Rational design and structure –activity relationship studies reveal new esterified C20-diterpenoid alkaloid analogues active against MCF-7 human breast cancer cells

AbstractAlthough various diterpenoid alkaloids have been evaluated recently for antiproliferative activity against human tumor cell lines, little information is available regarding the antiproliferative effects of C20-diterpenoid alkaloids against MCF-7 cells. Six new diterpenoid alkaloid derivatives (13,14,22,23,25,26) were prepared by C-11 and 15 esterification of kobusine (6). The natural parent alkaloid6 and all synthesized derivatives (7 − 27,12a,15a,15b,18a,18b) were evaluated for antiproliferative activity against MCF-7 cells. The structure-based design strategy resulted in an initial lead derivative, 11,15-dibenzoylkobusine (7; IC50 8.6  µM). Subsequent synthesized 11,15-diacylkobusine derivatives (9,16,20,21,23,25, and26) showed substantially increased suppressive effects against the MCF-7 cell line (IC50 2.3 −4.4 µM). In contrast, parent alkaloid6, two 11-acylkobusine derivatives (15a,18a), and two 15-acylkobusine derivatives (15b,18b) showed no effect. 11,15-Diacylation appears to be critical for producing antiproliferative activity in this alkaloid class and could introduce a new avenue in overcoming breast cancer cell proliferation using natural product derivatives. In a preliminary mechanism of action study, representative derivatives (5,8,9, and17) decreased cyclin D1 mRNA expression.Graphical abstract
Source: Journal of Natural Medicines - Category: Drugs & Pharmacology Source Type: research