Structural features of metallobleomycins bound to DNA

Petering, David H.; Mao, Qunkai; Fulmer, Patricia; DeRose, Eugene F.; Otvos, James D.; Antholine, William E.

doi:10.1016/0162-0134(95)97308-d

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“…Bleomycin (Blm) is a glycopeptide antibiotic that is clinically employed as an antitumor agent. , The source of bleomycin's cytotoxicity is generally accepted to be its ability to effect both single- and double-strand breaks in DNA, the latter being more difficult for the cell to repair. ,,4a-f It has been established in vitro that this reaction is dependent on Fe(II)Blm + O 2 and involves the formation of HOO−Fe(III)Blm according to the following reactions: 1,4a-g Blm also complexes with Co(II) and subsequently reacts with O 2 in an analogous series of reactions…”

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confidence: 99%

Resonance Raman Studies of HOO−Co(III)Bleomycin and Co(III)Bleomycin: Identification of Two Important Vibrational Modes, ν(Co−OOH) and ν(O−OH)

2004

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Bleomycin is an antitumor agent whose cytotoxicity is dependent on its ability to bind DNA in the nucleus and effect double-stranded DNA cleavage, which is difficult for the cell to repair. In order for this DNA cleavage to occur, bleomycin must, through a series of reactions, form a low-spin Fe(III) complex, the putative "activated" form of the drug, HOO-Fe(III)bleomycin. The relative strengths of the bonds in the Fe(III)-OOH linkage have not been determined due to the weakness of the hydroperoxo-to-iron(III) charge-transfer transition. The much more stable HOO-Co(III)bleomycin has often been studied as a structural analogue of HOO-Fe(III)bleomycin, and hence, an understanding of the relative bond strengths in the Co-OOH linkage may serve to enhance our understanding of the analogous Fe-OOH linkage. In this report, we present resonance Raman data that identify two important vibrational modes in the Co-OOH linkage, the stretching modes, nu(Co-OOH) and nu(O-OH). Both of these vibrational modes were found to be unperturbed by complexation of the drug with calf thymus DNA. Advantage was also taken of the isostructural realtionship between Fe-bleomycin and Co-bleomycin to analyze and assign the high-frequency modes for HOO-Co(III)bleomycin and Co(III)bleomycin (A(2) and B(2)). These data could be useful for future studies of photoactivated Co-bleomycin and Co-bleomycin analogues in an attempt to characterize oxygen-independent DNA damage pathways.

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