Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods.
- X-Ray Science Division
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{sup III} peroxy level species, termed activated bleomycin (ABLM). DNA strand scission is initiated through the abstraction of the C-4{prime} 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{sup III}BLM and ABLM as (BLM)Fe{sup III}-OH and (BLM)Fe{sup III}({eta}{sup 1}-OOH) species, respectively. The NRVS spectra of Fe{sup III}BLM and ABLM are strikingly different because in ABLM the {delta}Fe-O-O bending mode mixes with, and energetically splits, the doubly degenerate, intense O-Fe-N{sub 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.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Organization:
- USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)
- DOE Contract Number:
- DE-AC02-06CH11357
- OSTI ID:
- 1011837
- Report Number(s):
- ANL/XSD/JA-69845; TRN: US201109%%651
- Journal Information:
- Proc. Natl. Acad. Sci. U.S.A., Vol. 107, Issue 52 ; Dec. 28, 2010
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
DNA sequence and structure recognition by Fe(II)[center dot]bleomycin
Studies on bleomycin and tRNA/sup Gly/