Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 39, Issue 8, Pages 649-655Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2004.05.001
Keywords
acronycine; acridone; benzo[b]acronycine; S-23906; DNA alkylation; guanine
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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. (C) 2004 Elsevier SAS. All rights reserved.
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