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Formation of Guanine-6-sulfonate from 6-Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study
Zou, Xiaoran; Zhao, Hongmei; Yu, Youqing; Su, Hongmei
Source PublicationJOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2013-03-20
DOI10.1021/ja400483j
Volume135Issue:11Pages:4509-4515
Indexed BySCI
SubtypeArticle
WOS HeadingsScience & Technology ; Physical Sciences
WOS SubjectChemistry, Multidisciplinary
WOS Research AreaChemistry
WOS KeywordDENSITY-FUNCTIONAL THEORY ; DNA-DAMAGE ; MOLECULAR-OXYGEN ; PROTON-TRANSFER ; CROSS-LINKING ; UVA LIGHT ; BASE-PAIR ; DEACTIVATION ; AZATHIOPRINE ; CELLS
AbstractAs an end metabolism product of the widely used thiopurine drugs, 6-thioguanine (6-TG) absorbs UVA and produces O-1(2) by photosensitization. This unusual photochemical property triggers a variety of DNA damage, among which the oxidation of 6-TG itself by O-1(2) to the promutagenic product guanine-6-sulfonate (G(SO3)) represents one of the major forms. It has been suspected that there exists an initial intermediate, G(SO), prior to its further oxidation to G(SO2) and G(SO3), but G(SO) has never been observed. Using density functional theory, we have explored the energetics and intermediates of 6-TG and O-1(2). A new mechanism via G(SOOH) -> G(SO2) -> G(SO4) -> G(SO3) has been discovered to be the most feasible energetically, whereas the anticipated G(SO) mechanism is found to encounter an inaccessibly high barrier and thus is prevented. The mechanism through the G(SOOH) and G(SO4) intermediates can be validated further by joint experimental measurements, where the fast rate constant of 4.9 X 10(9) M-1 s(-1) and the reaction stoichiometry of 0.58 supports this low-barrier new mechanism. In addition to the dominant pathway of G(SOOH) -> G(SO2) -> G(SO4) -> G(SO3), a side pathway with higher barrier, G(SOOH) -> G, has also been located, providing a rationalization for the observed product distributions of G(SO2) and G(SO3) as major products and G as minor product. From mechanistic and kinetics points of view, the present findings provide new chemical insights to understand the high phototoxicity of 6-TG in DNA and point to methods of using 6-TG as a sensitive fluorescence probe for the quantitative detection of O-1(2), which holds particular promise for detecting O-1(2) in DNA-related biological surroundings.
Language英语
WOS IDWOS:000316774100046
Citation statistics
Cited Times:23[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://cas-ir.dicp.ac.cn/handle/321008/137967
Collection中国科学院大连化学物理研究所
AffiliationChinese Acad Sci, Inst Chem, State Key Lab Mol React Dynam, BNLMS, Beijing 100190, Peoples R China
Recommended Citation
GB/T 7714
Zou, Xiaoran,Zhao, Hongmei,Yu, Youqing,et al. Formation of Guanine-6-sulfonate from 6-Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,2013,135(11):4509-4515.
APA Zou, Xiaoran,Zhao, Hongmei,Yu, Youqing,&Su, Hongmei.(2013).Formation of Guanine-6-sulfonate from 6-Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study.JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,135(11),4509-4515.
MLA Zou, Xiaoran,et al."Formation of Guanine-6-sulfonate from 6-Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 135.11(2013):4509-4515.
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