Choi Sunhee, Cooley Richard B, Voutchkova Adelina, Leung Chin Hin, Vastag Livia, Knowles Darcy E
Department of Chemistry and Biochemistry, Middlebury College, Middlebury, VT 05753, USA.
J Am Chem Soc. 2005 Feb 16;127(6):1773-81. doi: 10.1021/ja045194n.
Many transition-metal complexes mediate DNA oxidation in the presence of oxidizing radiation, photosensitizers, or oxidants. The DNA oxidation products depend on the nature of the metal complex and the structure of the DNA. Earlier we reported trans-d,l-1,2-diaminocyclohexanetetrachloroplatinum (trans-Pt(d,l)(1,2-(NH(2))(2)C(6)H(10))Cl(4), [Pt(IV)Cl(4)(dach)]; dach = diaminocyclohexane) oxidizes 2'-deoxyguanosine 5'-monophosphate (5'-dGMP) to 7,8-dihydro-8-oxo-2'-deoxyguanosine 5'-monophosphate (8-oxo-5'-dGMP) stoichiometrically. In this paper we report that [Pt(IV)Cl(4)(dach)] also oxidizes 2'-deoxyguanosine 3'-monophosphate (3'-dGMP) stoichiometrically. The final oxidation product is not 8-oxo-3'-dGMP, but cyclic (5'-O-C8)-3'-dGMP. The reaction was studied by high-performance liquid chromatography, (1)H and (31)P nuclear magnetic resonance, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The proposed mechanism involves Pt(IV) binding to N7 of 3'-dGMP followed by nucleophilic attack of a 5'-hydroxyl oxygen to C8 of G and an inner-sphere, 2e(-) transfer to produce cyclic (5'-O-C8)-3'-dGMP and [Pt(II)Cl(2)(dach)]. The same mechanism applies to 5'-d[GTTTT]-3', where the 5'-dG is oxidized to cyclic (5'-O-C8)-dG. The Pt(IV) complex binds to N7 of guanine in cGMP, 9-Mxan, 5'-d[TTGTT]-3', and 5'-d[TTTTG]-3', but no subsequent transfer of electrons occurs in these. The results indicate that a good nucleophilic group at the 5' position is required for the redox reaction between guanosine and the Pt(IV) complex.
许多过渡金属配合物在存在氧化辐射、光敏剂或氧化剂的情况下介导DNA氧化。DNA氧化产物取决于金属配合物的性质和DNA的结构。早些时候我们报道反式 - d，l - 1，2 - 二氨基环己烷四氯铂（反式 - Pt(d，l)(1，2 - (NH₂)₂C₆H₁₀)Cl₄，[Pt(IV)Cl₄(dach)]；dach = 二氨基环己烷）化学计量地将2'-脱氧鸟苷5'-单磷酸（5'-dGMP）氧化为7，8 - 二氢 - 8 - 氧代 - 2'-脱氧鸟苷5'-单磷酸（8 - 氧代 - 5'-dGMP）。在本文中我们报道[Pt(IV)Cl₄(dach)]也化学计量地氧化2'-脱氧鸟苷3'-单磷酸（3'-dGMP）。最终氧化产物不是8 - 氧代 - 3'-dGMP，而是环状（5'-O - C8）- 3'-dGMP。通过高效液相色谱、¹H和³¹P核磁共振以及基质辅助激光解吸电离飞行时间质谱对该反应进行了研究。提出的机制涉及Pt(IV)与3'-dGMP的N7结合，随后5'-羟基氧对G的C8进行亲核攻击以及内球2e⁻转移以产生环状（5'-O - C8）- 3'-dGMP和[Pt(II)Cl₂(dach)]。相同的机制适用于5'-d[GTTTT]-3'，其中5'-dG被氧化为环状（5'-O - C8）- dG。Pt(IV)配合物与cGMP、9 - Mxan、5'-d[TTGTT]-3'和5'-d[TTTTG]-3'中的鸟嘌呤的N7结合，但在这些情况下不会发生随后的电子转移。结果表明鸟苷与Pt(IV)配合物之间的氧化还原反应需要在5'位置有一个良好的亲核基团。
