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Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods

Liu, Lei V., Bell, Caleb B. III., Wong, Shaun D., Wilson, Samuel A., Kwak, Yeonju, Chow, Marina S., Zhao, Jiyong, Hodgson, Keith O., Hedman, Britt, Solomon, Edward I.
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.52 pp. 22419-22424
DNA, DNA damage, X-radiation, absorption, antineoplastic agents, glycopeptides, hydrogen, iron, spectroscopy, sugars, thermodynamics
Bleomycin (BLM) is a glycopeptide anticancer drug capable of effecting single- and double-strand DNA cleavage. The last detectable intermediate prior to DNA cleavage is a low spin FeIII peroxy level species, termed activated bleomycin (ABLM). DNA strand scission is initiated through the abstraction of the C-4' hydrogen atom of the deoxyribose sugar unit. Nuclear resonance vibrational spectroscopy (NRVS) aided by extended X-ray absorption fine structure spectroscopy and density functional theory (DFT) calculations are applied to define the natures of FeIIIBLM and ABLM as (BLM)FeIII[horizontal line]OH and (BLM)FeIII(η¹[horizontal line]OOH) species, respectively. The NRVS spectra of FeIIIBLM and ABLM are strikingly different because in ABLM the δFe[horizontal line]O[horizontal line]O bending mode mixes with, and energetically splits, the doubly degenerate, intense O[horizontal line]Fe[horizontal line]Nax transaxial bends. DFT calculations of the reaction of ABLM with DNA, based on the species defined by the NRVS data, show that the direct H-atom abstraction by ABLM is thermodynamically favored over other proposed reaction pathways.