Synthesis, cytotoxic evaluation and molecular docking study of 2-alkylthio-4-(2,3,4-trimethoxyphenyl)-5-aryl-thiazoles as tubulin polymerization inhibitors.
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.
Department of Medicinal Chemistry, Faculty of Pharmacy and Drug Design & Development Research Center, Tehran University of Medical Sciences, Tehran 14176, Iran.
Marjan
M
Salehi
Mohsen
M
Amini
Seyed Nasser
SN
Ostad
Gholam Hossein
GH
Riazi
Amir
A
Assadieskandar
Bentolhoda
B
Shafiei
Abbas
A
Shafiee
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D058105:Polymerization / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D014404:Tubulin / Q000378:metabolism*
D000970:Antineoplastic Agents; D013844:Thiazoles; D014404:Tubulin
2-Alkylthio-4,5-diaryl-thiazole; Cell cycle analysis; Cytotoxicity; Molecular docking; Tubulin inhibitor