Michael Acceptors as a Tool for Anticancer Drug Design

Abstract:

Interaction of antitumor drugs with cellular targets involves various types of chemical binding, of which covalent binding is one of important strategies in designing effective anticancer molecules. The anticancer compounds employing covalent binding, structurally diverse, belong to many chemical classes, including quinones, mustards, nitrosourea, alkylsulfonate, pyrrolo[l,4]benzodiazepines, and others. Most of these compounds contain, or acquire by cellular metabolism, electrophilic centers, and some are Michael acceptors in a broader sense. Recent evidences suggest that antineoplastic alkylating compounds bind directly to various cellular nucleophiles, thus lacking in a selectivity. Meanwhile, Michael acceptors can be structurally modified, so that they can react selectively with target nucleophiles or they can be converted into a selective Michael acceptors during metabolism. Moreover, we often meet these Michael acceptors in biochemical process of cellular respiration or in metabolisms of some drugs or xenobiotics. A group of representative natural cytotoxic compounds containing Michael acceptor are naphthoquinones such as menadione and shikonin analogues, cytotoxic quassinoids, sesquiterpenoid benzoquinones, and others. Mitomycin, meanwhile, is transformed by reductive activation into a conjugated dienone as a Michael acceptor. In this review, chemistry, cytotoxicity and antitumor action of anticancer agents containing Michael acceptors will be discussed in the respect of structure-activity relationship. More in-depth review will be given of the naphthazarin analogues. Also, cytotoxic terpenes such as ar-turmerone analogues, quassinoids, and others will be reviewed.