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

• Published in: Journal of medicinal chemistry Vol. 31; no. 8; pp. 1520 - 1526
• Main Authors: Zalkow, Leon H, Glinski, Jan A, Gelbaum, Leslie T, Moore, David, Melder, Deborah, Powis, Garth
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.08.1988
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - therapeutic use; Chemical Phenomena; Chemistry; Esters; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Humans; Leukemia P388 - drug therapy; Organic chemistry; Preparations and properties; Pyrrolizidine Alkaloids - chemical synthesis; Pyrrolizidine Alkaloids - pharmacology; Pyrrolizidine Alkaloids - therapeutic use; Structure-Activity Relationship; Tumor Cells, Cultured - drug effects; Antineoplastic agent; Alkaloid; Angular nitrogen heterocycle; P388-Leukemia; Bicyclic compound; Amine oxide; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00403a008

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.