SYNTHESES, STRUCTURES AND REACTIVITIES OF DESIGNED ANALOGS OF COBALT (III)-BLEOMYCINS - INSIGHT INTO THE MECHANISM OF SEQUENCE-SPECIFIC DNACLEAVAGE UPON ILLUMINATION

Citation
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
Citations number
36
Categorie Soggetti
Chemistry
ISSN journal
02534134
Volume
107
Issue
4
Year of publication
1995
Pages
459 - 476
Database
ISI
SICI code
0253-4134(1995)107:4<459:SSAROD>2.0.ZU;2-8
Abstract
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.