Planta Med 2012; 78 - PD11
DOI: 10.1055/s-0032-1320369

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

K Wada 1, 2, E Ohkoshi 2, SL Morris-Natschke 2, KF Bastow 2, KH Lee 3
  • 1Medicinal Chemistry, School of Pharmacy, Hokkaido Pharmaceutical University, 7–1, Katsuraoka-cho, Otaru 047–0264, Japan
  • 2Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA
  • 3Natural Products Research Laboratories, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA and Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan

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.