α-L-2'-去氧呋喃核苷的合成及抗病毒活性评价

Synthesis and antiviral evaluation of α-L-2'-deoxythreofuranosyl nucleosides.

机构信息

Laboratory for Medicinal Chemistry, FFW, UGent, Harelbekestraat 72, 9000 Gent, Belgium.

出版信息

Eur J Med Chem. 2011 Sep;46(9):3704-13. doi: 10.1016/j.ejmech.2011.05.036. Epub 2011 May 20.

DOI:10.1016/j.ejmech.2011.05.036

Abstract

The synthesis of a series of α-L-2'-deoxythreofuranosyl nucleosides featuring the nucleobases A, T, C and U is described in seven steps from 1,2-O-isopropyledene-α-L-threose, involving a Vorbrüggen coupling and a Barton-McCombie deoxygenation protocol as the key steps. All analogues, including a phosphoramidate nucleoside phosphate prodrug of the T analogue, were evaluated against a broad panel of different viruses but found inactive, while also lacking notable cellular toxicity. The thymidine analogue showed inhibition to mitochondrial thymidine kinase-2 (TK-2), herpes simplex virus type 1 (HSV-1) TK, varicella-zoster virus (VZV) TK and Mycobacterium tuberculosis thymidylate kinase.

摘要

本文描述了一系列 α-L-2'-去氧胸苷核苷的合成，这些核苷以 A、T、C 和 U 为碱基，从 1,2-O-异丙叉-α-L-苏糖醇出发，经过 Vorbrüggen 偶联和 Barton-McCombie 脱氧步骤，共七个步骤完成。所有的类似物，包括 T 类似物的磷酰胺核苷磷酸前药，都针对多种不同的病毒进行了评估，但没有发现活性，同时也没有明显的细胞毒性。胸苷类似物对线粒体胸苷激酶-2（TK-2）、单纯疱疹病毒 1 型（HSV-1）TK、水痘带状疱疹病毒（VZV）TK 和结核分枝杆菌胸苷酸激酶有抑制作用。