From multiply active natural product to candidate drug? Antibacterial (and other) minor groove binders for DNA

Abstract

Natural products that bind to DNA in the minor groove are valuable templates for drug design. Examples include distamycin, netropsin, duocarmycin and anthramycin. Anticancer and anti-infective drugs feature strongly amongst their derivatives. The structures and activities of chemotypes with various therapeutic actions are discussed in the context of the broader field of therapeutically active minor groove binders. The evolution of a series of exceptionally potent and nontoxic antibacterial compounds is discussed using the general design principle of introducing additional hydrophobicity into the distamycin template to increase the strength of binding to DNA. As well as potent antibacterial compounds, antifungal and antiparasitic compounds with exceptional cellular activity against trypanosomes have been identified. Possible mechanisms of action including gene regulation and topoisomerase inhibition are discussed with the need in mind to understand selective toxicity in the series to support future drug discovery.