Discovery of C 20 -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 20 -diterpenoid alkaloids, such as kobusine ( 1 ), likewise as their derivatives. A total of 43 novel diterpenoid alkaloid derivatives ( 2-10 , 2b , 3a , 3b , 6a-16a , 7b , 9b , 10b , 13 , 15-26 , 15b , 18a , 23a , 27a ) were prepared by C-11 and -15 esterification of 1 . Antiproliferative effects of the natural parent compound ( 1 ) 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 ( 3 ; average IC 50 7.3 μM). Several newly synthesized kobusine derivatives (particularly, 5-8 , 10 , 13 , 15-26 ) exhibited substantial suppressive effects against all tested human cancer cell lines. In contrast, kobusine ( 1 ), 11,15-O-diacetylkobusine ( 2 ), 11-acylkobusine derivatives ( 3a , 6a , 9a , 11a , 12a , 15a , 27a ), and 15-acylkobusine derivatives ( 2b , 3b , 7b , 9b , 10b , 15b ) 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 ( 3 , 6-10 , 13 , 15 , 16 , 18 , 23 ) were more potent compared with 11- and 15-acylkobusine derivatives ( 3a , 3b , 6a-10a , 7b , 9b , 10b , 13a , 15a , 15b , 16a , 18a , 23a ). Derivatives 13 and 25 induced MDA-MB-231 cells to the sub-G1 phase within 12 h. 11,15-Diacylation of kobusine ( 1 ) 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.