A COMPARISON OF DNA CLEAVAGE BY NEOCARZINOSTATIN CHROMOPHORE AND ITS AGLYCON - EVALUATING THE ROLE OF THE CARBOHYDRATE RESIDUE

Through a comparative analysis of the reactivity and DNA cleaving acti vity of neocarzinostatin (NCS) chromophore (1) and the corresponding a glycon (2), we show that the carbohydrate residue (aminoglycoside) of 1 both accelerates the rate and improves the efficiency of DNA cleavag e versus the aglycon (2), but does not appear to be a major determinan t of the base specificity of DNA cleavage by 1. This stands in contras t to earlier findings with another enediyne antibiotic, calicheamicin gamma(1), where the carbohydrate residue was found to be a major deter minant of the sequence specificity of DNA cleavage, in addition to pla ying a functional role in the reductive activation step. Thiol additio n experiments with NCS aglycon (2) provide further evidence that the c arbohydrate amino group of 1 functions as an internal base in the firs t step leading to DNA cleavage, thiol. activation. Evidence is also pr esented supporting the proposal that NCS aglycon (2) is bound tightly and reversibly by the neocarzinostatin binding protein (apo-NCS) and t hat this binding stabilizes the aglycon in solution.