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

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.