Barchi Joseph J, Karki Rajeshri G, Nicklaus Marc C, Siddiqui Maqbool A, George Clifford, Mikhailopulo Igor A, Marquez Victor E
Laboratory of Medicinal Chemistry, National Cancer Institute, Frederick, National Institutes of Health, 376 Boyles Street, P.O. Box B, Frederick, Maryland 21702, USA.
J Am Chem Soc. 2008 Jul 16;130(28):9048-57. doi: 10.1021/ja800964g. Epub 2008 Jun 18.
The conformations of three 2',3'-difluoro uridine nucleosides were studied by X-ray crystallography, NMR spectroscopy, and ab initio calculations in an attempt to define the roles that the two vicinal fluorine atoms play in the puckering preferences of the furanose ring. Two of the compounds examined contained fluorine atoms in either the arabino or xylo dispositions at C2' and C3' of a 2',3'-dideoxyuridine system. The third compound also incorporated fluorine atoms in the xylo configuration on the furanose ring but was substituted with a 6-azauracil base in place of uracil. A battery of NMR experiments in D 2O solution was used to identify conformational preferences primarily from coupling constant and NOE data. Both (1)H and (19)F NMR data were used to ascertain the preferred sugar pucker of the furanose ring through the use of the program PSEUROT. Compound-dependent parameters used in the PSEUROT calculations were newly derived from complete sets of conformations calculated from high-level ab initio methods. The solution and theoretical data were compared to the conformations of each molecule in the solid state. It was shown that both gauche and antiperiplanar effects may be operative to maintain a pseudodiaxial arrangement of the C2' and C3' vicinal fluorine atoms. These data, along with previously reported data by us and others concerning monofluorinated nucleoside conformations, were used to propose a model of how fluorine influences different aspects of nucleoside conformations.
通过X射线晶体学、核磁共振光谱和从头算计算研究了三种2',3'-二氟尿苷核苷的构象，旨在确定两个邻位氟原子在呋喃糖环的褶皱偏好中所起的作用。所研究的两种化合物在2',3'-二脱氧尿苷系统的C2'和C3'处的阿拉伯糖或木糖构型中含有氟原子。第三种化合物在呋喃糖环上也含有木糖构型的氟原子，但用6-氮杂尿嘧啶碱基取代了尿嘧啶。在D2O溶液中进行了一系列核磁共振实验，主要从耦合常数和NOE数据中确定构象偏好。1H和19F核磁共振数据均用于通过使用PSEUROT程序确定呋喃糖环的优选糖环构象。PSEUROT计算中使用的化合物相关参数是新从由高水平从头算方法计算得到的完整构象集中推导出来的。将溶液和理论数据与每个分子在固态下的构象进行了比较。结果表明，gauche效应和反式共平面效应可能都起作用，以维持C2'和C3'邻位氟原子的假双轴排列。这些数据，连同我们和其他人先前报道的关于单氟核苷构象的数据，被用于提出一个氟如何影响核苷构象不同方面的模型。
