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Unlocking P(V): Reagents for chiral phosphorothioate synthesis
Science ( IF 44.7 ) Pub Date : 2018-08-02 , DOI: 10.1126/science.aau3369
Kyle W. Knouse 1 , Justine N. deGruyter 1 , Michael A. Schmidt 2 , Bin Zheng 2 , Julien C. Vantourout 1 , Cian Kingston 1 , Stephen E. Mercer 3 , Ivar M. Mcdonald 3 , Richard E. Olson 3 , Ye Zhu 2 , Chao Hang 2 , Jason Zhu 2 , Changxia Yuan 2 , Qinggang Wang 2 , Peter Park 4 , Martin D. Eastgate 2 , Phil S. Baran 1
Affiliation  

A swift citrusy path to chiral phosphorus The phosphates in the backbones of DNA and RNA are often drawn like crosses but are in fact tetrahedral. Sulfur is sometimes substituted for one of the phosphate oxygens during development of nucleotide-based drugs. Because of the geometry, this swap can lead to two different isomers. Knouse et al. report a pair of phosphorus reagents that conveniently produce either isomer selectively. This ability depended on the configuration of appended limonene substituents that are subsequently jettisoned. In addition to simplifying the route to sulfur-substituted oligonucleotides, these reagents will enable more precise studies of each isomer's distinct bioactivity. Science, this issue p. 1234 Limonene-substituted phosphorus reagents offer a simplified and stereoselective route to nucleotide-based drug candidates. Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]–based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

中文翻译:

解锁 P(V):用于手性硫代磷酸酯合成的试剂

通向手性磷的快速柑橘路径 DNA 和 RNA 骨架中的磷酸盐通常画成十字形,但实际上是四面体。在基于核苷酸的药物开发过程中,硫有时会取代磷酸氧之一。由于几何形状,这种交换会导致两种不同的异构体。诺斯等人。报告了一对可以方便地选择性地产生任一异构体的磷试剂。这种能力取决于随后被抛弃的附加柠檬烯取代基的构型。除了简化硫取代寡核苷酸的路线外,这些试剂还可以更精确地研究每种异构体的不同生物活性。科学,这个问题 p。1234 柠檬烯取代的磷试剂为基于核苷酸的候选药物提供了一种简化的立体选择性途径。硫代磷酸核苷酸已成为其天然磷酸二酯类似物的强大药理学替代品,在反义寡核苷酸 (ASO) 治疗和环二核苷酸 (CDN) 合成中具有重要的转化应用。这种手性基序的立体控制安装长期以来一直受到基于磷(III)[P(III)]的试剂系统作为寡核苷酸组装唯一实用手段的系统使用的阻碍。本文描述了一种根本不同的方法:发明了一种基于 P(V) 的试剂平台,用于可编程、无痕、非对映选择性磷硫掺入。
更新日期:2018-08-02
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