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

  • Bioorg Med Chem Lett. 2012 Jan 1;22(1):249-52. doi: 10.1016/j.bmcl.2011.11.026.
Koji Wada  1 ,  Emika Ohkoshi ,  Susan L Morris-Natschke ,  Kenneth F Bastow ,  Kuo-Hsiung Lee
Affiliations
  • 1. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 7568, USA.
PMID: 22142543 DOI: 10.1016/j.bmcl.2011.11.026
Abstract

C-6 Esterifications of delpheline (1) were carried out to provide 20 new diterpenoid alkaloid derivatives (4-22, 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-3-methylbenzoyl)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.