Design, synthesis, and biological activity of unnatural enediynes and related analogues equipped with pH-dependent or phototriggering devices

Abstract

Oxidative DNA cleavage by the diradical species generated from enediyne or enyne-cumulene progenitor is believed to be at the heart of the biological activity of the naturally occurring enediyne antibiotics. These serve as a perfect example of a prodrug designed by Nature. The promotion of certain members of this class of natural products to the actual clinical stage against certain types of tumors has generated an unprecedented flurry of research activities in the field of chemistry, biology, and medicine in search of new therapeutic agents. Various factors, such as ring strain, the proximity of carbon atoms undergoing covalent connectivity, etc., play important roles in controlling the process of diradical generation via cycloaromatization, and the lead from Mother Nature continues to be followed, as evidenced from the report of numerous synthetic mimics of the natural products. A major focus of research in this field involves the synthesis of designed enediynes to correlate their chemical and biological activity coupled with a novel triggering mechanism. Triggering of enediynes is necessary to activate them to generate the reactive form under appropriate conditions. Variations of pH and photo-irradiation are two important methods for triggering enediynes that are stable under ambient conditions. In this review, the synthesis and reactivity of endiynes and analogous molecules equipped with such triggering devices is discussed along with the analysis of the current level of biological activity achieved thus far.