Formation of Guanine-6-sulfonate from 6-Thioguanine and Singlet Oxygen: A Combined Theoretical and Experimental Study

doi:10.1021/ja400483j

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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
刊名	JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
	2013-03-20
卷号	135 期号:11 页码:4509-4515
ISSN号	0002-7863
DOI	10.1021/ja400483j
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.
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000316774100046
内容类型	期刊论文
源URL	[http://ir.iccas.ac.cn/handle/121111/54333]
专题	中国科学院化学研究所
通讯作者	Su, Hongmei
作者单位	Chinese Acad Sci, Inst Chem, State Key Lab Mol React Dynam, BNLMS, Beijing 100190, Peoples R China
推荐引用方式 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.