Guo Xiurong, Leonard Peter, Ingale Sachin A, Seela Frank
Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology, Heisenbergstraße 11, 48149, Münster, Germany.
Laboratorium für Organische und Bioorganische Chemie, Institut für Chemie neuer Materialien, Universität Osnabrück, Barbarastraße 7, 49069, Osnabrück, Germany.
Chemistry. 2017 Dec 14;23(70):17740-17754. doi: 10.1002/chem.201703427. Epub 2017 Nov 22.
The stability of silver-mediated "dC-dC" base pairs relies not only on the structure of the nucleobase, but is also sensitive to structural modification of the sugar moiety. 2'-Fluorinated 2'-deoxycytidines with fluorine atoms in the arabino (up) and ribo (down) configuration as well as with geminal fluorine substitution (anticancer drug gemcitabine) and the novel fluorescent phenylpyrrolo-gemcitabine ( PyrGem) have been synthesized. All the nucleosides display the recognition face of naturally occurring 2'-deoxycytidine. The nucleosides were converted into phosphoramidites and incorporated into 12-mer oligonucleotides by solid-phase synthesis. The addition of silver ions to DNA duplexes with a fluorine-modified "dC-dC" pair near the central position led to significant duplex stabilization. The increase in stability was higher for duplexes with fluorinated sugar residues than for those with an unchanged 2'-deoxyribose moiety. Similar observations were made for "dC-dT" pairs and to a minor extent for "dC-dA" pairs. The increase in silver ion mediated base-pair stability was reversed by annulation of a pyrrole ring to the cytosine moiety, as shown for 2'-fluorinated PyrGem in comparison with phenylpyrrolo-dC ( PyrdC). This phenomenon results from stereoelectronic effects induced by fluoro substitution, which are transmitted from the sugar moiety to the silver ion mediated base pairs. The extent of the effect depends on the number of fluorine substituents, their configuration, and the structure of the nucleobase.
银介导的“dC-dC”碱基对的稳定性不仅取决于核碱基的结构，还对糖部分的结构修饰敏感。已合成了具有阿拉伯糖（向上）和核糖（向下）构型的氟原子的2'-氟化2'-脱氧胞苷，以及具有偕二氟取代的（抗癌药物吉西他滨）和新型荧光苯基吡咯-吉西他滨（PyrGem）。所有核苷都呈现出天然存在的2'-脱氧胞苷的识别面。这些核苷被转化为亚磷酰胺，并通过固相合成掺入12聚体寡核苷酸中。向中心位置附近具有氟修饰的“dC-dC”对的DNA双链体中添加银离子导致双链体显著稳定。与具有未改变的2'-脱氧核糖部分的双链体相比，具有氟化糖残基的双链体稳定性增加更高。对于“dC-dT”对也有类似观察结果，而对于“dC-dA”对则在较小程度上有此现象。与苯基吡咯-dC（PyrdC）相比，如2'-氟化的PyrGem所示，通过在胞嘧啶部分环化吡咯环可逆转银离子介导的碱基对稳定性的增加。这种现象是由氟取代诱导的立体电子效应引起的，该效应从糖部分传递到银离子介导的碱基对。效应的程度取决于氟取代基的数量、它们的构型以及核碱基的结构。
