Discovery of C-Diterpenoid Alkaloid Kobusine Derivatives Exhibiting Sub-G1 Inducing Activity.

Although many diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human cancer cell lines, little data have been offered relating to the antiproliferative effects of hetisine-type C-diterpenoid alkaloids, such as kobusine (), likewise as their derivatives. A total of 43 novel diterpenoid alkaloid derivatives (, , , , , , , , , , , , , ) were prepared by C-11 and -15 esterification of . Antiproliferative effects of the natural parent compound () and all synthesized kobusine derivatives against human cancer cell lines, including a triple-negative breast cancer (TNBC) cell line as well as a P-glycoprotein overexpressing multidrug-resistant subline, were assessed. The structure-based design strategy resulted in the lead derivative 11,15-dibenzoylkobusine (; average IC 7.3 μM). Several newly synthesized kobusine derivatives (particularly, , , , ) exhibited substantial suppressive effects against all tested human cancer cell lines. In contrast, kobusine (), 11,15-O-diacetylkobusine (), 11-acylkobusine derivatives (, , , , , , ), and 15-acylkobusine derivatives (, , , , , ) showed no effect. The most active kobusine derivatives primarily had two specific substitution patterns, C-11,15 and C-11. Notably, 11,15-diacylkobusine derivatives (, , , , , , ) were more potent compared with 11- and 15-acylkobusine derivatives (, , , , , , , , , , , ). Derivatives and induced MDA-MB-231 cells to the sub-G1 phase within 12 h. 11,15-Diacylation of kobusine () appears to be crucial for inducing antiproliferative activity in this alkaloid class and could introduce a new avenue to overcome TNBC using natural product derivatives.