Assignment of absolute configurations of the enantiomeric spiroiminodihydantoin nucleobases by experimental and computational optical rotatory dispersion methods
Assignment of absolute configurations of the enantiomeric spiroiminodihydantoin nucleobases by experimental and computational optical rotatory dispersion methods
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DOI：
10.1021/tx060078e
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发表时间：
2006-07-17
影响因子：
4.1
通讯作者：
Geacintov, Nicholas E.
中科院分区：
文献类型：
--
作者：
Durandin, Alexander;Jia, Lei;Geacintov, Nicholas E.
非对映体螺亚氨基二乙内酰脲（Sp）损伤是鸟嘌呤和8-氧代-7，8-二氢鸟嘌呤（8-氧代G）的氧化产物，并且由于它们在体内的立体化学依赖性诱变性质而引起了相当大的兴趣（亨德森，P.T.，等人（2003）Biochemistry 42，9257- 9262）。然而，两种非对映异构体的绝对构型尚未阐明，并且此类信息可证明对于理解DNA水平上的生物学功能与结构之间的关系是有价值的（Jia，L.，Shafirovich，V.，夏皮罗河，Geacintov，N. E、和Broyde，S.（2005）Biochemistry 44，13342-13353）。我们已经合成了两个手性Sp核苷水解dSp 1和dSp 2表示根据其洗脱顺序在HPLC实验中使用Hypercarb柱，并确定其绝对配置使用的组合实验测量的旋光色散（ORD）光谱在水溶液中和计算的ORD比旋光度使用密度泛函理论（DFT）。最近的发展已经表明，DFT方法现在对于预测手性分子的ORD值是足够稳健的（Polavarapu，P.L.（2002）Chirality 14，768-781）。核碱基Sp1和Sp2表现出实验测量的CD和ORD光谱，其在形状和符号上非常接近于相应的前体核苷dSp 1和dSp 2的CD和ORD光谱。来自典型Hypercarb HPLC柱的第一个核苷立体异构体（dSp 1）至dSp 2具有（-）-S，而第二个（dSp 2）具有（+）-R绝对构型。在每种情况下，R和S分配适用于氨基互变异构形式。
The diastereomeric spiroiminodihydantoin (Sp) lesions are oxidation products of guanine and 8-oxo-7,8-dihydroguanine (8-oxoG) and have generated considerable interest because of their stereochemistry-dependent mutagenic properties in vivo (Henderson, P. T., et al. ( 2003) Biochemistry 42, 9257- 9262). However, the absolute configurations of the two diastereomers have not yet been elucidated, and such information may prove valuable for understanding relationships between biological function and structure at the DNA level (Jia, L., Shafirovich, V., Shapiro, R., Geacintov, N. E., and Broyde, S. (2005) Biochemistry 44, 13342-13353). We have synthesized the two chiral Sp nucleobases by hydrolysis of the nucleosides denoted by dSp1 and dSp2 according to their elution order in HPLC experiments using a Hypercarb column, and determined their absolute configurations using a combination of experimentally measured optical rotatory dispersion (ORD) spectra in aqueous solutions and computed ORD specific rotations using density functional theory (DFT). Recent developments have shown that DFT methods are now sufficiently robust for predicting ORD values of chiral molecules (Polavarapu, P. L. (2002) Chirality 14, 768-781). The nucleobases Sp1 and Sp2 exhibit experimentally measured CD and ORD spectra that are very close to those of the respective precursor nucleosides dSp1 and dSp2 in shape and sign. The first nucleoside stereoisomer (dSp1) to elute from a typical Hypercarb HPLC column has (-)-S, while the second (dSp2) has (+)-R absolute configuration. The R and S assignments are applicable to the amino tautomeric forms in each case.