期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 59, 期 11, 页码 5264-5283出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.6b00021
关键词
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资金
- National Natural Science Foundation of China [21302235, 20972198]
- Guangdong Natural Science Foundation [2014A030313124]
- Fundamental Research Funds for the Central Universities [15ykpy04]
Twenty-nine novel indole-chalcone derivatives were synthesized and evaluated for antiproliferative activity. Among them, 14k exhibited most potent activity, with IC50 values of 3-9 nM against six cancer cells, which displayed a 3.8-8.7-fold increase in activity when compare with compound 2. Further investigation revealed 14k was a novel tubulin polymerization inhibitor binding to the colchicine site. Its low cytotoxicity toward normal human cells and nearly equally potent activity against drug resistant cells revealed the possibility for cancer therapy. Cellular mechanism studies elucidated 14k arrests cell cycle at G(2)/M phase and induces apoptosis along with the decrease of mitochondrial membrane potential. Furthermore, good metabolic stability of 14k was observed in mouse liver microsomes. Importantly, 14k and its phosphate salt 14k-P inhibited tumor growth in xenograft models in vivo without apparent toxicity, which was better than the reference compound CA-4P and 2. In summary, 14k deserves consideration for cancer therapy.
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