Benzo[b]acronycine derivatives: a novel class of antitumor agents.
A hypothesis of bioactivation of the antitumor alkaloid acronycine by transformation of the 1,2-double bond into the corresponding epoxide in vivo and the suggestion that acronycine could interact with DNA, led to develop 1,2-dihydroxy-1,2-dihydrobenzo[b]acronycine diesters (1,2-dihydroxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one diesters) as new anticancer drug candidates. Compared to acronycine these compounds were markedly more potent, both in terms of cytotoxicity and antitumor activity. The biological activity of these compounds was strongly related with their ability to give covalent adducts with purified as well as genomic DNA. Formation of those adducts involves alkylation of the exocyclic N-2 amino groups of guanines exposed in the minor groove of double helical DNA by the carbocation produced by the elimination of the acyloxy leaving group at position 1 of the drug. A transesterification process of the ester group from position 2 to position 1 accounted for the intense activity of cis-1-hydroxy-2-acyloxy-1,2-dihydrobenzo[b]acronycine derivatives. Cis-1,2-diacetoxy-1,2-dihydrobenzo[b]acronycine, which displays a particularly impressive broad antitumor spectrum, is currently developed by Servier Laboratories under the code S23906-1.
Michel
Sylvie
S
Laboratoire de pharmacognosie de l'université René Descartes, UMR/CNRS No. 8638, faculté de pharmacie, 4, avenue de l'Observatoire, Paris 75006, France.
Gaslonde
Thomas
T
Tillequin
François
F
D000175:Acronine / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000494:pharmacology; D001554:Benzene / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans
D000972:Antineoplastic Agents, Phytogenic; D001554:Benzene; D000175:Acronine