Bioinspired computational design of lankacidin derivatives for improvement in antitumor activity.

The 17-membered polyketide, lankacidin C, exhibits considerable antitumor activity as a microtubule stabilizer by binding to the paclitaxel binding site. Esterification of the C-7/C-13 hydroxyl in lankacidin C was performed with acetyl, cinnamoyl and hydrocinnamoyl groups and their antitumor activity was assessed to improve the cytotoxicity of lankacidins through bioinspired computational design. Compared with the cytotoxicity of parent lankacidin C against the HeLa cell line, 13--cinnamoyl-lankacidin C demonstrated sevenfold higher cytotoxicity. Furthermore, 7,13-di--cinnamoyl-lankacidin C exhibited considerable antitumor activity against three tested cell lines. C13-esterification by a cinnamoyl group dramatically improved antitumor activity, in agreement with computational predictions. This finding provides a potential substrate for next-generation lankacidin derivatives with significant antitumor activity.