The metal bonding domain of the antitumor drug Fe(II)-bleomycin: a DFT investigation.

The geometric and electronic structure of ferrous complexes of bleomycin (Fe(II)BLM) has been investigated by means of density functional theory (DFT) calculations. The active site of this antitumor drug is a highly distorted octahedral complex, with the coordination sphere completed by the five known endogenous ligands, including pyrimidine, imidazole, deprotonated amide, and secondary and primary amines. We have addressed the controversial issue of the nature of the sixth axial ligand, which we have identified as the oxygen of the carbamoyl group. Our conclusions are further validated by a comparison with structural data derived from NMR experiments. Moreover, because of the high sensitivity of structural data on the pH of the environment, we have investigated the effect of a different protonation state of the histidine amide on the geometric structure of the Fe(II)BLM complex. The extensive model of the active site of bleomycin considered in this work allows us to check the limitations of previous investigations based on simplified models.