Abstract:
Due to the high reactivity of Bergman cyclization at ambient temperature which generates diradical intermediates and high cytotoxicity in physiological environments, enediyne compounds have emerged as a class of promising candidates in anticancer treatment. In this work, the enediyne containing long alkynyl chains was chosen as a model compound to study the Michael addition reaction of maleimide-based enediyne compounds. The results showed that in polar solvents, the triple bond moiety of enediyne was quickly attacked by primary amine to generate a 1, 6-addition product with no Bergman cyclization reactivity. While in nonpolar solvents or when a primary amine with bulky substituents was used, the Michael addition reaction was sluggish. Screening the reaction in aqueous solution showed that the Michael addition was preferred in neutral media. In weak acidic environment, the enediyne compound was intact and maintained its Bergman cyclization activity. The overall results provide an important guide for molecular design of enediyne compounds and show great promise in constructing smart enediyne antibiotics delivery system for potential clinical applications.