Mechanism of Action-Governed Design of Anthracycline Antibiotics: A "Turn-Off/ Turn-On" Approach

Abstract

We present a novel approach to the design of more effective anthracyclines based on structUre­ mechanism of action relationships rather than on classical structure-activity relationships . The core of this approach is first, the identification of structural elements critical for a particular mechanism of action and then, the use of chemical modifications to "tum off ," or reduce participation of, certain mechanism s while "turning on," i.e., maintaining or increasing participation of, the desired mechanism. Subse-quently , this approach will lead to a better understanding of the molecular interaction of anthracyclines with targets . To illustrate the potential of this approach for anthracycline s, we focus on chemical alterations that can tum · off P-glycoprotein-mediated efflux and in consequence allow circumvention of multidrug resistance without suppressing the drug's ability to inhibit topoisomerase II. We review the mechanistic effects of deamination and decreased basicity, as well as their biological relevance. Particularly, we concentrate on . the effects of amino group removal from C-3' and replacement with a hydroxy group, a change that leads to increased activity against multidrug-resistant tumors in vitro and in vivo . Using this approach, we have selected and developed Annamycin, a new drug with clearly altered mechanisms of action that is currently undergoing phase I clinical evaluation.