期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 56, 期 8, 页码 3318-3329出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm4001117
关键词
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资金
- NIH [R01CA148706, 1S10RR026377-01, 1S10OD010678-01]
- GTx, Inc.
- NATIONAL CANCER INSTITUTE [R01CA148706] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR026377] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD010678] Funding Source: NIH RePORTER
A series of 4-aryl-2-benzoyl-imidazoles were designed and synthesized based on our previously reported 2-aryl-4-benzoyl-imidazole (ABI) derivatives. The new structures reversed the aryl group and the benzoyl group of previous ABI structures and were named as reverse ABI (RABI) analogues. RABIs were evaluated for biological activity against eight cancer cell lines including multidrug-resistant cancer cell lines. In vitro assays indicated that several RABI compounds had excellent antiproliferative properties, with IC50 values in the low, nanomolar range. The average IC50 of the most active compound 12a is 14 nM. In addition, the mechanism of action of these new analogues was investigated by cell cycle analysis, tubulin polymerization assay, competitive mass spectrometry binding assay, and molecular docking studies. These studies confirmed that these new RABI analogues maintain their mechanisms of action by disrupting tubulin polymerization, similar to their parental ABI analogues.
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