一系列新型1,5-脱水己糖醇核苷的合成、生物学评价及结构分析

Synthesis, biological evaluation, and structure analysis of a series of new 1,5-anhydrohexitol nucleosides.

作者信息

Verheggen I, Van Aerschot A, Van Meervelt L, Rozenski J, Wiebe L, Snoeck R, Andrei G, Balzarini J, Claes P, De Clercq E

机构信息

Laboratory of Pharmaceutical Chemistry, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.

出版信息

J Med Chem. 1995 Mar 3;38(5):826-35. doi: 10.1021/jm00005a010.

DOI:10.1021/jm00005a010

PMID:7877148

Abstract

In view of the selective anti-HSV activity of 1,5-anhydro-2,3-dideoxy-2- (5-iodouracil-1-yl)-D-arabino-hexitol, a series of novel 1,5-anhydrohexitol nucleosides were synthesized and evaluated for their inhibitory activity against several viruses. The 5-iodouracil 3 and the 5-ethyluracil 4 derivatives are highly selective TK-dependent inhibitors of HSV-1 and HSV-2. Broad anti-herpes virus activity was noticed for 5-fluorocytosine 6 and 2,6-diaminopurine 10 analogues. From a transport study of 3, using the thymidine influx competition method, one can conclude that intracellular uptake of this compound most probably occurs by passive diffusion. X-ray analysis of compounds 3 and 9 showed that the heterocyclic base of 1,5-anhydrohexitol pyrimidine and purine is placed in the axial position and that the sugar ring adopts a slightly distorted chair conformation.

摘要

鉴于1,5-脱水-2,3-二脱氧-2-(5-碘尿嘧啶-1-基)-D-阿拉伯己糖醇具有选择性抗单纯疱疹病毒（HSV）活性，合成了一系列新型1,5-脱水己糖醇核苷，并对其抗几种病毒的活性进行了评估。5-碘尿嘧啶3和5-乙基尿嘧啶4衍生物是HSV-1和HSV-2高度选择性的胸苷激酶（TK）依赖性抑制剂。5-氟胞嘧啶6和2,6-二氨基嘌呤10类似物具有广泛的抗疱疹病毒活性。通过使用胸苷流入竞争法对3进行转运研究，可以得出结论，该化合物的细胞内摄取很可能通过被动扩散发生。化合物3和9的X射线分析表明，1,5-脱水己糖醇嘧啶和嘌呤的杂环碱基处于轴向位置，糖环采用略微扭曲的椅式构象。