Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine.

Abstract

The C-9 and C-7 monoesters and C-7, C-9 diesters of heliotridine with (S)-(+) and (R)-(-)-2-hydroxy-2-phenylbutyric acid were prepared, converted into their N-oxides, and compared with the corresponding C-9 monoesters of retronecine in the in vivo P388 lymphocytic leukemia screen. Relative in vitro cytotoxicities of some of the free bases and their corresponding N-oxides were also measured against the A204 rhabdomyosarcoma cell line by using the soft agar colony forming assay. Stereochemistry at C-7 of the necine and at C-2' of the necine acid appears to have a significant effect on the antitumor activity in this system. In the heliotridine series, the configuration of the necic acid has a pronounced effect on the site selectivity (C-7 vs C-9) in esterification with carbodiimidazole. An explanation for this site selectivity is offered.

• Authors: L H Zalkow, J A Glinski, L T Gelbaum, D Moore, D Melder, G Powis
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 31 Issue 8 Pg. 1520-6 (Aug 1988) ISSN: 0022-2623 [Print] United States
• PMID: 3397989 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Esters
• Pyrrolizidine Alkaloids
• retronecine

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, therapeutic use)
• Chemical Phenomena
• Chemistry
• Esters
• Humans
• Leukemia P388 (drug therapy)
• Pyrrolizidine Alkaloids (chemical synthesis, pharmacology, therapeutic use)
• Structure-Activity Relationship
• Tumor Cells, Cultured (drug effects)