Design, synthesis, and study of 9-substituted ellipticine and 2-methylellipticinium analogues as potential CNS-selective antitumor agents.
N,N-Dimethylformamide (DMF) dineopentyl acetal-mediated O-alkylations of 9-hydroxyellipticine gave 9-ethoxy-, 9-(1-methylethoxy)-, and 9-(1,1-dimethylethox)ellipticine (3a, 4a, and 5a, respectively). Methylation of the O-alkylellipticines gave the corresponding N-methylpyridinium iodides (3b, 4b, and 5b). The iodides were converted to the acetates (3c, 4c, and 5c) by ion-exchange resin. Attempts to prepare 9-(2,2,2-trifluoroethoxy)ellipticine (6a) using the DMF acetal gave 10-(2,2,2-trifluoroethoxy)-9-hydroxyellipticine (8a). 9-(2,2,2-Trifluoroethoxy)- and 9-phenoxyellipticine (6a and 7a, respectively) were prepared by total synthesis. The ellipticines and N-methylellipticinium derivatives were evaluated for in vitro antitumor activity against a panel of human tumors. 2-Methyl-9-(1,1-dimethylethoxy)ellipticinium acetate (5c) was inactive, but all of the other compounds exhibited significant antitumor activity. The ellipticines showed no significant subpanel specificity; however, the N-methylellipticinium compounds tested did exhibit specificity for the CNS tumor subpanel.
Anderson
W K
WK
Department of Medicinal Chemistry, School of Pharmacy, State University of New York at Buffalo 14260.
Gopalsamy
A
A
Reddy
P S
PS
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004611:Ellipticines / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004611:Ellipticines; C034192:ellipticine; C027211:2-methylellipticinium