Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods.
Proc Natl Acad Sci U S A
; 107(52): 22419-24, 2010 Dec 28.
Article
em En
| MEDLINE
| ID: mdl-21149675
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 Fe(III) 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 Fe(III)BLM and ABLM as (BLM)Fe(III)âOH and (BLM)Fe(III)(η(1)âOOH) species, respectively. The NRVS spectra of Fe(III)BLM and ABLM are strikingly different because in ABLM the δFeâOâO bending mode mixes with, and energetically splits, the doubly degenerate, intense OâFeâN(ax) 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Bleomicina
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Compostos Férricos
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Espectroscopia de Ressonância Magnética
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Ferro
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2010
Tipo de documento:
Article
País de afiliação:
Estados Unidos