INTERPLAY OF HYDROGEN ABSTRACTION AND RADICAL REPAIR IN THE GENERATION OF SINGLE-STRAND AND DOUBLE-STRAND DNA-DAMAGE BY THE ESPERAMICINS

The source of hydrogens for the quenching of the phenylene diradical p roduced by esperamicin A (espA) and by esperamicin C (espC) in the pre sence of specifically deuteriated, double-stranded DNA (dsDNA) has bee n determined. Remarkably, both espA and espC were quenched at both pos itions of the diphenylene radical by exclusive abstraction of hydrogen from dsDNA. EspC, a predominantly ds-cleaver, afforded results consis tent with 4'- and 5'-hydrogen transfer. EspA, a predominantly ss-cleav er, revealed no 4'-hydrogen transfer; however, results were consistent with 5'-hydrogen transfer and with the recently proposed 1'-hydrogen transfer (Yu, L.; Golik, J.; Harrison, R.; Dedon, P. J. Am. Chem. Sec. 1994, 116, 9733-9738). For espA, insufficient double strand DNA damag e was produced to account for the role of DNA as the exclusive hydroge n source. Tn order to resolve this discrepancy, several reductants wer e used to activate espA and espC. The results indicated that a substan tial portion of radical lesions produced in DNA by the esperamicins is subjected to repair by hydrogen transfer from the reductant. The effi ciency of repair depended on the structural features of the reductant. The findings demonstrate that caution must be exercised when evaluati ng the propensity of DNA cleavers for ss- and ds-cleavage in the prese nce of reductants.