Synthesis,cytotoxic evaluation and molecular docking study of 2-alkylthio-4-(2,3,4-trimethoxyphenyl)-5-aryl-thiazoles as tubulin polymerization inhibitors |
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Authors: | Marjan Salehi Mohsen Amini Seyed Nasser Ostad Gholam Hossein Riazi Amir Assadieskandar Bentolhoda Shafiei Abbas Shafiee |
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Institution: | 1. Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran;2. Department of Toxicology and Pharmacology, Faculty of Pharmacy and Rational Drug Use Research Center, Tehran University of Medical Sciences, Tehran, Iran;3. Institute of Biochemistry and Biophysics, University of Tehran, Tehran 13145-1384, Iran;4. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran |
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Abstract: | A series of cis-restricted 2-alkylthio-4-(2,3,4-trimethoxyphenyl)-5-aryl-thiazole analogues of combretastatin A-4 were synthesized and investigated for inhibition of cell proliferation against three cancer cell lines, HT-29, MCF-7, and AGS, and a normal mouse fibroblastic cell line, NIH-3T3, using an MTT assay. The biological study showed that 2-(methylthio) substituted compounds showed little cytotoxic activity against the four cell lines. In contrast, the presence of the 2-(benzylthio) group on the thiazole ring resulted in a significant improvement in cytotoxic activity relative to the 2-(methylthio) substituted derivatives. Furthermore, the inhibition of tubulin polymerization by some potent compounds was evaluated. All the compounds studied were moderate tubulin polymerization inhibitors. The flow cytometry analysis confirmed that the synthesized compounds led to cell cycle arrest at the G2/M phase. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. |
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Keywords: | 2-Alkylthio-4 5-diaryl-thiazole Tubulin inhibitor Cytotoxicity Cell cycle analysis Molecular docking |
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