CobaltIII bleomycin complexes

The bleomycins (Blms) are a group of glycopeptide antibiotics isolated from Streptomyces verticillus, which are used clinically for treating cancers of the head, neck and testes, as well as certain lymphomas.54 These antibiotics require a metal ion like iron(II) and dioxygen as co-factors to produce their drug action.9,55 58 When iron(II) reacts with bleomycin in the presence of O2, activated bleomycin HOO—Fe(III)Blm is formed which is proposed to have a square bipyramidal metal ion coordination.59,60 This species is particularly difficult to study because it is unstable and reacts with itself in the absence of DNA.60 62 At the same time, HOO—Fe(III)Blm, Fe(III)- and Fe(II)Blm are also paramagnetic, making nuclear magnetic resonance (NMR) structural investigations difficult.

The Co(II)Blm complex has been used as a model for FeBlm as it can be aerobically oxygenated in a fashion reminiscent of Fe(II)Blm to create HOO—Co(III)Blm (green) and H2O—Co(III)Blm (brown), respectively.63,64 The diamagnetic and stable nature of Co(III)Blm have made them excellent subjects for NMR structural investigations.

Recently, the structure of Co(III)Blm bound to oligonucleotide substrates has been studied in detail by NMR spectroscopy.2,65 70 Examination of HOO—Co(III)Blm associated with DNA oligomers containing a specific binding site of 5'-guanine-pyrimidine-3' reveals that the metal domain and linker are folded into a unit that interacts with the minor groove edge of the guanine. The drug's bithiazole moiety partially intercalates DNA and hydrogen bonding occurs between the pyrimidine moiety and minor groove of the G residue proximate to the intercalation site. In the process of association, the hydroperoxide ligand becomes oriented toward the C4'-hydrogen of the deoxyribose. These NMR studies also provided a number of observations to support the hypothesis that HOO—Co(III)Blm is an excellent structural model of activated FeBlm.2,65,69

Although Co(III)Blms strongly bind to DNA, previous studies indicate that they do not cause damage to DNA under aerobic conditions. However, the situation was changed in 1982 when Chang and Meares first observed a significant DNA photocleavage by a cobalt(III)-bleomycin complex.71 This renewed interest in the photochemistry of cobalt(III) complexes with bleomycin. Subsequently, Saito and co-workers studied the photocleavage characteristics of HOO—Co(III)Blm (green).72 When the self-complementary dodecamer 5'-CGCTTTAAAGCG-3' was used as the target, selective cleavage was observed after alkali treatment at positions C-3 and C-11. Free cytosine and alkali-labile lesions were detected as the products of the reaction by high performance liquid chromatography (HPLC) and attributed to cleavage at C-3 initiated by hydrogen atom abstraction from C-4' of deoxyribose. These results clearly demonstrate that the site of attack by cobalt(III)Blm is deoxyribose, but they do not offer insight into the oxidizing species or for its mechanism of formation.

To elucidate the mechanism of the light-induced DNA strand cleavage reaction, Mascharak and co-workers73,74 have synthesized a series of Co(III)-PMAH complexes as simplified Co(III)Blm analogues that lack the DNA-binding bithia-zole moiety of the natural ligand. DNA cleavage and spin-trapping experiments demonstrate that the UV light-induced DNA cleavage reaction by

Co(III)-PMAHs is neither a consequence of photoreduction of the complexes to cobalt(II) nor are they initiated by singlet oxygen. They should be attributed to the formation of the C/N-based radical on the ligand framework, which rapidly reacts with water to produce hydroxyl radicals near to the DNA helix with consequent cleavage. Recently, Nishida et al. have suggested a different mechanism for visible light-induced DNA cleavage reaction by HOO—Co(III)Blm.75 The cleavage process is related to the peroxide adduct. When the system is irradiated by visible light, it seems quite likely that a direct hydroxylation reaction may occur at the C4' position associated with a concerted heterolytic O—O cleavage reaction without formation of a C4' radical.

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