DNA recognition by metallotripeptides of the form nickel(II).Xaa-Xaa-His: Binding selectivity and mechanism of strand scission

DNA cleavage by synthetic tripeptides of the form NH 2-Xaa-Xaa-His-CONH2 was investigated in the presence of Ni(II) and oxygen activating agents. The metallotripeptides Ni(II)•Gly-Gly-His, Ni(II)•Lys-Gly-His, and Ni(II)•Arg-Gly-His were found to induce strand scission via a non-diffusible, non-base specific oxidant in the minor groove. The positively charged metallopeptides Ni(II)•Lys-Gly-His and Ni(II)•Arg-Gly-His have a high tendency to cleave DNA at mixed A/T-rich regions. Substitution of D-His for L-His in the tripeptide is believed to alter the site-selectivity observed due to structural differences of the two metal complex isomers. The site-selectivity of the metallopeptides may be due to the formation of a direct molecular interaction or steric complementarity, which is facilitated by electrostatic interactions.;Analysis of cleaved DNA fragments at single nucleotide resolution points to a mechanism similar to Fe(II)•bleomycin induced DNA cleavage, initiated from the abstraction of a C4'-H and resulting in the release of 3'- and 5'-phosphate fragments, 3'-phosphoglycolates, 3'-alkaline-labile fragments, and monomeric products (nucleobases and nucleobase propenals). The reaction pathways were sensitive to the structure of the metallopeptides. However, the site-selectivity and reaction pathways of DNA cleavage induced by Ni(II)•Lys-Gly-His were not affected by the activating agent (oxone, MMPP, and H2O2) employed nor common radical scavengers (ethanol, t-butyl alcohol, DMSO, and mannitol). These observations indicate that the active intermediate generated from activation of these metallotripeptides is most likely a ligand-bound Ni(III)-O•- or Ni(IV)=O species.;These studies demonstrate that this relatively simple tripeptide series is sensitive to DNA structure and is capable of interacting site-selectively, suggesting the possibility of exploiting the chemical diversity and chirality of peptides in the further design of DNA binding and modifying agents.