具有抗病毒和细胞毒性活性的5-[1-羟基（或甲氧基）-2-溴（或氯）乙基]-2'-脱氧尿苷及相关卤代醇类似物的合成。

Synthesis of 5-[1-hydroxy(or methoxy)-2-bromo(or chloro)ethyl]-2'-deoxyuridines and related halohydrin analogues with antiviral and cytotoxic activity.

作者信息

Kumar R, Wiebe L I, Hall T W, Knaus E E, Tovell D R, Tyrrell D L, Allen T M, Fathi-Afshar R

机构信息

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.

出版信息

J Med Chem. 1989 May;32(5):941-4. doi: 10.1021/jm00125a003.

DOI:10.1021/jm00125a003

PMID:2709380

Abstract

A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2'-(deoxyuridines (4a,b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl) (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 microgram/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2'-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 micrograms/mL relative to melphalan (ED50 = 0.15 micrograms/mL).

摘要

通过将HOX（X = Br、Cl、I）加成到相应的5-乙烯基-2'-脱氧尿苷（2、5、7）的乙烯基取代基上，以60 - 70%的产率合成了一系列新的5-(1-羟基-2-卤代乙基)-2'-脱氧尿苷（3、6、8）。用甲醇硫酸处理3a、b得到相应的5-(1-甲氧基-2-卤代乙基)-2'-(脱氧尿苷（4a、b）。5-(1-羟基-2-氯乙基)（3b）、5-(1-甲氧基-2-溴乙基)（4a）、5-(1-羟基-2-溴-2-(乙氧羰基)乙基)（6a）和5-(1-羟基-2-碘-2-(乙氧羰基)乙基)（6b）衍生物对1型单纯疱疹病毒（HSV-1）表现出体外抗病毒活性（ID50 = 0.1 - 1微克/毫升范围）。5-(1-羟基-2-溴-2-(乙氧羰基)乙基)-2'-脱氧尿苷（6a）是体外L1210筛选中最具活性的细胞毒剂，相对于美法仑（ED50 = 0.15微克/毫升），其ED50为11微克/毫升。