Semisynthetic pyrrolizidine alkaloid N-oxide antitumor agents. Esters of heliotridine.
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.
Zalkow
L H
LH
School of Chemistry, Georgia Institute of Technology, Atlanta 30332.
Glinski
J A
JA
Gelbaum
L T
LT
Moore
D
D
Melder
D
D
Powis
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D055598:Chemical Phenomena; D002621:Chemistry; D004952:Esters; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy; D011763:Pyrrolizidine Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004952:Esters; D011763:Pyrrolizidine Alkaloids; C014795:retronecine