Bioactivation as a Model for Drug Design Bioreductive Alkylation

Abstract

The concept of bioreductive alkylation as put forth by Lin, Cosby, Shansky and Sartorelli and further elaborated here is of potential major significance as a mechanism of action of many naturally occurring and synthetic antineoplastic compounds as well as antibiotics. It allows the synthesis chemist to envisage a plethora of compounds that possibly show such activity. It permits examination of known compounds for the key structural features that may be responsible for their biological activity. Many possible modes of action other than that of bioreductive alkylation can be envisaged for a number of compounds discussed in this article. Some of these may be more reasonable than the concepts which were outlined. Structural features that are necessary for quinone methide formation, directly or subsequent to an in vivo reductive process, apparently are ubiquitous. The possibility of appropriately substituted compounds functioning as bioreductive alkylating agents provides a logical model that has a great deal of predictive power.