Cytotoxic esterified diterpenoid alkaloid derivatives with increase selectivity against a drug-resistant cancer cell line

Abstract

C-6 Esterifications of delpheline (1) were carried out to provide 20 new diterpenoid alkaloid derivatives (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) 24). Three natural alkaloids (1-3) and all synthesized compounds (4-25) were evaluated for cytotoxic activity against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines and interestingly, showed an improved drug resistance profile compared to paclitaxel. Particularly, 6-(4-fluoro-3methylbenzoyl)delpheline ( 22) displayed 2.6-fold greater potency against KB-VIN cells compared with the parental non-drug resistant KB cells. 6-Acylation of 1 appears to be critical for producing cytotoxic activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents. KeywordsDelpheline; C 19 -diterpenoid alkaloid; Cytotoxicity Natural products have been the major sources of currently available anticancer drugs. According to a review of New Chemical Entities (NCE) from 1981 to 2006, approximately 73% of anticancer drugs were not purely synthetic compounds, with 47% being natural products, directly derived from natural products, or mimicking natural products in one form or another. 1 Diterpenoid alkaloids have been isolated from the genera Aconitum, Consolida and Delphinium of the Ranunculaceae family, and the genus Spiraea of the Rosaceae family. Diterpenoid alkaloids are classified according to their chemical structure as C 18 -diterpenoid alkaloids, which have either a lappaconitine or a ranaconitine skeleton, C 19 -diterpenoid alkaloids, which have either an aconitine, lycoctonine, lactone-type, pyro-type, rearranged-