Chiralities of Complexes of BleomycirvType Ligands, a Neglected Feature in Structural Studies Relevant to Anticancer Drug Action

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Abstract
Bleomycin (BLM) is a glycopeptide antibiotic used clinically for treating cancers of the head, neck, and testes, as well as certain lymphomas. The anticancer activity of BLM is related to the ability of an iron complex to bind and cleave DNA. High-spin Fe(II)BLM reacts with O2 to form a short-lived transient species that evolves to “activated BLM,” the species responsible for DNA cleavage. In order to gain insight into the possible arrangements of BLM in metal complexes, the coordination properties of BLM have been studied with a variety of metals. Since no X-ray structures of these metallobleomycins (M-BLMs) are known, 2D NMR and/or molecular modeling techniques have provided the most useful insight into the BLM arrangement in M-BLMs. In most proposals, five drug N-donors are aiTanged around the metal as in a square-pyramid (sp). However, the exact arrangement of the drug and the nature of the ligand donor atoms in M-BLMs is still controversial; the donors usually suggested are the N's from the terminal β-aminoalanine (two amino groups), the pyrimidinylpropionamide (pyrimidine), and the β-hydroxyhistidine (amide and imidazole). In a few cases, metal binding by the mannose carbamoyl group has been proposed. Furthermore, although BLM complexation to any metal creates new chiral centers, few published studies have assessed chirality. Because of some contradictory results and the absence of a comprehensive chirality analysis, we recently chose to examine the coordination of Zn(II) to tallysomycin A (TLMA, a glycopeptide related to BLM). This study led to the proposal of new structural models for ZnTLMA (i.e., sp-basket and trigonal bipyramid (tbp)) and hence a new ligand arrangement for M-BLMs. These novel ZnTLMA models raise the possibility that the disaccharide (i.e., gulose and mannose) may protect the Fe(II) center in Fe(II)BLM from oxidation until the drug binds to DNA. In this article, the traditional sp and novel sp-basket and tbp arrangements of this type of drug are classified and discussed. Common features are pointed out, along with the significant differences among these arrangements. Since the geometry of the metal-binding domain in M-BLMs may affect the conformation of the rest of the molecule and the binding to DNA, the relevance of the M-BLM structure to the mechanism of drug action is also addressed.