Design, synthesis, and evaluation of DNA minor groove binding agents: the duocarmycins

A summary of recent investigations of the duocarmycins is provided including the total synthesis of (+)-and ent-(-)-duocarmycin SA, the preparation and evaluation of the minimum potent pharmacophore of the alkylation subunit constituting the common pharmacophore of duocarmycin A and SA, the definition and characterization of the DNA alkylation properties of the agents and their correlation with biological properties, and studies to define the fundamental reactivity and molecular recognition principles relating the agents structure and properties. The duocarmycins'-3 constitute exceptionally potent antitumor-antibiotics that exert their biological effects through participation in a characteristic minor p v e adenine N3 alkylation of duplex DNA,4-9 Fig. 1. duocarmycin B, X Br duocarmycin C, X = CI (pyrindamycin 6) duocarmydn B, X = Br duocarmydn C, X = CI (pyrindamycin A) .. . . . Duocarmycin A C: J. Antibiotic 1988,41, 1915, 1285 J. Antibiotic 1989, 42, 1299 Duocarmycin SA: J. Antibiot. 1990, 43, 1037 X-ray of Pyrindamydn A: absolute configuration J. Antibiotic 1988.41. 1515