Molecular basis for recognition and binding of specific DNA sequences by calicheamicin and duocarmycin

Abstract

This chapter discusses molecular basis for recognition and binding of specific DNA sequences by calicheamicin and duocarmycin. Current chemotherapy is largely based on drugs with poor selective cytotoxicities. Minor groove binding ligands with increased selectivity should produce a greater pharmacological response for a given dose than non-selective binders. The enediyne family of antitumor antibiotics is characterized by a unique molecular architecture, an intriguing mode of action, and highly potent biological and pharmacological activity. These compounds exert strong and selective DNA damage by generating a diradical species capable of cleaving the DNA-duplex. Enediynes possess a common reactive center along with a chemical functionality that can trigger a cascade of events to form a highly reactive aryl-diradical. These molecules also possess a clasp device, responsible for delivering and securing their position to the biological target—that is, DNA. The calicheamicin family possesses activity against Gram-positive and Gram-negative bacteria and also shows activity against murine leukemias, solid neoplasms, and melanomas. The duocarmycin and CC-1065 are the parent members of a class of exceptionally potent antitumor antibiotics that exert their biological activity through sequence selective alkylation of duplex DNA.