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.