Formation of guanine-6-sulfonate from 6-thioguanine and singlet oxygen: a combined theoretical and experimental study.
Formation of guanine-6-sulfonate from 6-thioguanine and singlet oxygen: a combined theoretical and experimental study.
复制标题
DOI：
10.1021/ja400483j
复制
发表时间：
2013-03
影响因子：
15
通讯作者：
Xiaoran Zou;Hongmei Zhao;Youqing Yu;Hongmei Su
中科院分区：
文献类型：
--
作者：
Xiaoran Zou;Hongmei Zhao;Youqing Yu;Hongmei Su
6-硫代鸟嘌呤(6-Tg)是广泛应用的硫代嘌呤类药物的终末代谢产物，它吸收UVA，通过光敏作用产生(1)O2。这种不同寻常的光化学性质引发了多种DNA损伤，其中6-TG自身被(1)O2氧化为致突变产物鸟嘌呤-6-磺酸(G(SO3))是主要形式之一。在G(SO)进一步氧化为G(SO_2)和G(SO_3)之前，人们怀疑存在一个初始中间体G(SO)，但从未观察到G(SO)。用密度泛函理论研究了6-TG和(1)O2的能级和中间体。通过G(SOOH)→G(SO2)→G(SO4)→G(SO3)的新机制被发现是能量上最可行的，而预期的G(SO)机制被发现遇到了难以接近的高势垒，因此被阻止了。通过G(SOOH)和G(SO4)中间体的联合实验测量进一步验证了这一反应机理，其中S(-1)和S(-1)的快反应速率常数分别为4.9×10(9)M(-1)和0.5 8。除了G(SOOH)→G(SO2)→G(SO4)→G(SO3)的优势途径外，还定位了一条具有较高势垒的旁路G(SOOH)→G，从而合理地解释了G(SO2)和G(SO3)为主产物、G(SO3)为次要产物的产物分布。从机理和动力学的角度，本研究结果为理解6-TG在DNA中的高光毒性提供了新的化学见解，并指出了利用6-TG作为灵敏的荧光探针定量检测(1)O2的方法，这对于检测与DNA相关的生物环境中的(1)O2具有特殊的前景。
As an end metabolism product of the widely used thiopurine drugs, 6-thioguanine (6-TG) absorbs UVA and produces (1)O2 by photosensitization. This unusual photochemical property triggers a variety of DNA damage, among which the oxidation of 6-TG itself by (1)O2 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 (1)O2. 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 × 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 (1)O2, which holds particular promise for detecting (1)O2 in DNA-related biological surroundings.