Nonionic analogs of RNA with dimethylene sulfone bridges
Nonionic analogs of RNA with dimethylene sulfone bridges
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DOI：
10.1021/ja952322m
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发表时间：
1996-05-15
影响因子：
15
通讯作者：
Benner, SA
中科院分区：
文献类型：
--
作者：
Richert, C;Roughton, AL;Benner, SA
已经合成了RNA的类似物，其中每个磷酸二酯连接基团被二亚甲基砜单元（RNA的砜连接的核酸类似物，或“rSNA”）取代。这些是第一个完全非离子的RNA类似物被制备为寡聚体。从双丙酮D-葡萄糖制备的作为结构单元的3 '，5'-双高-β-核糖核苷衍生物制备了导致八聚体5 '-r（A（SO2）U（SO2）G（SO2）U（SO2）C（SO2）-A（SO2）U）-3'的序列，并探索了它们的化学性质。在溶液中通过来自一个片段的硫醇和来自另一个片段的溴化物之间的S（N）2反应进行偶联，将所得硫醚氧化成砜，并将末端伯羟基脱保护并在仲羟基存在下将其区域选择性转化成活性基团（硫醇或溴化物）以产生用于偶联的另一个片段。碱基不稳定的保护基团用于核碱基，并且使用IM NaOH实现一步完全脱保护。通过NMR、UV光谱和质谱对目标八聚体和每个分离的中间体进行表征。虽然涉及较长rSNA的化学反应在几种情况下相对于与单体的类似反应被延迟，但某些速率被增强。在水中，rSNA八聚体在高于65 ° C的UV光谱中显示出热转变，具有大的增色性。rSNA的行为表明DNA和RNA中的聚阴离子骨架的作用超出了其赋予水溶性的作用。天然寡核苷酸中重复的阴离子电荷显然也控制了这些功能丰富的分子的有效分子识别特性，将链-链相互作用引导到远离骨架的生物聚合物部分（核碱基的沃森-克里克边缘），使聚合物有利于延伸构象，并确保寡核苷酸的物理特性在很大程度上与其序列无关。这表明通常必须构建到非离子寡核苷酸类似物中的结构特征。
Analogs of RNA have been synthesized where each of the phosphodiester linking groups is replaced by dimethylene sulfone units (sulfone-linked nucleic acid analogs of RNA, or ''rSNAs''). These are the first fully nonionic analogs of RNA to be prepared as oligomers. Sequences leading to the octamer 5'-r(A(SO2)U(SO2)G(SO2)U(SO2)C(SO2)-A(SO2)U)-3' have been prepared from 3',5'-bishomo-beta-ribonucleoside derivatives as building blocks prepared from diacetone D-glucose, and their chemistry has been explored. Coupling was performed in solution via S(N)2 reactions between a thiol from one fragment and a bromide from the other, oxidation of the resulting thioether to the sulfone, and deprotection of a terminal primary hydroxyl group and regioselective conversion of it-in the presence of secondary hydroxyl groups--to an active group (thiol or bromide) to yield another fragment for coupling. Base-labile protecting groups were used for the nucleobases, and one-step full deprotection was achieved using 1 M NaOH. The target octamer and each isolated intermediate were characterized by NMR, UV spectroscopy, and mass spectrometry. While chemical reactions involving longer rSNAs were in several cases retarded relative to analogous reactions with monomers, some rates were enhanced. In water, the rSNA octamer displayed a thermal transition in the UV spectrum above 65 degrees C with a large hyperchromicity. The behaviors of rSNAs suggest roles for the polyanionic backbone in DNA and RNA beyond its role in conferring aqueous solubility. The repeating anionic charges in natural oligonucleotides evidently also control the potent molecular recognition properties of these richly functionalized molecules, direct strand-strand interactions to the part of the biopolymer distant from the backbone (the Watson-Crick edge of the nucleobases), cause the polymer to favor an extended conformation, and ensure that the physical properties of the oligonucleotide are largely independent of its sequence. This suggests structural features that must be built into nonionic oligonucleotide analogs generally.