Covalent modification and single-strand scission of DNA by a new antitumor antibiotic kapurimycin A3

Kapurimycin A3 is a new antitumor Antibiotic isolated from a Streptomyces. It contains the anthrapyrone skeleton and a beta,gamma-unsaturated delta-keto carboxylic acid moiety in the structure. In vitro, kapurimycin causes single-strand cleavage of supercoiled pBR322 DNA. The diminished cytotoxicity and DNA cleaving activity for 13-decarboxykapurimycin A3 indicates that the beta, gamma-unsaturated delta-keto carboxylic acid moiety is important for the activity of kapurimycin. Kapurimycin A3 binds to calf thymus DNA at 4 degrees C, and the thermal treatment of this adduct results in release of a guanine covalently attached to C-16 of kapurimycin via one of its nitrogen atoms. Thus, the epoxide is the alkylating functional group of kapurimycin, and this is consistent with the lack of DNA cleaving and cytotoxic activities for 14,16-deoxy-14,16-dihydroxykapurimycin. These findings have revealed that DNA strand scission by kapurimycin is due to the alkylation of guanine by ring opening of the epoxide group of kapurimycin, depurination of modified guanine, and presumably subsequent hydrolysis of the phosphate ester backbone at the resultant apurinic sites.