期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 46, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116376
关键词
Acridine and quinoline derivatives; Tubulin inhibitor; Colchicine binding site; Apoptosis; Anticancer agents
资金
- Thousand Youth Talents Program from the Organization Department of the CPC Central Committee, China [C1080092]
- International Science and Technology Cooperation Projects of Guangdong Province [G819310411]
- Scientific Research Project of High Level Talents in Southern Medical University of China [G618319142]
Compound 3b, designed as a tubulin inhibitor targeting the colchicine binding site, showed high antiproliferative activity against HepG-2 cells, with the ability to suppress microtubule polymerization, disrupt dynamics, inhibit cancer cell migration, induce cell cycle arrest and apoptosis. Docking studies indicated its potential as a novel tubulin inhibitor deserving further investigation.
A series of acridine and quinoline derivatives were designed and synthesized based on our previous work as novel tubulin inhibitors targeting the colchicine binding site. Among them, compound 3b exhibited the highest antiproliferative activity with an IC50 of 261 nM against HepG-2 cells (the most sensitive cell line). In addition, compound 3b was able to suppress the formation of HepG-2 colonies. Mechanism studies revealed that compound 3b effectively inhibited tubulin polymerization in vitro and disrupted microtubule dynamics in HepG-2 cells. Furthermore, compound 3b inhibited the migration of cancer cells in a dose dependent manner. Moreover, compound 3b induced cell cycle arrest in G2/M phase and led to cell apoptosis. Finally, docking studies demonstrated that compound 3b fitted nicely in the colchicine binding site of tubulin and overlapped well with CA-4. Collectively, these results suggested that compound 3b represents a novel tubulin inhibitor deserving further investigation.
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