Inorganic Chemistry, Vol.35, No.9, 2637-2643, 1996
Photoinduced DNA Cleavage Reactions by Designed Analogs of Co(III)-Bleomycin - The Metalated Core Is the Primary-Determinant of Sequence Specificity
A 2,4’-bithiazole group has been covalently attached to the Co(III) complex of a designed ligand PMAH that mimics the metal-binding locus of the antitumor drug bleomycin (BLM). The deprotonated PMA(-) ligand binds Co(III) via five nitrogens located in primary and secondary amines, a pyrimidine and an imidazole ring, and a peptide moiety. The 2,4’-bithiazole group is tethered to the [Co(PMA)](2+) unit via an imidazole that is connected to the bithiazole moiety with a (CH2)(3) spacer. The structure of this hybrid analogue, namely, [Co(PMA)(Bit)]Cl-2 (7, Bit = 2’-methyl-2,4’-bithiazole-4-carboxamido-N’-(3-propyl)imidazole) has been established by spectroscopic techniques. 7 promotes photocleavage of DNA at micromolar concentrations. Unlike simpler analogues like [Co(PMA)(H2O)](2+) and [Co(PMA)Cl)](+) which induce random DNA cleavage upon UV illumination, 7 exhibits sequence specificity in the DNA photocleavage reaction. Intriguing is to note that 7 exhibits the same 5’GG-N3’ sequence preference as another hybrid analogue [Co(PMA)(Int-A)]Cl-2 (6, Int-A = acridine-9-carboxamido-N’-(3-propyl)imidazole) that contains an acridine moiety as the DNA-binding group. The observed sequence specificity of 6 and 7 therefore does not reflect the sequence preferences of the DNA-binding groups (acridine and bithiazole). The results indicate that the metalated core of the hybrid analogues, i.e., the [Co(PMA)](2+) unit is the key factor in determining their sequence specificity.
Keywords:DEOXYRIBONUCLEIC-ACID;COBALT BLEOMYCIN;BASE SPECIFICITY;BINDING;COMPLEXES;NICKING;OXYGEN;DRUG