保护基介导的C4'-甲基化尿苷类似物的非对映选择性合成及其对人呼吸道合胞病毒的活性

Protecting-Group-Mediated Diastereoselective Synthesis of C4'-Methylated Uridine Analogs and Their Activity against the Human Respiratory Syncytial Virus.

作者信息

Köllmann Christoph, Sake Svenja M, Jones Peter G, Pietschmann Thomas, Werz Daniel B

机构信息

Technische Universität Braunschweig, Institute for Organic Chemistry, Hagenring 30, 38106 Braunschweig, Germany.

Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture Between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Feodor-Lynen-Str. 7, 30625 Hannover, Germany.

出版信息

J Org Chem. 2020 Mar 20;85(6):4267-4278. doi: 10.1021/acs.joc.9b03425. Epub 2020 Feb 26.

DOI:10.1021/acs.joc.9b03425

PMID:32036652

Abstract

Adjusting the protecting group strategy, from an alkyl ether to a bidentate ketal at the carbohydrate backbone of uridine, facilitates a switchable diastereoselective α- or β-C4'/C5'-spirocyclopropanation. Using these spirocyclopropanated nucleosides as key intermediates, we synthesized a variety of C4'-methylated d-ribose and l-lyxose-configured uridine derivatives by a base-mediated ring-opening of the spirocyclopropanol moiety. Investigations of antiviral activity against the human respiratory syncytial virus were carried out for selected derivatives, showing moderate activity.

摘要

调整保护基策略，即在尿苷的碳水化合物主链上从烷基醚变为双齿缩酮，有助于实现可切换的非对映选择性α-或β-C4'/C5'-螺环丙烷化。以这些螺环丙烷化的核苷为关键中间体，我们通过碱介导的螺环丙醇部分的开环反应，合成了多种具有C4'-甲基化的d-核糖和l-来苏糖构型的尿苷衍生物。对选定的衍生物进行了针对人呼吸道合胞病毒的抗病毒活性研究，结果显示其具有中等活性。