Chemistry of drug-induced DNA lesions.

Recent results on the action mechanisms of naturally occurring DNA-damaging antitumor antibiotics have been described. These antibiotics include neocarzinostatin (NCS) and DNA alkylating, duocarmycin A and kapurimycin A3. A series of duplex hexanucleotides of modified bases were prepared and their selectivity for C5' and C4' oxidation in the NCS-mediated degradation was investigated. Based on the cleavage data, a new binding model that permits competitive hydrogen abstraction from C5' and C4' of the DNA deoxyribose moiety has been described. Chemistry of alkylation of self complementary octanucleotide d(CGTATACG)2 by antitumor antibiotic duocarmycin A was described. It was demonstrated that N3 of adenine6 attacks the cyclopropane subunit of duocarmycin A to produce the covalently alkylated adduct. In contrast, antibiotic kapurimycin A3 alkylate N7 of guanine4 of d(CGCG)2 to provide the corresponding covalent adduct. Heating at 90 degrees C degraded the adduct to kapurimycin A3-guanine adduct and the respective abasic site-containing oligonucleotide. The structures of heat-induced abasic sites were unambiguously characterized.