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Discovery of Novel 4-Arylisochromenes as Anticancer Agents Inhibiting Tubulin Polymerization. 2018

Wenlong Li, and Wen Shuai, and Feijie Xu, and Honghao Sun, and Shengtao Xu, and Hong Yao, and Jie Liu, and Hequan Yao, and Zheying Zhu, and Jinyi Xu
Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, P. R. China.

XJP-L (8), a derivative of the natural product (±)-7,8-dihydroxy-3-methylisochroman-4-one isolated from the peel of Musa sapien tum L., was found to exhibit weak inhibitory activity of tubulin polymerization (IC50 = 10.6 μM) in our previous studies. Thus, a series of 4-arylisochromene derivatives were prepared by incorporating the trimethoxyphenyl moiety into 8, among which compound (±)-19b was identified as the most potent compound with IC50 values ranging from 10 to 25 nM against a panel of cancer cell lines. Further mechanism studies demonstrated that (±)-19b disrupted the intracellular microtubule network, caused G2/M phase arrest, induced cell apoptosis, and depolarized mitochondria of K562 cells. Moreover, (±)-19b exhibited potent in vitro antivascular and in vivo antitumor activities. Notably, the R-configured enantiomer of (±)-19b, which was prepared by chiral separation, was slightly more potent than (±)-19b and was much more potent than the S-configured enantiomer in both antiproliferative and antitubulin assays. Our findings suggest that (±)-19b deserves further research as a potential antitubulin agent for the treatment of cancers.

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