Li Wenlong, Shuai Wen, Xu Feijie, Sun Honghao, Xu Shengtao, Yao Hong, Liu Jie, Yao Hequan, Zhu Zheying, Xu Jinyi
Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
Department of Organic Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.
ACS Med Chem Lett. 2018 Sep 25;9(10):974-979. doi: 10.1021/acsmedchemlett.8b00217. eCollection 2018 Oct 11.
XJP-L (), a derivative of the natural product (±)-7,8-dihydroxy-3-methylisochroman-4-one isolated from the peel of ., was found to exhibit weak inhibitory activity of tubulin polymerization (IC = 10.6 μM) in our previous studies. Thus, a series of 4-arylisochromene derivatives were prepared by incorporating the trimethoxyphenyl moiety into , among which compound was identified as the most potent compound with IC values ranging from 10 to 25 nM against a panel of cancer cell lines. Further mechanism studies demonstrated that disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis, and depolarized mitochondria of K562 cells. Moreover, exhibited potent antivascular and antitumor activities. Notably, the -configured enantiomer of , which was prepared by chiral separation, was slightly more potent than and was much more potent than the S-configured enantiomer in both antiproliferative and antitubulin assays. Our findings suggest that deserves further research as a potential antitubulin agent for the treatment of cancers.
