CC-1065 and the duocarmycins: Understanding their biological function through mechanistic studies

Abstract

We review here studies defining the DNA alkylation properties of a class of potent antitumor antibiotics that includes CC-1065 and the duocarmycins, as well as investigations that delineate fundamental relationships between their structure, functional reactivity, and biological properties. In conjunction with the study of the natural products themselves, the examination of synthetic agents containing deep-seated structural changes, the unnatural enantiomers of the natural products, and related analogs has defined the structural basis for the sequence selective alkylation of duplex DNA and proved to be the key to understanding the fundamental relationships between chemical structure, functional reactivity, and biological properties. The characteristic DNA alkylation proceeds by reversible, stereoelectronically controlled adenine-N3 addition to the least substituted carbon of the activated cyclopropane within AT-rich minor groove sites. Both the natural and unnatural enantiomers alkylate DNA, and the sequence selectivity of both is controlled and dominated by the preferential noncovalent binding of the agents within the narrower, deeper, AT-rich minor groove and the steric accessibility to the alkylation site on penetration of this groove. Among the fundamental relationships between structure and properties, the most striking is the direct relationship between chemical or functional stability and biological potency. Within a short time, simplified and readily accessible synthetic agents rationally based on the natural product leads have been developed, which exhibit comparable and exceptional biological potency (IC50 = 50 to 51 pM) and improved efficacy. The fundamental relationships that have been defined to date can be expected to provide the foundation for future developments and advances. © VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1996.