SYNTHESES, STRUCTURES, AND REACTIVITIES OF SYNTHETIC ANALOGS OF THE 3 FORMS OF CO(III)-BLEOMYCIN - PROPOSED MODE OF LIGHT-INDUCED DNA DAMAGE BY THE CO(III) CHELATE OF THE DRUG

Three cobalt(III) complexes of a designed ligand PMAH, that mimics the metal-binding locus of the antitumor drug bleomycin (BLM), have been synthesized and structurally characterized. The complex [Co(PMA)(H2O)](NO3)2 (5) crystallizes in the triclinic space group P1BAR with a = 7.608 (3) angstrom, b = 10.542 (3) angstrom, c = 13.116 (4) angstrom, alpha = 71.14 (2)-degrees, beta = 74.59 (3)-degrees, gamma = 81.66 (3)-degrees, Z = 2, and V = 957.7 (6) angstrom 3. The complex [Co(PMA)(N-MeIm)](NO3)2.H2O (6) also crystallizes in the triclinic space group P1BAR with a = 8.485 (2) angstrom, b = 10.737 (3) angstrom, c = 15.080 (3) angstrom, alpha = 71.06 (2)-degrees, beta = 73.92 (2)-degrees, gamma = 69.94 (2)-degrees, Z = 2, and V = 1199.3 (6) angstrom 3. The third complex [Co(PMA)Cl]Cl.EtOH (7) crystallizes in the orthorhombic space group Pbcn with a = 13.228 (3) angstrom, b = 15.259 (4) angstrom, c = 21.287 (5) angstrom, Z = 8, and V = 4297 (2) angstrom 3. In all three complexes, the deprotonated PMA- ligand binds the cobalt(III) center in a pentadentate fashion with five N donors situated in the pyrimidine and imidazole rings, primary and secondary amine groups, and the amide moiety. Only change in the sixth ligand (H2O, N-MeIm, and Cl-, respectively) gives rise to the brown (5), orange (6), and green (7) products. These complexes exhibit properties similar to the BROWN, ORANGE, and GREEN Co(III)-BLMs and therefore qualify as good models for the cobalt(III) chelates of the drug. For example, like Co(III)-BLMs, the present complexes 5-7 inflict strand breaks in DNA upon UV illumination and this photocleavage reaction does not require the presence of dioxygen. The light-induced DNA cleavage reaction by 5-7 is neither a consequence of photoreduction of the complexes to Co2+ nor are they initiated by singlet oxygen. Both DNA cleavage and spin-trapping experiments demonstrate that UV irradiation of 5-7 generates a C/N-based radical on the ligand framework which rapidly reacts with water to produce .OH radical. Since the positively-charged complexes bind DNA rather strongly, UV illumination results in rapid production of .OH radical in close proximity of the DNA helix with concomitant strand scission. A similar mechanism could account for the photocleavage of DNA by Co(III)-BLMs.