Proposed structure of the anthramycin–DNA adduct

Abstract

Anthramycin, an antitumour antibiotic produced by Streptomyces refuineus¹, belongs to the pyrrolo(1,4)benzodiazepine antibiotic group². Antibiotics within this group are potent inhibitors of nucleic acid synthesis because of their ability to form a labile covalent adduct with DNA^2–6. The reaction of anthramycin with DNA is unusual in that the rate of adduct formation is slow^2,4,5, shows an absolute specificity for deoxyguanosine in a double-stranded template⁴, and is only stable as long as the secondary structure of DNA is retained⁶. Experiments using confluent non-dividing human cell lines have demonstrated that while repair-proficient cells are able to remove up to 84% of the adduct within 72 h, xeroderma pigmentosum cells in complementation group A were only able to remove 49% during the same incubation period¹⁰. We propose here a Corey, Pauling and Koltun (CPK) molecular model for the anthramycin–DNA adduct in which anthramycin is attached through the 2-amino group of guanine and lies hidden in the narrow groove. Experimental data supporting this model are provided. The model is based on information about the probable covalent binding sites on anthramycin and guanine together with the known crystal structure of anthramyin⁷.