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题名: Formation of Guanine-6-sulfonate from 6-Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study
作者: Zou, Xiaoran1;  Zhao, Hongmei1;  Yu, Youqing1;  Su, Hongmei1
刊名: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
发表日期: 2013-03-20
DOI: 10.1021/ja400483j
卷: 135, 期:11, 页:4509-4515
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Physical Sciences
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
英文摘要: As 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.
关键词[WOS]: DENSITY-FUNCTIONAL THEORY ;  DNA-DAMAGE ;  MOLECULAR-OXYGEN ;  PROTON-TRANSFER ;  CROSS-LINKING ;  UVA LIGHT ;  BASE-PAIR ;  DEACTIVATION ;  AZATHIOPRINE ;  CELLS
语种: 英语
WOS记录号: WOS:000316774100046
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137967
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Inst Chem, State Key Lab Mol React Dynam, BNLMS, Beijing 100190, Peoples R China

Recommended Citation:
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.
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