Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Dual inhibitors of hepatitis C virus and hepatocellular carcinoma: design, synthesis and docking studies.

ABSTRACT: Aim:Simultaneous inhibition of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may enhance anti-HCV effects and reduce resistance and side effects. Results/methodology:Novel hybrid derivatives were designed and synthesized to exhibit dual activity against HCV and its associated major complication, HCC. The synthesized compounds were screened for their potential activity against HCV and HCC. Compounds 5f, 5j, 5l, 5p, 5q, 5r, 6c and 6d exhibited potential in vitro anticancer activity against HCC cell line HepG2, while compounds 5a, 5l, 5p and 5v showed in vitro anti-HCV activity. Docking studies suggested that the newly synthesized compounds could suppress HCC through VEGFR2 tyrosine kinase inhibition. Conclusion:Compounds 5l and 5p exhibited dual activity against HCV and HCC in vitro.

SUBMITTER: El-Miligy MM

PROVIDER: S-EPMC5729604 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Dual inhibitors of hepatitis C virus and hepatocellular carcinoma: design, synthesis and docking studies.

El-Miligy Mostafa Mm MM Rida Samia M SM Ashour Fawzia A FA Badr Mona H MH El-Bassiony Ehab M EM El-Demellawy Maha A MA Omar Ashraf M AM

Future science OA 20171025 1

<h4>Aim</h4>Simultaneous inhibition of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) may enhance anti-HCV effects and reduce resistance and side effects.<h4>Results/methodology</h4>Novel hybrid derivatives were designed and synthesized to exhibit dual activity against HCV and its associated major complication, HCC. The synthesized compounds were screened for their potential activity against HCV and HCC. Compounds <b>5f, 5j, 5l, 5p, 5q, 5r, 6c</b> and <b>6d</b> exhibited potential <i ...[more]

PMID: 29255624

Similar Datasets

Dual Kit/Aur Inhibitors as Chemosensitizing Agents for the Treatment of Melanoma: Design, Synthesis, Docking Studies and Functional Investigation.

Project description:Melanoma is the most serious form of skin cancer but its medication is still far from being safe and thoroughly effective. The search of novel therapeutic approaches represents therefore a health emergency to push through eagerly. In this study, we describe a novel class of dual c-Kit/Aur inhibitors, characterized by a 1,2,4-triazole core and developed by a structure-based optimization of a previously developed hit, and report the evidence of their significance as drug candidates for the treatment of melanoma. Compound 6a, merging the best inhibitory profile against the target kinases, showed anti-proliferative efficacy against the human melanoma cell lines A2058, expressing the BRAF V600D mutation, and WM266-4, expressing BRAF V600E. Significantly, it displayed also a highly synergistic profile when tested in combination with vemurafenib, thus proving its efficacy not only per se but even in a combination therapy, which is nowadays acknowledged as the cornerstone approach of the forthcoming tumour management.

| S-EPMC6617451 | biostudies-literature

N-Heterocycles Scaffolds as Quorum Sensing Inhibitors. Design, Synthesis, Biological and Docking Studies.

Project description:Quorum sensing is a communication system among bacteria to sense the proper time to express their virulence factors. Quorum sensing inhibition is a therapeutic strategy to block bacterial mechanisms of virulence. The aim of this study was to synthesize and evaluate new bioisosteres of N-acyl homoserine lactones as Quorum sensing inhibitors in Chromobacterium violaceum CV026 by quantifying the specific production of violacein. Five series of compounds with different heterocyclic scaffolds were synthesized in good yields: thiazoles, 16a-c, thiazolines 17a-c, benzimidazoles 18a-c, pyridines 19a-c and imidazolines 32a-c. All 15 compounds showed activity as Quorum sensing inhibitors except 16a. Compounds 16b, 17a-c, 18a, 18c, 19c and 32b exhibited activity at concentrations of 10 µM and 100 µM, highlighting the activity of benzimidazole 18a (IC50 = 36.67 µM) and 32b (IC50 = 85.03 µM). Pyridine 19c displayed the best quorum sensing inhibition activity (IC50 = 9.66 µM). Molecular docking simulations were conducted for all test compounds on the Chromobacterium violaceum CviR protein to gain insight into the process of quorum sensing inhibition. The in-silico data reveal that all 15 the compounds have higher affinity for the protein than the native AHL ligand (1). A strong correlation was found between the theoretical and experimental results.

| S-EPMC7765044 | biostudies-literature

Hepatitis C virus-induced hepatocellular carcinoma.

Project description:Hepatitis C virus (HCV) is a leading etiology of hepatocellular carcinoma (HCC). The interaction of HCV with its human host is complex and multilayered; stemming in part from the fact that HCV is a RNA virus with no ability to integrate in the host's genome. Direct and indirect mechanisms of HCV-induced HCC include activation of multiple host pathways such as liver fibrogenic pathways, cellular and survival pathways, interaction with the immune and metabolic systems. Host factors also play a major role in HCV-induced HCC as evidenced by genomic studies identifying polymorphisms in immune, metabolic, and growth signaling systems associated with increased risk of HCC. Despite highly effective direct-acting antiviral agents, the morbidity and incidence of liver-related complications of HCV, including HCC, is likely to persist in the near future. Clinical markers to selectively identify HCV subjects at higher risk of developing HCC have been reported however they require further validation, especially in subjects who have experienced sustained virological response. Molecular biomarkers allowing further refinement of HCC risk are starting to be implemented in clinical platforms, allowing objective stratification of risk and leading to individualized therapy and surveillance for HCV individuals. Another role for molecular biomarker-based stratification could be enrichment of HCC chemoprevention clinical trials leading to smaller sample size, shorter trial duration, and reduced costs.

| S-EPMC4493352 | biostudies-literature

Angular Phenozaxine Ethers as Potent Multi-microbial Targets Inhibitors: Design, Synthesis, and Molecular Docking Studies.

Project description:The reaction of diaza-5H-benzo[a]phenoxazin-5-one and 5H-benzo[a]phenoxazin-5-one with various phenols catalyzed by Pd/t-BuXPhos/K3PO4 system gave previously unknown ether derivatives (7a-f and 8a-f) in good yields. UV-visible, FTIR, and 1H NMR data were used to confirm structures of the synthesized compounds. The parent compounds and the derivatives were screened in-silico for their drug-likeness and binding affinities to the microbial targets through molecular docking. Molinspiration software and AutoDock were used for the drug-likeness and docking studies, respectively. All the synthesized compounds showed strong drug-likeness. They also showed excellent binding affinities with glucosamine-6-phosphate synthase (2VF5), AmpC beta-lactamase (1KE4), and Lanosterol-14?-demethylase (3JUV), with compound 7e having the highest binding energies -9.5, -9.3, and -9.3 kcal/mol, respectively. These were found to be higher than the binding energies of the standard drugs. The binding energies of ciprofloxacin with 2VF5 and 1KE4 were -7.8 and -7.5 kcal/mol, respectively, while that of ketoconazole with 3JUV was -8.6 kcal/mol. The study showed that the synthesized compounds have multi-target inhibitory effects and can be very useful in multi-drug resistance cases. A 2D quantitative structural activity relationship (QSAR) model against target Glucosamine-6-phosphate synthase (2VF5) was developed using partial least squares regression (PLS) with good internal prediction (R2 = 0.7400) and external prediction (R2_ predicted = 0.5475) via Molecular Operating Environment (2014).

| S-EPMC5712349 | biostudies-literature

Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors.

Project description:Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3-related kinase (ATR). These kinases induce cell cycle arrest in response to chemo- and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochemical and cellular activity against ATM (EC50 = 28 nmol/L) and ATR (EC50 = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo® assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA analysis. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors.

| S-EPMC6102578 | biostudies-literature

Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors.

Project description:A series of macrocyclic pyrido-pentapeptide candidates 2⁻6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, ¹H and 13C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC50 values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases.

| S-EPMC6222410 | biostudies-literature

Novel adamantyl clubbed iminothiazolidinones as promising elastase inhibitors: design, synthesis, molecular docking, ADMET and DFT studies.

Project description:Porcine Pancreatic Elastase (PPE) is a serine protease that is homologous to trypsin and chymotrypsin that are involved in various pathologies like inflammatory disease, Chronic Obstructive Pulmonary Disease (COPD), acute respiratory distress syndrome, cystic fibrosis, and atherosclerosis. PPE if remained uninhibited would lead to digestion of important connective tissue. We developed new structurally diverse series of adamantyl-iminothiazolidinone hybrids to divulge elastase inhibition assay. To identify potent derivatives, in silico screening was conducted and in vitro studies disclosed that the compounds 5a, 5f, 5g, and 5h showed excellent binding energies and low IC50 values. In silico studies including molecular docking, DFT studies (using the B3LYP/SVP basis set in the gas phase) drug likeness scores and molecular dynamic simulation studies were conducted to evaluate protein-ligand interactions and to determine the stability of top ranked conformation. In silico studies further supported the results of in vitro experiments and suggest these derivatives as novel inhibitors of elastase enzyme.

| S-EPMC9016748 | biostudies-literature

Molecular Signature of Hepatitis D Virus-Associated Hepatocellular Carcinoma

Project description:To investigate the role of viral and host factors in HDV-associated HCC we carried out an integrated clinicopathological and gene expression study of tissue specimens and laser microdissected hepatocytes obtained at the time of liver transplantation from livers with HDV-HCC, HDV-cirrhosis without HCC, HCV-HCC and HBV-HCC. References to GSM series of HDV and HBV livers, already deposited in GEO, are included in this series. Part of data of HCV livers are a re-analysis of GSE series GSE69715 and GSE78737, the re-analyzed GSM is indicated in the 'description' column and with a link at the bottom of the page.

2018-04-09 | GSE107170 | GEO

Molecular Signature of Hepatitis D Virus-Associated Hepatocellular Carcinoma

Project description:To investigate the role of viral and host factors in HDV-related HCC we analyzed the serum, tissue specimens and laser microdissected hepatocytes obtained at the time of liver transplantation from five patients with HDV-HCC. Livers of seven patients with HDV-cirrhosis without HCC were also analyzed. We carried out an integrated clinicopathological analysis and gene expression profiling,

2018-04-09 | GSE98383 | GEO

Design, synthesis, anticancer activity and docking studies of novel quinazoline-based thiazole derivatives as EGFR kinase inhibitors.

Project description:The in vitro anticancer efficacy of a new series of quinazoline-based thiazole derivatives was explored. Three cancer cell lines, MCF-7, HepG2, and A548, as well as the normal Vero cell lines, were tested employing the synthesized quinazoline-based thiazole compounds (4a-j). All of these compounds showed a moderate to significant cytotoxic impact that would have been noticeable and, in some cases, much more pronounced than the widely used drug erlotinib. For the MCF-7, HepG2, and A549 cell lines, respectively, the IC50 values of compound 4i were 2.86, 5.91, and 14.79 μM while those of compound 4j were 3.09, 6.87, and 17.92 μM. For their in vitro inhibitory effects against different EGFR kinases, such as the wild-type, L858R/T790 M, and L858R/T790 M/C797S, all the synthesized compounds were tested. The IC50 values for compound 4f against the wild-type, L858R/T790 M, and L858R/T790 M/C797S mutant EGFR kinases were 2.17, 2.81, and 3.62 nM, respectively. Investigations on the molecular docking of significant molecules indicated potential mechanisms of binding into the EGFR kinase active sites. By using in-silico simulations, compounds' putative drug-like qualities were verified. Finally, it has been shown that the newly synthesized compounds 4i and 4j are good candidates and beneficial for future design, optimization, and research to build more potent and selective EGFR kinase inhibitors with higher anticancer activity.

| S-EPMC10560058 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data