ABSTRACT
A series of 12 novel acylhydrazone, chalcone and amide-bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, (1)H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 µM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential.
Subject(s)
Cell Proliferation/drug effects , Neoplasms/drug therapy , Stilbenes/chemical synthesis , Tubulin Modulators/chemical synthesis , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Chalcone/chemistry , Drug Screening Assays, Antitumor/methods , Humans , Hydrazones/chemistry , Mice , Neoplasms/pathology , Stilbenes/chemistry , Structure-Activity Relationship , Tubulin/chemistry , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
As an important enzyme in bacterial protein biosynthesis, tyrosyl-tRNA synthetase (TyrRS) has been an absorbing therapeutic target for exploring novel antibacterial agents. A series of metronidazole-based antibacterial agents has been synthesized and identified as TyrRS inhibitors with low cytotoxicity and significant antibacterial activity, especially against Gram-negative organisms. Of the compounds obtained, 4f is the most potent agent which inhibited the growth of Pseudomonas aeruginosa ATCC 13525 (MIC = 0.98 µg/mL) and exhibited TryRS inhibitory activity (IC50 = 0.92 µm). Docking simulation was performed to further understand its potency. Membrane-mediated apoptosis in P. aeruginosa was verified by flow cytometry.
Subject(s)
Bacteria/drug effects , Drug Design , Metronidazole/chemistry , Metronidazole/pharmacology , Pyrazoles/chemistry , Tyrosine-tRNA Ligase/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Apoptosis/drug effects , Dose-Response Relationship, Drug , Humans , Metronidazole/chemical synthesis , Microbial Sensitivity Tests , Models, Molecular , Molecular Docking Simulation , Pseudomonas aeruginosa/drug effects , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Signal Transduction/drug effectsABSTRACT
A series of 1-methyl-1H-indole-pyrazoline hybrids were designed, synthesized, and biologically evaluated as potential tubulin polymerization inhibitors. Among them, compound e19 [5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide] showed the most potent inhibitory effect on tubulin assembly (IC50 =2.12â µm) and inâ vitro growth inhibitory activity against a panel of four human cancer cell lines (IC50 values of 0.21-0.31â µm). Further studies confirmed that compound e19 can induce HeLa cell apoptosis, cause cell-cycle arrest in G2 /M phase, and disrupt the cellular microtubule network. These studies, along with molecular docking and 3D-QSAR modeling, provide an important basis for further optimization of compound e19 as a potential anticancer agent.
Subject(s)
Antineoplastic Agents/pharmacology , Indoles/pharmacology , Pyrazoles/pharmacology , Tubulin Modulators/pharmacology , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Binding Sites , Cell Line, Tumor , G2 Phase Cell Cycle Checkpoints , Humans , Indoles/chemical synthesis , Molecular Docking Simulation , Pyrazoles/chemical synthesis , Quantitative Structure-Activity Relationship , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemical synthesisABSTRACT
A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC50 values ranging from 0.13µM to 128.06µM in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC50 value of 0.26µM/0.51µM, respectively, comparable to the positive control erlotinib (IC50=0.41µM for HER-2 and IC50=0.20µM for EGFR) and lapatinib (IC50=0.54µM for HER-2 and IC50=0.28µM for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Nitroimidazoles/chemistry , Nitroimidazoles/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Design , ErbB Receptors/metabolism , Humans , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Receptor, ErbB-2/metabolismABSTRACT
A series of 18 novel 1-indolyl acetate-5-nitroimidazole 3a-3r were designed, synthesized, and evaluated for their in vitro biological activities as potential tubulin polymerization inhibitors. Among these compounds, 3p displayed strong antitumor activity with IC50 of 2.00, 1.05, 0.87 µM against A549, Hela and U251 respectively, and also showed the most potent PLK1 inhibitory activity with IC50 of 2.4 µM. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized 1-indolyl acetate-5-nitroimidazolefor potential tubulin polymerization inhibitors.
Subject(s)
Drug Design , Molecular Docking Simulation , Nitroimidazoles/chemistry , Nitroimidazoles/pharmacology , Protein Multimerization/drug effects , Tubulin/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Humans , Nitroimidazoles/chemical synthesis , Nitroimidazoles/metabolism , Protein Structure, Quaternary , Quantitative Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacologyABSTRACT
A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives (C1-C24) have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-RafV600E (IC50 = 0.15 µM) and WM266.4 human melanoma cell line (GI50 = 1.75 µM), being comparable with the positive control (Vemurafenib and Erlotinib) and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.
Subject(s)
Antineoplastic Agents/chemical synthesis , Phenols/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Pyrazoles/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression , Humans , Molecular Docking Simulation , Phenols/chemistry , Phenols/pharmacology , Protein Binding , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/chemistry , Proto-Oncogene Proteins B-raf/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacologyABSTRACT
A series of 2-styryl-5-nitroimidazole derivatives containing 1,4-benzodioxan moiety (3a-3r) has been designed, synthesized and their biological activities were also evaluated as potential antiproliferation and focal adhesion kinase (FAK) inhibitors. Among all the compounds, 3p showed the most potent activity in vitro which inhibited the growth of A549 with IC50 value of 3.11 µM and Hela with IC50 value of 2.54 µM respectively. Compound 3p also exhibited significant FAK inhibitory activity (IC50=0.45 µM). Docking simulation was performed for compound 3p into the FAK structure active site to determine the probable binding model.
