which were stable in aqueous solution up to 75°C and in typical aptamer storage conditions at least for 30 days. Post-SELEX modifications on Sgc8-c aptamer, in order to prepare conjugate for further transformations to radiopharmaceuticals, are described.



3D-QSAR, molecular docking, and ONIOM studies on the structure–activity relationships and action mechanism of nitrogen-containing bisphosphonates

2017-11-16T00:30:52.108438-05:00

Nitrogen-containing bisphosphonates (N-BPs) have been used widely to treat various bone diseases by inhibiting the key enzyme farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. Understanding the structure–activity relationships and the action mechanisms of these bisphosphonates is instructive for the design and the development of novel potent inhibitors. Here, a series of N-BPs inhibitors of human FPPS (hFPPS) were investigated using a combination of three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking, and three-layer ONIOM studies. The constructed 3D-QSAR model yielded a good correlation between the predicted and experimental activities. Based on the analysis of comparative molecular field analysis (CoMFA) contour maps, a series of novel N-BPs inhibitors were designed and ten novel potent N-BPs inhibitor candidates were screened out. Molecular docking and ONIOM (B3LYP/6-31 + G*:PM6:Amber) calculations revealed that the inhibitors bound to the active site of hFPPS via hydrogen-bonding interactions, hydrophobic interactions, and cation-π interactions. Six novel N-BPs inhibitors with better biological activities and higher lipophilicity were further screened out from ten candidates based on the calculated interaction energy. This study will facilitate the discovery of novel N-BPs inhibitors with higher activity and selectivity. A 3D-QSAR model was constructed for 53 N-BPs with the inhibition activities on hFPPS. A series of novel N-BPs inhibitors were designed and six novel N-BPs inhibitors with better biological activities and higher lipophilicity were screened out. Molecular docking and ONIOM (B3LYP/6-31 + G*:PM6:Amber) calculations showed that the inhibitors bound to the active site of hFPPS via hydrogen-bonding interactions, hydrophobic interactions, and cation-π interactions.



Structural basis for the agonist action at free fatty acid receptor 1 (FFA1R or GPR40)

2017-11-16T00:30:37.16193-05:00

G-protein-coupled receptor 40 (GPR40) was recently identified as an interesting target for treatment of type 2 diabetes. The high level of expression in pancreatic beta cells and the dependence of glucose on stimulating the secretion of insulin led to great excitement in this field. The identification of this target was followed by the development of a series of agonists with great potential for the treatment of diabetes. All known agonists have the presence of a pharmacophoric carboxylic acid group in their structure, which makes several polar interactions at the binding site of this receptor. In this report, we provide a review of the structure–activity relationships of GPR40 agonists with a focus on the main strategies of medicinal chemistry used to develop each one of the main structural patterns exploited for this purpose. Additionally, we provide a general model for the design of GPR40 ligands that can help researchers to follow up some strategies and implement them in the development of novel agonists of this receptor. The high level of expression in pancreatic beta cells and the dependence of the glucose to stimulate the secretion of insulin make theGPR40 an interesting target for treatment of type 2 diabetes. The development of novel agonists of this receptor is a hot topic in Medicinal Chemistry. Herein, we describe a review on the structure–activity relationships of GPR40 agonists focusing on the main strategies of medicinal chemistry used to develop each one of the main structural patterns exploited for this purpose, and we provide a general model for the design of novel GPR40 ligands.



Perspectives on the discovery of NOTCH2-specific inhibitors

2017-11-15T00:13:40.465597-05:00

The Notch pathway is a cell-cell communication system where membrane-bound ligands interact with the extracellular region of Notch receptors to induce intracellular, downstream effects on gene expression. Aberrant Notch signaling promotes tumorigenesis, and the Notch pathway has tremendous potential for novel targeting strategies in cancer treatment. While γ-secretase inhibitors as Notch-inhibiting agents are already promising in clinical trials, they are highly non-specific with adverse side-effects. One of the underlying challenges is that two of the four known human Notch paralogs, NOTCH1 and 2, share very high structural similarity but play opposing roles in some tumorigenesis pathways. This perspective explores the feasibility of developing Notch-specific small molecule inhibitors targeting the anti-NOTCH2 antibody-binding epitopes or the “S2-Leu-plug-binding site” using a computer-aided drug discovery approach. We review current Notch inhibitors of small molecules and expensive monoclonal antibodies. Our computational modeling of the Notch proteins suggests that the S2 cleavage site, blocked by a conserved Leucine residue in the receptor's inactive state, is a plausible Notch-specific therapeutic site to target. Synthetic antibody mimics present an attractive future drug modality to target specific Notch paralogs and replace monoclonal antibodies.



Novel 1,3,5-triazine derivatives exert potent anti-cervical cancer effects by modulating Bax, Bcl2 and Caspases expression

2017-11-15T00:12:53.732318-05:00

This study aimed to develop novel 1,3,5-triazine derivatives as potent anti-cervical cancer agents. The compounds were synthesized in short steps with an excellent yield and characterized via various spectroscopic and analytical methods. A structure–activity relationship study suggested that electron-withdrawing substituents showed greater anticancer activity than electron-donating groups. Compound 7p (p-fluoro) showed the highest activity against cervical cancer cells. In a nude mouse xenograft model inoculated with HeLa cells, 7p showed dose-dependent inhibition of cervical tumour growth. Histopathological examination of excised tumour-bearing tissues showed that 7p improved the microstructure in a dose-dependent manner. Compound 7p also increased the proportions of HeLa cells in G0/G1 and S-phase and significantly decreased that of G2/M-phase. The effects of 7p on C-caspase-3, C-caspase-9, Bcl-2 and Bax expression in HeLa cells were also determined. Structure–activity relationship study suggested that the halogen-containing compounds (F and Cl) had higher anticancer activity than non-halogen (OH, OCH3 and CH3) compounds.



GLUT1-mediated venlafaxine-thiamine disulfide system-glucose conjugates with “lock-in” function for central nervous system delivery

2017-11-11T07:53:21.742373-05:00

Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT1) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT1, “lock-in” thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain. A novel venlafaxine conjugate V-TDS-G was designed and synthesized in this work. The evaluation in vivo demonstrated that V-TDS-G had an improved targeting ability, which indicated that the G-TDS could act as a vector to enhance the delivery of CNS drugs into brain.



Identification and characterization of novel host defense peptides from the skin secretion of the fungoid frog, Hydrophylax bahuvistara (Anura: Ranidae)

2017-02-11T01:45:26.338982-05:00

Two novel peptides (brevinin1 HYba1 and brevinin1 HYba2) were identified from the skin secretion of the frog Hydrophylax bahuvistara, endemic to Western Ghats, India, and their amino acid sequences were confirmed using cDNA cloning and LC/MS/MS. Antibacterial, hemolytic, and cytotoxic activities of brevinin1 peptides and their synthetic analogs (amidated C-terminus) were investigated and compared. All the peptides except the acidic forms showed antibacterial activity against all tested Gram-positive and Gram-negative bacteria. They exhibited low hemolysis on human erythrocytes and showed potent cytotoxic activity against Hep 3B cancer cell line. Upon amidation, the peptides showed increased activity against the tested microbes without altering their hemolytic and cytotoxic properties. The study also emphasizes the need for screening endemic amphibian fauna of Western Ghats, as a potential source of host defense peptides with possible therapeutic applications in the future. Two novel peptides (brevinin1 HYba1 and brevinin1 HYba2) were identified from the skin secretion of the frog Hydrophylax bahuvistara. Amidation proved to be a favorable modification, which enhanced the biological activity of the brevinin1 peptides without affecting its low hemolytic property. These peptides also showed very high cytotoxicity toward Hep 3B cancer cell lines.



Issue Information

2018-01-19T20:32:55.767715-05:00




Expression in Escherichia coli of fusion protein comprising α-conotoxin TxIB and preservation of selectivity to nicotinic acetylcholine receptors in the purified product

2017-09-25T04:10:32.75308-05:00

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, which are widely distributed in the central and peripheral nervous system. The α6β2* nAChR is an important subtype, which is closely associated with nicotine addiction and movement disorders etc. α-conotoxin TxIB with 16-amino acid residues specifically targets α6β2* nAChR with no obvious effect on other nAChR subtypes. However, chemical synthesis of TxIB is expensive, and the quantity of native TxIB extracted from cone snail is limited. In the present study, we attempted to obtain TxIB using biological method based on the recombinant expression in Escherichia coli (E. coli). The synthetic gene encoding mature peptide of TxIB was inserted in pET-31b(+) vector and transformed into E. coli strain BLR(DE3)pLysS for expression. The recombinant fusion protein KSI-TxIB-His6 (KSI, ketosteroid isomerase) was expressed successfully as inclusion body in E. coli, which was purified by Ni-NTA affinity chromatography column and cleaved by cyanogen bromide (CNBr) to release recombinant α-conotoxin TxIB (rTxIB). Then, rTxIB was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) and was identified by electrospray ionization mass spectrometry (ESI-MS). Pharmacological activity of rTxIB was assessed by electrophysiological approaches. The results indicated that it preserved about 50% of potency, but, was even more important, had the same selectivity as the natural conotoxin which may provide an alternative method for quantity production of small peptides with low cost on the premise of not changing their potency. This study was attempted to obtain α-conotoxin TxIB using biological method based on the recombinant expression in Escherichia coli (E. coli). The recombinant fusion protein KSI-TxIB-His6 was expressed successfully as inclusion body in E. coli, which was purified by Ni-NTA affinity chromatography column and cleaved by cyanogen bromide to release recombinant α-conotoxin TxIB (rTxIB). Pharmacological activity of rTxIB was assessed by electrophysiological approaches. The results showed that rTxIB preserved about 50% of potency, but, was even more important, had the same selectivity as the natural conotoxin.



Potential biological targets for bioassay development in drug discovery of Sturge–Weber syndrome

2017-10-11T23:50:27.123101-05:00

Sturge–Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested. With perspective to the clinical importance of drug discovery for Sturge-Weber (SWS) syndrome, development of new bioassays using some molecular targets are suggested. Designing the respective assays may lead to the discovery of more efficient compounds especially from the unlimited diverse chemical space of natural compounds.



Structural properties of bioactive peptides with α-glucosidase inhibitory activity

2017-09-18T00:06:19.371907-05:00

Bioactive peptides are emerging as promising class of drugs that could serve as α-glucosidase inhibitors for the treatment of type 2 diabetes. This article identifies structural and physicochemical requirements for the design of therapeutically relevant α-glucosidase inhibitory peptides. So far, a total of 43 fully sequenced α-glucosidase inhibitory peptides have been reported and 13 of them had IC50 values several folds lower than acarbose. Analysis of the peptides indicates that the most potent peptides are tri- to hexapeptides with amino acids containing a hydroxyl or basic side chain at the N-terminal. The presence of proline within the chain and alanine or methionine at the C-terminal appears to be relevant for high activity. Hydrophobicity and isoelectric points are less important variables for α-glucosidase inhibition whilst a net charge of 0 or +1 was predicted for the highly active peptides. In silico simulated gastrointestinal digestion revealed that the high and moderately active peptides, including the most potent peptide (STYV), were gastrointestinally unstable, except SQSPA. Molecular docking of SQSPA, STYV, and STY (digestion fragment of STYV) with α-glucosidase suggested that their hydrogen bonding interactions and binding energies were comparable with acarbose. The identified criteria will facilitate the design of new peptide-derived α-glucosidase inhibitors. Identified structural requirements for α-glucosidase inhibitory peptides are tri – to hexapeptides with serine, threonine, tyrosine, lysine or arginine as the ultimate N-terminal residue and proline preferably at the penultimate C- terminal position while alanine or methionine at ultimate C-terminal position while hydrophobicity and charge are less important variables



Aromatic interactions at the ligand–protein interface: Implications for the development of docking scoring functions

2017-08-31T06:12:24.013282-05:00

The ability to design and fine-tune non-covalent interactions between organic ligands and proteins is indispensable to rational drug development. Aromatic stacking has long been recognized as one of the key constituents of ligand–protein interfaces. In this communication, we employ a two-parameter geometric model to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand–protein complexes, considering various combinations of aromatic amino acid residues and ligand rings. The geometry of interfacial π–π stacking in crystal structures accords with experimental and theoretical data collected for simple systems, such as the benzene dimer. Many contemporary ligand docking programs implicitly treat aromatic stacking with van der Waals and Coulombic potentials. Although this approach generally provides a sufficient specificity to model aromatic interactions, the geometry of π–π contacts in high-scoring docking conformations could still be improved. The comprehensive analysis of aromatic geometries at ligand–protein interfaces lies the foundation for the development of type-specific statistical potentials to more accurately describe aromatic interactions in molecular docking. A Perl script to detect and calculate the geometric parameters of aromatic interactions in ligand–protein complexes is available at https://github.com/michal-brylinski/earomatic. The dataset comprising experimental complex structures and computer-generated models is available at https://osf.io/rztha/. Aromatic stacking has long been recognized as one of key constituents of drug–protein interfaces. A two-parameter geometric model is employed in this study to conduct a large-scale statistical analysis of aromatic contacts in the experimental and computer-generated structures of ligand–protein complexes. Although contemporary molecular docking programs quite reliably describe aromatic interactions, the geometry of π–π contacts in high-scoring docking conformations could still be improved with type-specific statistical potentials derived from the Protein Data Bank.



Discovery of naphthyl-N-acylhydrazone p38α MAPK inhibitors with in vivo anti-inflammatory and anti-TNF-α activity

2017-09-10T23:40:47.727666-05:00

Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen-activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti-inflammatory profile of new naphthyl-N-acylhydrazone derivatives using animal models. Although all tested compounds (3a–d) have been characterized as p38α MAPK inhibitors and have showed in vivo anti-inflammatory action, LASSBio-1824 (3b) presented the best performance as p38α MAPK inhibitor, with IC50 = 4.45 μm, and also demonstrated to be the most promising anti-inflammatory prototype, with good in vivo anti-TNF-α profile after oral administration. New naphthyl-N-acylhydrazone derivatives were reported as MAPK p38α inhibitors. Ensemble docking studies at p38α MAPK active site and LASSBio-1824 presented an unusual binding mode at kinase active site. LASSBio-1824 showed in vivo anti-inflammatory and anti-TNF-α properties.



Docking field-based QSAR and pharmacophore studies on the substituted pyrimidine derivatives targeting HIV-1 reverse transcriptase

2017-09-18T00:05:54.678696-05:00

HIV-1 reverse transcriptase (RT) is one of the most important enzymes required for viral replication, thus acting as an attractive target for antiretroviral therapy. Pyrimidine analogues reportedly have selective inhibition on HIV-1 RT with favorable antiviral activities in our previous study. To further explore the relationship between inhibitory activity and pharmacophoric characteristics, field-based QSAR models were generated and validated using Schrodinger Suite (correlation coefficient of .8078, cross-validated value of 0.5397 for training set and Q2 of 0.4669, Pearson's r of .7357 for test set). Docking, pocket surfaces, and pharmacophore study were also investigated to define the binding pattern and pharmacophoric features, including (i) π–π interaction with residue Tyr181, Tyr188, and Trp229 and p–π interaction with His235 and (ii) hydrogen bond with residue Lys101 and halogen bond with residue Tyr188. The pharmacophore features of six-point hypothesis AADRRR.184, AAADRR.38, and AADRRR.26 further complimented to the docking and QSAR results. We also found that the protein-ligand complex exhibited high relative binding free energy. These observations could be potentially utilized to guide the rational design and optimization of novel HIV-1 RT inhibitors. The results of 3D-QSAR, binding pocket, and pharmacophore analyses of pyrimidine HIV-1 RT inhibitors would rationally clarify 3D-QSAR and pharmacophore features of pyrimidine analogues and help in the design the potential inhibitors of HIV-1 RT.



Lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine-1-acetohydroxamic acid analogues as trypanocidal and leishmanicidal agents: An extended SAR study

2017-09-18T00:10:23.869677-05:00

We have previously described a number of lipophilic conformationally constrained spiro carbocyclic 2,6-diketopiperazine (2,6-DKP)-1-acetohydroxamic acids as potent antitrypanosomal agents. In this report, we extend the SAR analysis in this class of compounds with respect to in vitro growth inhibition of Trypanosoma and Leishmania parasites. Introduction of bulky hydrophobic substituents at the vicinal position of the basic nitrogen atom in the spiro carbocyclic 2,6-DKP ring system can provide analogues which are potently active against bloodstream form Trypanosoma brucei and exhibit significant activities toward Trypanosoma cruzi epimastogotes and Leishmania infantum promastigotes and intracellular amastigotes. In particular, compounds possessing a benzyl or 4-chlorobenzyl substituent were found to be the most active growth inhibitors, with activities in the low nanomolar and low micromolar ranges for T. brucei and L. infantum, respectively. The benzyl-substituted (S)-enantiomer was the most potent derivative against T. brucei (IC50 = 6.8 nm), T. cruzi (IC50 = 0.21 μm), and L. infantum promastigotes (IC50 = 2.67 μm) and intracellular amastigotes (IC50 = 2.60 μm). Moreover, the (R)-chiral benzyl-substituted derivative and its racemic counterpart displayed significant activities against L. donovani. Importantly, the active compounds show high selectivity in comparison with two mammalian cell lines. The present work has extended the structure–activity relationships of spiro carbocyclic 2,6-DKP-1-acetohydroxamic acids in determining in vitro growth inhibition of trypanosomal and leishmanial parasites. Our studies demonstrate that the antiparasitic activity of this class of compounds is greatly dependent upon the alkyl or the arylalkyl substitution on either the basic nitrogen atom (N-methylation) or at its vicinal position (C-alkylation or arylmethylation) in the spiro carbocyclic 2,6-DKP skeleton.



Bitter substances from plants used in traditional Chinese medicine exert biased activation of human bitter taste receptors

2017-09-14T02:58:18.48436-05:00

The number and variety of bitter compounds originating from plants are vast. Whereas some bitter chemicals are toxic and should not be ingested, other compounds exhibit health beneficial effects, which is manifest in the cross-cultural believe that the bitterness of medicine is correlated with the desired medicinal activity. The bitter taste receptors in the oral cavity serve as sensors for bitter compounds and, as they are expressed in numerous extraoral tissues throughout the body, may also be responsible for some physiological effects exerted by bitter compounds. Chinese herbal medicine uses bitter herbs since ancient times for the treatment of various diseases; however, the routes by which these herbs modify physiology are frequently not well understood. We therefore screened 26 bitter substances extracted from medical herbs for the activation of the 25 human bitter taste receptors. We identified six receptors activated by in total 17 different bitter compounds. Interestingly, we observed a bias in bitter taste receptor activation with 10 newly identified agonists for the broadly tuned receptor TAS2R46, seven agonists activating the TAS2R14 and two compounds activating narrowly tuned receptors, suggesting that these receptors play dominant roles in the evaluation and perhaps physiological activities of Chinese herbal medicines. To identify the human bitter taste receptors activated by bitter substances present in plants used in Chinese herbal medicine, compounds were extracted from these plants and purified. In total 26 bitter compounds were subjected to a functional screening of all 25 human bitter taste receptors. We identified 17 substances activating 6 receptors, which may be particularly important for the taste and potentially some of the physiological activities of medicinal herbs.



Synthesis, enzyme inhibitory kinetics, and computational studies of novel 1-(2-(4-isobutylphenyl) propanoyl)-3-arylthioureas as Jack bean urease inhibitors

2017-11-07T23:40:57.033762-05:00

In this article, synthesis of a novel 1-(2-(4-isobutylphenyl)propanoyl)-3-arylthioureas (4a–j) as jack bean urease inhibitors has been described. Freshly prepared 2-(4-isobutylphenyl) propanoyl isothiocyanate was treated with substituted aromatic anilines in one pot using anhydrous acetone. The compounds 4e, 4h, and 4j showed IC50 values 0.0086 nm, 0.0081 nm, and 0.0094 nm, respectively. The enzyme inhibitory kinetics results showed that compound 4h inhibit the enzyme competitively while derivatives 4e and 4j are the mixed type inhibitors. The compound 4h reversibly binds the urease enzyme showing Ki value 0.0012 nm. The Ki values for 4e and 4j are 0.0025 nm and 0.003 nm, respectively. The antioxidant activity results reflected that compounds 4b, 4i, and 4j showed excellent radical scavenging activity. Moreover, the cytotoxic activity of the target compounds was evaluated using brine shrimp assay and it was found that all of the synthesized compounds exhibited no cytotoxic effects to brine shrimps. The computational molecular docking and molecular dynamic simulation of title compounds were also performed, and results showed that the wet laboratory findings are in good agreement to the dry laboratory results. Based upon our results, it is proposed that compound 4h may act as a lead candidate to design the clinically useful urease inhibitors. The present work reports the synthesis, enzyme inhibitory kinetics, and computational studies of some novel aryl thioureas as jack bean urease inhibitors.



Sofosbuvir as treatment against dengue?

2017-09-13T05:46:05.581085-05:00

Dengvaxia® (CTD-TDV), the only licensed tetravalent dengue vaccine by Sanofi Pasteur, was made available since 2015. However, administration of CTD-TDV, in general, has not received the prequalification recommendation from the World Health Organization. Having a universal antidengue agent for treatment will therefore beneficial. Accordingly, the development of nucleoside inhibitors specific to dengue viral polymerase that perturb dengue infection has been studied by many. Alternatively, we have used a marketed anti-HCV prodrug sofosbuvir to study its in silico and in vitro effects against dengue. As a result, the active metabolite of sofosbuvir (GS-461203) was predicted to bind to the catalytic motif (Gly-Asp-Asp) of dengue viral polymerase with binding affinity of −6.9 kcal/mol. Furthermore, sofosbuvir demonstrated excellent in vitro viral inhibition with an EC90 of 0.4 μm. In addition, this study demonstrated the requirement of specific liver enzymes to activate the prodrug into GS-461203 to exert its antidengue potential. All in all, sofosbuvir should be subjected to in-depth studies to provide information of its efficacy toward dengue and its lead potential as DENV polymerase inhibitor in human subjects. In conclusion, we have expended the potential of the clinically available drug sofosbuvir as treatment for dengue. Molecular docking of the activated structure of sofosbuvir, GS-461203, was performed on dengue virus polymerase. The findings were then validated using in vitro model of dengue virus infection. This study revealed the potential antidengue activity of sofosbuvir, and GS-461203 could serve as a lead compound in the development of novel antiviral agents against dengue virus.



Synthesis, quality control, and bio-evaluation of 99mTc-cyclophosphamide

2017-10-09T06:11:19.798815-05:00

Cancer is found to be the leading cause of death worldwide characterized by uncontrolled cell division. Nuclear medicines imaging using radiopharmaceuticals have pronounced potential for the diagnosis and treatment of cancers. Cyclophosphamide (CPH) is an antineoplastic drug which targets selectively cancer cells. In the present work, labeling of CPH with Tc-99m is performed for diagnostic purpose, which gave labeling yield as high as 99% using 20 μg SnCl2·2H2O, 200 μg of ligand at pH 7 for 10 min reaction time at room temperature. The characterization of the prepared complex was performed using ITLC, electrophoresis, and HPLC. In vitro stability was analyzed in the presence of human serum at 37°C which has maximum value of 94 ± 0.5. The biodistribution studies of 99mTc-CPH were performed in normal and tumor bearing Swiss Webster mice. The high accumulation of 99mTc-CPH was observed in liver and tumours respectively at 4 hr after injection. Biodistribution results revealed that 99mTc-CPH may be a potential tumour diagnostic agent simultaneously with chemotherapy. The 99mTc-labeled-CPH was prepared very efficiently through a simple method. Biodistribution results revealed that 99mTc-CPH may be a potential tumor diagnostic agent simultaneously with chemotherapy.



New insights into the mechanism of action of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives endowed with anticancer potential

2017-10-11T23:51:15.983926-05:00

Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, in silico studies have been achieved to better understand the chemical space of the interactions. Interestingly some meaningful structural features, useful for further developments, were found. The 8,9-di-Cl substituted derivative revealed as the most effective in the intercalative process, as well as on the inhibition of catalytic activity of topoisomerase II. Predicted ADME studies confirm that PBTs are promising as potential drug candidates. Selected most active PBTs were submitted to further investigations in order to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism (LD), including the interference with the catalytic cycle of topoisomerase II and the influence on the cleavable complex stabilization (poisoning effect). In support of the experimental data, to better understand the chemical space of the interactions, in silico studies have been achieved. Useful insights for future development were found.



Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors

2017-10-09T06:12:11.234569-05:00

Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC50 values against human cancer cell lines MV4-11, A375, and HeLa were 4.2, 7.1, and 11.6 μm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound-healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5. In this study, pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulation were employed to get novel BRD4 inhibitors. Twelve hits were obtained for bioactivity test and two of them showed good anticancer activity. Among them, compound 5 exhibited potent anticancer activity against three cancer cell lines. Colony formation assay, cell cycle and apoptosis analysis, and wound-healing migration assay were carried out to learn the bioactivity of compound 5. The result suggested a promising candidate for further optimization.



Ensemble docking to difficult targets in early-stage drug discovery: Methodology and application to fibroblast growth factor 23

2017-11-03T23:16:16.330147-05:00

Ensemble docking is now commonly used in early-stage in silico drug discovery and can be used to attack difficult problems such as finding lead compounds which can disrupt protein–protein interactions. We give an example of this methodology here, as applied to fibroblast growth factor 23 (FGF23), a protein hormone that is responsible for regulating phosphate homeostasis. The first small-molecule antagonists of FGF23 were recently discovered by combining ensemble docking with extensive experimental target validation data (Science Signaling, 9, 2016, ra113). Here, we provide a detailed account of how ensemble-based high-throughput virtual screening was used to identify the antagonist compounds discovered in reference (Science Signaling, 9, 2016, ra113). Moreover, we perform further calculations, redocking those antagonist compounds identified in reference (Science Signaling, 9, 2016, ra113) that performed well on drug-likeness filters, to predict possible binding regions. These predicted binding modes are rescored with the molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) approach to calculate the most likely binding site. Our findings suggest that the antagonist compounds antagonize FGF23 through the disruption of protein–protein interactions between FGF23 and fibroblast growth factor receptor (FGFR). An ensemble docking protocol is presented which is used to computationally propose compounds to anatagonize FGF23 activity. Further simulations propose a binding pocket and propose a mechanism of action for the experimentally verified FGF23 antagonist compounds.



Novel tetrahydroacridine derivatives with iodobenzoic acid moiety as multifunctional acetylcholinesterase inhibitors

2017-10-24T00:00:36.436518-05:00

New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules 3a–3i interacted with both cholinesterases—acetylcholinesterase and butyrylcholinesterase—delivered nanomolar IC50 values. The structure–activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BuChE than N-ethyl and N-propyl moieties compounds. The most potent compound toward acetylcholinesterase was inhibitor 3f (IC50 = 31.2 nm), and it was more active than reference drug, tacrine (IC50 = 100.2 nm). Compound 3f showed strong inhibition of butyrylcholinesterase (IC50 = 8.0 nm), also higher than tacrine (IC50 = 16.3 nm). In the kinetic studies, compound 3f revealed mixed type of acetylcholinesterase inhibition. The computer modeling was carried out. The most active compound 3f was confirmed as peripheral anionic site inhibitor of acetylcholinesterase. Moreover, molecule 3f inhibited β-amyloid aggregation (at the concentration 10 μm—24.96% of inhibition, 25 μm—72%, 50 μm—78.44%, and 100 μm—84.92%). Therefore, among all examined, compound 3f is the most promising molecule for further, more detailed research of novel multifunctional agents in the therapy of Alzheimer's disease. New synthesized series of 9-amino-1,2,3,4-tetrahydroacridine derivatives with iodobenzoic acid moiety were studied for their inhibitory activity toward cholinesterase and against β-amyloid aggregation. All novel molecules interacted with both cholinesterases—acetylcholinesterase and butyrylcholinesterase—delivered nanomolar IC50 values. The structure–activity relationship showed that N-butyl moiety derivatives are stronger inhibitors toward AChE and BChE than N-ethyl and N-propyl moieties compounds.



Molecular modeling studies of pseudouridine isoxazolidinyl nucleoside analogues as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase

2017-10-09T06:12:18.723349-05:00

In this paper, we investigated the hypothesis that pseudouridine isoxazolidinyl nucleoside analogues could act as potential inhibitors of the pseudouridine 5ʹ-monophosphate glycosidase. This purpose was pursued using molecular modeling and in silico ADME-Tox profiling. From these studies emerged that the isoxazolidinyl derivative 1 5ʹ-monophosphate can be effectively accommodated within the active site of the enzyme with a ligand efficiency higher than that of the natural substrate. In this context, the poor nucleofugality of the N-protonated isoxazolidine prevents or slows down, the first mechanistic step proposed for the degradation of the pseudouridine 5ʹ-monophosphate glycosidase, leading to the enzyme inhibition. Finally, the results of the physicochemical and ADME-Tox informative analysis pointed out that compound 1 is weakly bounded to plasma protein, only moderately permeate the blood–brain barrier, and is non-carcinogen in rat and mouse. To the best of our knowledge, this is the first paper that introduces the possibility of inhibition of pseudouridine 5ʹ-monophosphate glycosidase by a molecule that competing with the natural substrate hinders the glycosidic C–C bond cleavage. A series of pseudouridine isoxazolidinyl nucleoside analogues were in silico screened for their capacity to compete with pseudouridine 5ʹ-monophosphate in the occupancy of the active site of the pseudouridine 5ʹ-monophosphate glycosidase. Based on the computationally obtained results, derivative 1 5ʹ-monophosphate resulted as an ideal candidate to potential inhibit the enzyme activity also showing a weak capacity to binding to the plasma protein, only a moderate capacity to permeate the blood–brain barrier, and a non-carcinogenicity in rat and mouse.



Design, synthesis, and biological evaluation of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives as xanthine oxidase inhibitors

2017-10-18T23:25:53.562323-05:00

A series of 5-(4-(pyridin-4-yl)-1H-1,2,3-triazol-1-yl)benzonitrile derivatives (1a–p) was designed, synthesized, and identified as xanthine oxidase inhibitors with micromolar level potencies. Among them, the most promising compounds 1j and 1k were obtained with IC50 values of 8.1 and 6.7 μm, respectively. The Lineweaver–Burk plot revealed that compound 1k acted as a mixed-type xanthine oxidase inhibitor. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency. The basis of xanthine oxidase inhibition by 1k was rationalized by molecular modeling studies. The title compounds were designed, synthesized, and identified as XO inhibitors. SAR analysis revealed that a carbon atom occupying the X3 position is not as effective as a nitrogen atom, and an iso-pentyloxy or a cyclopentyloxy at the 2-position of benzonitrile moiety will benefit the inhibitory potency. The Lineweaver–Burk plot revealed that compound lk acted as a mixed-type xanthine oxidase inhibitor and the molecular modeling studies rationalized the basis of XO inhibition by lk.



Legumain correlates with neuroblastoma differentiation and can be used in prodrug design

2017-10-31T06:46:18.013963-05:00

Neuroblastoma (NB) is a highly malignant solid tumor in children. The cysteine endopeptidase legumain is expressed in adult solid tumors, but its expression in NB has not been examined. In this study, we assayed legumain expression in two NB cell lines and in microarrays of tumor tissues collected from 46 children with undifferentiated NB, differentiated NB, and ganglioneuroblastoma. Correlation analyses showed that legumain was expressed in all NB cell lines tested and that expression correlated with the degree of tumor differentiation. The efficacy, specificity, and toxicity of EMC-AANL-DOX, a novel doxorubicin-based legumain-activated prodrug, were then evaluated in mouse model of NB. Compared with DOX, EMC-AANL-DOX showed greater inhibition of tumor growth and a lower toxicity at high doses. Neither leukocyte or platelet counts nor renal function or cardiac anatomy differed significantly between the EMC-AANL-DOX and control groups (p > .05), suggesting that the prodrug caused minimal bone marrow depression and did not induce renal or cardiac damage. The good specificity and efficacy of EMC-AANL-DOX and low toxicity recommend its use in the treatment of NB. Correlation analyses of NB differentiation and legumain expression may reveal a novel anti-tumor-related functions of the drug and a new strategy for the treatment of pediatric solid tumors. Legumain correlated with neuroblastoma differentiation by detection of clinic tumors. EMC-AANL-DOX activated by legumain presented better efficacy and lower toxicity in tumor-bearing models of neuroblastoma.



Synthesis and evaluation of a novel 99mTc nitrido radiopharmaceutical with alendronate dithiocarbamate as a potential bone-imaging agent

2017-10-31T06:40:30.185394-05:00

Currently, a popular strategy for designing novel radioprobes as bone-imaging agents is based on the concept of bifunctional radiopharmaceuticals. Considering the dithiocarbamate ligand can act as a suitable bifunctional linking agent to attach technetium-99m (99mTc) to corresponding target molecules, in this study, alendronate dithiocarbamate (ALNDTC) was synthesized and radiolabeled with [99mTc≡N]2+ core by ligand exchange reaction to produce 99mTcN-ALNDTC complex, for the potential use as a novel probe for bone imaging. The radiochemical purity of the complex was over 90%. The complex was stable in vitro and could bind to hydroxyapatite. The partition coefficient result indicated it was hydrophilic, and an evaluation of biodistribution in mice indicated that the complex exhibited a higher bone uptake than did 99mTc-labeled methylenediphosphonate (99mTc-MDP). Further, single photon emission computed tomography imaging study indicated clear accumulation in bone, suggesting that 99mTcN-ALNDTC would be a promising candidate for bone imaging. 99mTcN-ALNDTC exhibits high radiochemical yield, good in vitro stability, high bone uptake, rapid blood clearance, and clear bone single photon emission computed tomography image. All of these results supported the perspective that 99mTcN-ALNDTC holds the potential for bone imaging.



Selective inhibition of TRPM2 channel by two novel synthesized ADPR analogues

2017-11-15T00:11:47.00085-05:00

Transient receptor potential melastatin-2 (TRPM2) channel critical for monitoring internal body temperature is implicated in the pathological processes such as neurodegeneration. However, lacking selective and potent TRPM2 inhibitors impedes investigation and validation of the channel as a drug target. To discover novel and selective TRPM2 inhibitors, a series of adenosine 5′-diphosphoribose analogues were synthesized, and their activities and selectivity were evaluated. Whole-cell patch-clamp recordings were employed for screen and evaluation of synthesized compounds. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC50 of 5.7 and 5.4 μm, respectively. Both 7i and 8a inhibited TRPM2 current without affecting TRPM7, TRPM8, TRPV1 and TRPV3. These two TRPM2 inhibitors can serve as new pharmacological tools for further investigation and validation of TRPM2 channel as a drug target, and the summarized structure–activity relationship (SAR) may also provide insights into further improving existing inhibitors as potential lead compounds. A series of adenosine 5′-diphosphoribose (ADPR) analogues were synthesized for discovering novel and selective TRPM2 inhibitors. Two compounds, 7i and 8a, were identified as TRPM2 inhibitors with IC50 of 5.7 and 5.4 μm, respectively, selective against TRPM7, TRPM8, TRPV1 and TRPV3. These two novels and TRP-subtype selective TRPM2 inhibitors can be used as tool for further investigation of the channel pharmacology.



Design of potent B-RafV600E inhibitors by multiple copy simulation search strategy

2017-12-15T05:29:49.125453-05:00

B-Raf kinase is a vital intermedium in the mitogen-activated protein kinase (MAPK) signaling pathway, which transforms extracellular signals into cellular mechanisms. Mutations in this kinase, for instance, the most common V600E mutation, can lead to the ERK signaling pathologically activated and hence cause severe diseases such as somatic tumors. So far, the development of B-Raf inhibitors has made remarkable progress. However, the resistance and relapse of approved Raf drugs have been widely reported, and the optimization for old drugs and the discovery for new inhibitors still remain a significant task. In this study, we designed and evaluated a series of novel B-RafV600E inhibitors. A fragment library has been established before the docking simulation carried out using the MCSS strategy (multicopy simulation search). The appropriate fragments were reassembled to provide new candidate compounds, which were further screened by iterative docking simulations and molecular dynamics. Bioassays were carried out to evaluate the pharmacological profile of the compounds identified and synthesized. The result showed that compound 5n had an impressive enzyme inhibitory and antiproliferation activity, suggesting a promising potential in the future study. The study shows that our design method and design intent are valid, and we can use the MCSS simulation to carry out the FBDD strategy to design a new inhibitor in other drug design campaigns.



Amphiphilic small peptides for delivery of plasmid DNAs and siRNAs

2017-11-13T01:12:01.402099-05:00

Although various delivery systems for nucleic acids have been reported, development of an efficient and non-toxic delivery carrier is still a key subject for gene therapy. To find new efficient delivery carriers for nucleic acids, we synthesized amphiphilic peptides composed of a guanidino group, an oleyl group, and a cysteine. We prepared both linear and branched types of peptides and found that the linear peptides were superior to the branched peptides as nucleic acid carriers. Our study also suggested that the intermolecular cysteine disulfides might allow the linear peptides to form the optimal particle sizes with nucleic acids for cellular uptake. The incorporation of a benzoyl group to the linear peptide gave rise to smaller, less suitable particle size with plasmid DNA, which greatly reduced the efficiency of plasmid DNA delivery. On the other hand, the benzoyl modification maintained the optimal particle size with siRNA, and interestingly it significantly enhanced the siRNA delivery. The higher efficiency is because the hydrophobicity from the benzoyl group might assist in interacting with the hydrophobic cell membrane. This demonstrates that a small structural change can modulate the preference of the carriers. Our study may provide an insight designing efficient delivery carriers. As novel nucleic acid carriers, linear and branched amphiphilic peptides were prepared. Each peptide was compared in terms of SNALP size, stability, and delivery activities for plasmid DNA (pDNA) and siRNA. Among the five peptides, a linear peptide H-RCL was an effective delivery carrier for both siRNA and pDNA. Introduction of a benzoyl group to H-RCL significantly enhanced siRNA delivery but greatly reduced pDNA delivery. These demonstrated that a small structural modification of the peptides can modulate their delivery properties.



Anticancer activity of VmCT1 analogs against MCF-7 cells

2017-11-29T01:20:36.589401-05:00

Antimicrobial peptides are considered promising drug candidates due to their broad range of activity. VmCT1 (Phe–Leu–Gly–Ala–Leu–Trp–Asn–Val–Ala–Lys–Ser–Val–Phe–NH2) is an α-helical antimicrobial peptide that was obtained from the Vaejovis mexicanus smithi scorpion venom. Some of its analogs showed to be as antimicrobial as the wild type, and they were designed for understanding the influence of physiochemical parameters on antimicrobial and hemolytic activity. Some cationic antimicrobial peptides exhibit anticancer activity so VmCT1 analogs were tested to verify the anticancer activity of this family of peptides. The analogs were synthesized, purified, characterized, and the conformational studies were performed. The anticancer activity was assessed against MCF-7 mammary cancer cells. The results indicated that [Glu]7-VmCT1-NH2, [Lys]3-VmCT1-NH2, and [Lys]7-VmCT1-NH2 analogs presented moderated helical tendency (0.23–0.61) and tendency of anticancer activity at 25 μmol/L in 24 hr of experiment; and [Trp]9-VmCT1-NH2 analog that presented low helical tendency and moderated anticancer activity at 50 μmol/L. These results demonstrated that single substitutions on VmCT1 led to different physicochemical features and could assist on the understanding of anticancer activity of this peptide family. VmCT1 and analogs with antimicrobial activity were tested in order to verify the anticancer activity against MCF-7 mammary cancer cells of this family of peptides. The results indicated that some analogs presented moderate helical tendency (0.23 to 0.61) and tendency of anticancer activity at 25 μmol/L, and that single substitutions on VmCT1 led to different physiochemical features and could assist on the understanding of the anticancer activity of this peptide family.



Ensemble-based ADME–Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

2017-11-10T06:20:30.433569-05:00

In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,βʹ-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%–90% inhibition of the target enzyme at 20 μm). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3ʹ-triketones with a Y-topology. Based on the predicted physicochemical and ADME–Tox properties, compound 2b has been identified as a new drug-like, non-mutagen, non-carcinogen, and non-neurotoxic lead candidate. Fused benzo[b]thiophenes and β,β′-triketones as electrophilic warheads binding CPB2.8. Computational data show irreversible and reversible covalent inhibition, respectively. Enzymatic screening show 12%–90% inhibition of the target enzyme at 20 μm.



Peptide ligands for targeting the extracellular domain of EGFR: Comparison between linear and cyclic peptides

2017-11-16T00:31:13.781904-05:00

Colorectal cancer (CRC) is the third most common solid internal malignancy among cancers. Early detection of cancer is key to increasing the survival rate of colorectal cancer patients. Overexpression of the EGFR protein is associated with CRC. We have designed a series of peptides that are highly specific for the extracellular domain of EGFR, based on our earlier studies on linear peptides. The previously reported linear peptide LARLLT, known to bind to EGFR, was modified with the goals of increasing its stability and its specificity toward EGFR. Peptide modifications, including D-amino acid substitution, cyclization, and chain reversal, were investigated. In addition, to facilitate labeling of the peptide with a fluorescent dye, an additional lysine residue was introduced onto the linear (KLARLLT) and cyclic peptides cyclo(KLARLLT) (Cyclo.L1). The lysine residue was also converted into an azide group in both a linear and reversed cyclic peptide sequences cyclo(K(N3)larllt) (Cyclo.L1.1) to allow for subsequent “click” conjugation. The cyclic peptides showed enhanced binding to EGFR by SPR. NMR and molecular modeling studies suggest that the peptides acquire a β-turn structure in solution. In vitro stability studies in human serum show that the cyclic peptide is more stable than the linear peptide. Based on the linear peptides that have an affinity for EGFR extracellular domain, cyclic peptides with enhanced affinity and stability were designed. Cyclic peptides exhibited serum stability and binding to EGFR protein. Such peptides can be conjugated with fluorescent labels for imaging EGFR-overexpressed colon cancer.



Nonsteroidal estrogen receptor isoform-selective biphenyls

2017-11-10T06:21:15.882078-05:00

Estrogen receptor (ER) has been a therapeutic target to treat ER-positive breast cancer, most notably by agents known as selective estrogen receptor modulators (SERMs). However, resistance and severe adverse effects of known drugs gave impetus to the search for newer agents with better therapeutic profile. ERα and ERβ are two isoforms sharing 56% identity and having different physiological functions and expressions in various tissues. Only two residues differ in the active sites of the two isoforms motivating us to design isoform-selective ligands. Guided by computational docking and molecular dynamics simulations, we have designed, synthesized, and tested, substituted biphenyl-2,6-diethanones and their derivatives as potential agents targeting ERα. Four of the molecules synthesized exhibited preferential cytotoxicity in ERα+ cell line (MCF-7) compared to ERβ+ cell line (MDA-MB-231). Molecular dynamics (MD) in combination with molecular mechanics-generalized Born surface area (MM-GBSA) methods could account for binding selectivity. Further cotreatment and E-screen studies with known ER ligands—estradiol (E2) and tamoxifen (Tam)—indicated isoform-selective anti-estrogenicity in ERα+ cell line which might be ER-mediated. ERα siRNA silencing experiments further confirmed the ER selective nature of ligands. Novel substituted biphenyl-2,6-diethanones are designed and synthesized targeting ERα isoform. MD simulations along with MM-GBSA accounted for the binding selectivity of 3b toward ERα over ERβ. Cotreatment and E-screen studies indicated the ERα selective nature of 3b and anti-estrogenicity. ERα siRNA silencing experiments further confirmed the isoform selectivity.



Synthesis and in vitro investigation of halogenated 1,3-bis(4-nitrophenyl)triazenide salts as antitubercular compounds

2017-09-14T05:20:30.206384-05:00

The diverse pharmacological properties of the diaryltriazenes have sparked the interest to investigate their potential to be repurposed as antitubercular drug candidates. In an attempt to improve the antitubercular activity of a previously constructed diaryltriazene library, eight new halogenated nitroaromatic triazenides were synthesized and underwent biological evaluation. The potency of the series was confirmed against the Mycobacterium tuberculosis lab strain H37Ra, and for the most potent derivative, we observed a minimal inhibitory concentration of 0.85 μm. The potency of the triazenide derivatives against M. tuberculosis H37Ra was found to be highly dependent on the nature of the halogenated phenyl substituent and less dependent on cationic species used for the preparation of the salts. Although the inhibitory concentration against J774A.1 macrophages was observed at 3.08 μm, the cellular toxicity was not mediated by the generation of nitroxide intermediate as confirmed by electron paramagnetic resonance spectroscopy, whereas no in vitro mutagenicity could be observed for the new halogenated nitroaromatic triazenides when a trifluoromethyl substituent was present on both the aryl moieties. Halogenated 1,3-Bis(4-Nitrophenyl)triazenide salts were synthesized and tested in vitro against Mycobacterium tuberculosis. The compounds showed selective activity towards Mycobacterium tuberculosis and Staphylococcus aureus but were unable to inhibit the growth of Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa and Candida albicans. The trifluoromethyl substituent proved crucial to prevent the metabolization of the compounds into gentoxic metabolites in vitro.



Design, synthesis, and cytotoxic evaluation of novel scopoletin derivatives

2017-11-09T04:25:32.475745-05:00

A series of scopoletin derivatives were designed and synthesized by introducing α-aminoacetamide, acrylamide and β-aminopropamide, respectively, to 3-position of scopoletin, and their chemical structures were confirmed by ESI-MS, IR, 1H NMR, and 13C NMR spectra. All target compounds were evaluated in vitro against four human cancer cell lines (MDA-MB-231, MCF-7, HepG2, and A549) by MTT method. Cytotoxic assay showed that compounds 7a, 7b, 7e, 7f, 8a, and 8e exhibited more potent cytotoxicities compared to scopoletin. Besides, we have further evaluated the growth inhibitory activities of these selected compounds against normal tissue cell lines HFL-1. Although compound 8a showed the strongest antiproliferative activity in vitro, it exhibited strong cytotoxicity on normal cells HFL-1, which limited its further study. Compound 7a and 7b exhibited higher antiproliferative activity against MDA-MB-231 and HepG2 cells and weak cytotoxicity on HFL-1, which suggested that 7a and 7b might be ideal anticancer candidates. The SARs showed that the introduction of the acrylamide and its analogues β-aminopropamide could significantly improve activity, while the α-aminoacetamide failed to enhance potency obviously. Therefore, the mechanism of compound 7a and 7b is worthy of further research and the structure of compound 8a should be further optimized. A series of scopoletin derivatives were synthesized and screened for cytotoxic activities against four human cancer cell lines with scopoletin as the positive control.



Peptide Bond Formations through Flow Chemistry

2017-11-03T23:15:49.770311-05:00

  Flow chemistry could play a key role in the development of fast-automated synthesis of peptides and proteins through the quick activation of intermediates for coupling at low concentrations of reagents. The selected examples highlight the role of flow chemistry for the advancements of peptides bond formations.