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

Author:
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.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.52 pp. 22419-22424
ISSN:
0027-8424
Subject:
DNA, DNA damage, X-radiation, absorption, antineoplastic agents, glycopeptides, hydrogen, iron, spectroscopy, sugars, thermodynamics
Abstract:
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.
Agid:
2371140