Impact of the 2′- and 3′-Sugar Hydroxyl Moieties on Gas-Phase Nucleoside Structure
Impact of the 2′- and 3′-Sugar Hydroxyl Moieties on Gas-Phase Nucleoside Structure
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DOI：
10.1007/s13361-019-02155-0
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发表时间：
2019-03
影响因子：
3.2
通讯作者：
L. Hamlow;Zachary J. Devereaux;H. Roy;N. A. Cunningham;G. Berden;J. Oomens;M. Rodgers
中科院分区：
文献类型：
--
作者：
L. Hamlow;Zachary J. Devereaux;H. Roy;N. A. Cunningham;G. Berden;J. Oomens;M. Rodgers
修饰的核苷已经成为用于治疗癌症、单纯疱疹病毒和人类免疫缺陷病毒（HIV）的药物开发的重要靶标。在这些核苷类似物中，基于2′，3 ′-双脱氧核糖的核苷类似物非常常见，特别是在抗HIV应用中。本文研究了几种质子化2′，3 ′-双脱氧核苷的气相结构，并与类似的质子化DNA、RNA和阿拉伯糖核苷的气相结构进行了比较，以阐明2′-羟基和结合的2′，3 ′-羟基对固有结构的影响。收集了腺苷、鸟苷、胞苷、胸苷和尿苷的质子化2′，3 ′-双脱氧形式[ddAdo+H]+、[ddGuo+ H]+、[ddCyd+H]+、[ddThd +H]+和[ddUrd+H]+的红外多光子解离（IRMPD）作用光谱，其红外指纹区和氢伸缩区的红外多光子解离（IRMPD）作用光谱。通过分子力学构象搜索和电子结构计算，生成质子化2′，3 ′-双脱氧核苷的低能构象和相应的预测线性红外光谱，以便于解释测量的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标准形式的质子化偏好。光谱和计算的结构表明C3′-内糖起皱的轻微偏好。3′-羟基和2′-羟基的存在增加了分子内氢键的机会，并使除鸟苷类似物以外的所有核苷的糖折叠模式略微偏向于C2′-内而不是C3′-内。
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′-endosugar 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′-endoover C3′-endo.