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Bioorg Chem ; 118: 105486, 2022 01.
Article in English | MEDLINE | ID: mdl-34801948

ABSTRACT

The colchicine binding site of tubulin is a promising target for discovering novel antitumor agents which exert the antiangiogenic effect and are not susceptible to multidrug resistance. For identifying novel tubulin inhibitors, structure-based virtual screening was applied to identify hit 9 which displayed moderate tubulin polymerization inhibition and broad-spectrum in vitro antitumor activity. Structural optimization was performed, and biological assay revealed analog E27 displayed the best antitumor activity with IC50 values ranging from 7.81 µM to 10.36 µM, and improved tubulin polymerization inhibitory activity (IC50 = 16.1 µM). It significantly inhibited cancer cell migration and invasion, induced cell apoptosis and arrested the cell cycle at G2/M phase. Moreover, the apoptotic effect of E27 is related to the increased ROS level, the decrease of MMP, and the abnormal expression of apoptosis-related proteins. Taken together, these results suggested E27 was a promising lead compound for discovering novel tubulin-targeted antitumor agents.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry
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