Design of novel antitumor DNA alkylating agents: the benzacronycine series.
Acronycine, a natural alkaloid originally extracted from the bark of the Australian ash scrub Acronychia baueri, has shown a significant antitumor activity in animal models. Acronycine has been tested against human cancers in the early 1980s, but the clinical trials showed modest therapeutic effects and its development was rapidly discontinued. In order to optimize the antineoplastic effect, different benzoacronycine derivatives were synthesized. Among those, the di-acetate compound S23906-1 was recently identified as a promising anticancer drug candidate and a novel alkylating agent specifically reacting with the exocylic 2-NH2 group of guanines in DNA. The study of DNA bonding capacity of acronycine derivatives leads to the identification of the structural requirements for DNA alkylation. In nearly all cases, the potent alkylating agents, such as S23906-1, were found to be much more cytotoxic than the unreactive analogs such as acronycine itself or diol derivatives. Alkylation of DNA by the monoacetate derivative S28687-1, which is a highly reactive hydrolysis metabolite of S23906-1, occurs with a marked preference for the N2 position of guanine. Other bionucleophiles can react with S23906-1. The benzacronycine derivatives, which efficiently alkylate DNA, also covalently bind to the tripeptide glutathione (GSH) but not to the oxidized product glutathione disulfide. Here we review the reactivity of S23906-1 and some derivatives toward DNA and GSH. The structure-activity relationships in the benzacronycine series validate the reaction mechanism implicating DNA as the main molecular target. S23906-1 stands as the most promising lead of a medicinal chemistry program aimed at discovering novel antitumor drugs based on the acronycine skeleton.
David-Cordonnier
Marie-Hélène
MH
INSERM U-524 et Laboratoire de Pharmacologie Antitumorale du Centre Oscar Lambret, IRCL, Lille 59045, France.
Laine
William
W
Gaslonde
Thomas
T
Michel
Sylvie
S
Tillequin
Francois
F
Koch
Michel
M
Léonce
Stéphane
S
Pierré
Alain
A
Bailly
Christian
C
D000175:Acronine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000478:Alkylation; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry* / Q000494:pharmacology; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006147:Guanine / Q000378:metabolism; D006801:Humans; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; C436732:S 23906-1; D006147:Guanine; D004247:DNA; D005978:Glutathione; D000175:Acronine