SYNTHESES, STRUCTURES AND REACTIVITIES OF DESIGNED ANALOGS OF COBALT (III)-BLEOMYCINS - INSIGHT INTO THE MECHANISM OF SEQUENCE-SPECIFIC DNACLEAVAGE UPON ILLUMINATION
Et. Farinas et Pk. Mascharak, SYNTHESES, STRUCTURES AND REACTIVITIES OF DESIGNED ANALOGS OF COBALT (III)-BLEOMYCINS - INSIGHT INTO THE MECHANISM OF SEQUENCE-SPECIFIC DNACLEAVAGE UPON ILLUMINATION, Proceedings of the Indian Academy of Sciences. Chemical sciences, 107(4), 1995, pp. 459-476
Three Co(III) complexes of a designed ligand PMAH that mimics the meta
l-binding domain of the antitumor antibiotic bleomycin (BLM) have been
isolated and structurally characterized. The coordination structures
of the various forms of Co(III)-BLMs have been established on the basi
s of spectral similarities between these synthetic analogues and the c
orresponding Co(III)-BLMs. All three analogues, like Co(III)-BLMs, ind
uce DNA strand scission upon UV illumination. Both DNA cleavage and sp
in trapping experiments demonstrate that UV irradiation of the analogu
es generates a C/N-based radical on the ligand framework which rapidly
reacts with water to produce OH radical near the DNA helix and causes
strand scission. A similar mechanism could account for the photoactiv
ity of the Co(III)-BLMs. Covalent attachment of DNA-binding groups to
these analogues enhances the DNA-affinities and photocleavage efficien
cies to a great extent. The hybrid analogues promote sequence-specific
DNA photodamage at micromolar concentrations. The metallated cores of
the hybrid analogues are the primary determinant of the observed sequ
ence-specificity. Details of the mode of binding of the hybrid analogu
es to DNA have been explored by NMR techniques.