SPECIFICITY OF INTERCALATION REACTIONS

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The long-range goal of the proposed research is to understand in molecular detail the sequence and conformational specificity of intercalcation reactions involving clinically important antibiotics. It is anticipated that information obtained in the proposed research will be of direct use in the rational design of new intercalating drugs with enhanced potency and specificity. The clinically important anthracycline antibiotics and a series of novel anthrapyrazole antibiotics will be studied. A quantitative deoxyribonuclease footprinting method will be implemented and exploited to obtain microscopic binding constants describing the interaction of these compounds with specific DNA binding. Stopped-flow and temperature-jump kinetic methods will be used to obtain data of use toward formulating a pluasible reaction mechanism describing the process by which an antibiotic molecule finds and interacts with its specific DNA binding site. Deoxyribonuclease footprinting and spectroscopic methods will be used to examine the interaction of intercalators with B-Z junctions and bends in DNA, in order to see if such regions are high affinity binding sites for intercalating drugs. Mechanistic studies of intercalators as allosteric effectors of DNA conformation will continue, emphasizing kinetic studies of the effect of intercalcators on the B to Z transition in DNA. The fundamental thermodynamics and kinetics of the interaction of a series of novel anthrapyrazole antibiotics with DNA will be examined. The combined results of these studies will provide fundamental details essential for understanding the intercalation process, an important reaction by which many clinically useful antibiotics interact with their prime cellular target, DNA.