Design, synthesis, and study of 9-substituted ellipticine and 2-methylellipticinium analogues as potential CNS-selective antitumor agents.

Abstract

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.

• Authors: W K Anderson, A Gopalsamy, P S Reddy
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 37 Issue 13 Pg. 1955-63 (Jun 24 1994) ISSN: 0022-2623 [Print] United States
• PMID: 8027977 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Ellipticines
• ellipticine
• 2-methylellipticinium

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, therapeutic use)
• Central Nervous System Neoplasms (drug therapy)
• Drug Design
• Drug Screening Assays, Antitumor
• Ellipticines (chemistry, therapeutic use)
• Humans
• Magnetic Resonance Spectroscopy
• Structure-Activity Relationship
• Tumor Cells, Cultured