Ni(II) chelated peptides of the form NH 2 -Xaa-Xaa-His-CONH 2 (Ni(II)·Xaa-Xaa-His) mediate deoxyribose damage through C4‘−H abstraction of a targeted nucleotide when activated with KHSO 5 (oxone), MMPP (magnesium monoperoxyphthalate), or H 2 O 2 . The products released and identified in comparison to the authentic C4‘−H oxidant Fe(II)·bleomycin included fragmented DNA terminating in 5‘-phosphates, 3‘-phosphates, and 3‘-phosphoglycolates; upon treatment of Ni(II)·Xaa-Xaa-His cleavage reactions with NaOH or NH 2 NH 2, fragmented DNA 3‘-termini were released consistent with the intermediate formation of keto-aldehyde abasic (alkaline-labile) sites. In addition, nucleobases and nucleobase propenals were detected in proportions consistent with abasic site and 3‘-phosphoglycolate termini formation, respectively. These results indicate that Ni(II)·Xaa-Xaa-His metallopeptides, like Fe(II)·bleomycin, degrade DNA through two pathways resulting from an initial C4‘−H modification. Importantly, the partitioning between these two pathways appears to be dependent on the structure of the Ni(II)·Xaa-Xaa-His metallopeptide employed in the cleavage reaction and the nucleotide sequence targeted. Further studies also indicate that metallopeptide activation with KHSO 5, MMPP, or H 2 O 2 yields identical reaction products and sequence-selective DNA cleavage suggesting the formation of a common “activated” metallopeptide responsible for C4‘−H deoxyribose damage, quite possibly a metal-bound hydroxyl radical. These studies also demonstrate that metallopeptide activation with KHSO 5 is condition- dependent resulting in (1) C4‘−H damage in common with MMPP or H 2 O 2 under relatively “low” ionic strength conditions (10 mM Na-cacodylate, pH 7.5, equimolar KHSO 5 /metallopeptide) or (2) guanine nucleobase oxidation under higher ionic strength conditions (100 mM NaCl, 10 mM phosphate, pH 7.0, excess KHSO 5 ).
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Liang et al. (1998) studied this question.