Department of Chemistry, Wayne State University, 5101 Cass Ave, Detroit, MI, 48202, USA.
Institute for Molecules and Materials, FELIX Laboratory, Radboud University, Toernooiveld 7c, 6525ED, Nijmegen, The Netherlands.
J Am Soc Mass Spectrom. 2019 May;30(5):832-845. doi: 10.1007/s13361-019-02155-0. Epub 2019 Mar 8.
Modified nucleosides have been an important target for pharmaceutical development for the treatment of cancer, herpes simplex virus, and the human immunodeficiency virus (HIV). Amongst these nucleoside analogues, those based on 2',3'-dideoxyribose sugars are quite common, particularly in anti-HIV applications. The gas-phase structures of several protonated 2',3'-dideoxyribose nucleosides are examined in this work and compared with those of the analogous protonated DNA, RNA, and arabinose nucleosides to elucidate the influence of the 2'- and combined 2',3'-hydroxyl groups on intrinsic structure. Infrared multiple photon dissociation (IRMPD) action spectra are collected for the protonated 2',3'-dideoxy forms of adenosine, guanosine, cytidine, thymidine and uridine, [ddAdo+H], [ddGuo+H], [ddCyd+H], [ddThd+H], and [ddUrd+H], in the IR fingerprint and hydrogen-stretching regions. Molecular mechanics conformational searching followed by electronic structure calculations generates low-energy conformers of the protonated 2',3'-dideoxynucleosides and corresponding predicted linear IR spectra to facilitate interpretation of the measured IRMPD action spectra. These experimental IRMPD spectra and theoretical calculations indicate that the absence of the 2'- and 3'-hydroxyls largely preserves the protonation preferences of the canonical forms. The spectra and calculated structures indicate a slight preference for C3'-endo sugar puckering. The presence of the 3'- and further 2'-hydroxyl increases the available intramolecular hydrogen-bonding opportunities and shifts the sugar puckering modes for all nucleosides but the guanosine analogues to a slight preference for C2'-endo over C3'-endo. Graphical Abstract.
经修饰的核苷一直是癌症、单纯疱疹病毒和人类免疫缺陷病毒（HIV）治疗药物开发的重要目标。在这些核苷类似物中，基于 2'，3'-二脱氧核糖糖的核苷类似物非常常见，特别是在抗 HIV 应用中。本工作研究了几种质子化 2'，3'-二脱氧核糖核苷的气相结构，并将其与类似的质子化 DNA、RNA 和阿拉伯糖核苷进行比较，以阐明 2'-和组合 2'，3'-羟基对固有结构的影响。收集了质子化 2'，3'-二脱氧形式的腺苷、鸟苷、胞苷、胸腺嘧啶和尿嘧啶、[ddAdo+H]、[ddGuo+H]、[ddCyd+H]、[ddThd+H]和[ddUrd+H]的红外多光子解离（IRMPD）作用光谱，在红外指纹区和氢键伸缩区。分子力学构象搜索，然后进行电子结构计算，生成质子化 2'，3'-二脱氧核苷的低能构象和相应的预测线性红外光谱，以方便解释测量的 IRMPD 作用光谱。这些实验 IRMPD 光谱和理论计算表明，2'-和 3'-羟基的缺失在很大程度上保留了规范形式的质子化偏好。光谱和计算结构表明，C3'-endo 糖构象略有偏好。3'-和进一步的 2'-羟基的存在增加了所有核苷但鸟苷类似物的分子内氢键形成机会，并将糖构象模式从轻微偏向 C3'-endo 转变为轻微偏向 C2'-endo。
