title: Definition of the intermediates and mechanism of the anticancer drug bleomycin using nuclear resonance vibrational spectroscopy and related methods.
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)─OH and (BLM)Fe(III)(η(1)─OOH) species, respectively. The NRVS spectra of Fe(III)BLM and ABLM are strikingly different because in ABLM the δFe─O─O bending mode mixes with, and energetically splits, the doubly degenerate, intense O─Fe─N(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.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305, USA.
authors.forename: Lei V
authors.initials: LV
authors.lastname: Liu
authors.forename: Caleb B
authors.initials: CB
authors.lastname: Bell
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Wong
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wilson
authors.forename: Yeonju
authors.initials: Y
authors.lastname: Kwak
authors.forename: Marina S
authors.initials: MS
authors.lastname: Chow
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
authors.forename: Keith O
authors.initials: KO
authors.lastname: Hodgson
authors.forename: Britt
authors.initials: B
authors.lastname: Hedman
authors.forename: Edward I
authors.initials: EI
authors.lastname: Solomon
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism; D001761:Bleomycin / Q000737:chemistry* / Q000378:metabolism; D003855:Deoxyribose / Q000737:chemistry / Q000378:metabolism; D005290:Ferric Compounds / Q000737:chemistry* / Q000378:metabolism; D006859:Hydrogen / Q000737:chemistry; D007501:Iron / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D015394:Molecular Structure; D010100:Oxygen / Q000737:chemistry; D013816:Thermodynamics; D014732:Vibration; D056928:X-Ray Absorption Spectroscopy
chemical_list: D000903:Antibiotics, Antineoplastic; D005290:Ferric Compounds; D001761:Bleomycin; D003855:Deoxyribose; D006859:Hydrogen; D007501:Iron; D010100:Oxygen