Pyrrolo[1,4]benzodiazepine antibiotics. Proposed structures and characteristics of the in vitro deoxyribonucleic acid adducts of anthramycin, tomaymycin, sibiromycin, and neothramycins A and B

Abstract

The pyrrolo[1,4]benzodiazepine antibiotics anthramycin, tomaymycin, sibiromycin and neothramycins A and B are potent antitumor agents that bind to DNA in a unique manner, resulting in some unusual biological consequences. This paper describes results on which the points of covalent linkage between the drugs (carbinolamine carbon atom) and DNA (N-2 of guanine) are deduced, as well as Corey-Pauling-Koltun (CPK) models for the various drug-DNA adducts. Predictions based upon these CPK models were tested and the results reported. These tested experimental predictions include instability of the drug-DNA adducts to denaturation of DNA, saturation binding limits, effect of drug binding on the structure of DNA, lack of unwinding and in vitro strand breakage of closed-ciruclar supercoiled simian virus 40 (SV-40) DNA, sensitivity of the secondary structure of DNA to drug binding, hydrodynamic properties of the drug-DNA adducts, hydrogen bonding of the 9-phenolic proton in anthramycin to DNA, structure-activity relationhsips and biological consequences of DNA damage, including cumulative damage and slow excision repair, double-strand breaks in DNA in repair-proficient cells and the selective inhibition of H-strand DNA synthesis in mitochondria. The results are completely in accord with postulated space-filling models.