title: Cytotoxic esterified diterpenoid alkaloid derivatives with increased 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 (4-22, 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.
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599 7568, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Wada
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000470:Alkaloids / Q000737:chemistry; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004224:Diterpenes / Q000494:pharmacology* / Q000633:toxicity*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D004224:Diterpenes; D017239:Paclitaxel