Syntheses of 4-[1-(2-deoxy-β-D-ribofuranosyl)]-derivatives of 2-substituted-5-fluoroaniline:: "cytosine replacement" analogs of deoxycytidine for evaluation as anticancer and antihuman immunodeficiency virus (anti-HIV) agents

被引:19
|
作者
Wang, ZX
Wiebe, LI
De Clercq, E
Balzarini, J
Knaus, EE [1 ]
机构
[1] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada
[2] Rega Inst Med Res, B-3000 Louvain, Belgium
来源
CANADIAN JOURNAL OF CHEMISTRY-REVUE CANADIENNE DE CHIMIE | 2000年 / 78卷 / 08期
关键词
fluoroanilines; deoxycytidine mimics; anticancer-antihuman immunodeficiency virus (HIV) evaluation;
D O I
10.1139/cjc-78-8-1081
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
A group of 4-[1-(2-deoxy-beta-D-ribofuranosyl)]-derivatives of 5-fluoroaniline possessing a variety of aryl C-2 substituents (6a R = H, 6b R = F, 6c R = Me) were synthesized. Accordingly, a Heck-type coupling reaction of the 4-iodoaniline derivatives (13a-c) with the bis(tert-butyldimethylsilyl)glycal (11) in the presence of Pd(OAc)(2) and Ph3As, followed by removal of the tert-butyldimethylsilyl protection groups using n-Bu4N+F-, yielded the corresponding 4-(beta-D-glycero-pentofuran-3-ulos-1-yl)aniline derivatives (14a-c) having a C-3 C=O in the sugar ring. Reduction of the C-3 C=O compounds (14a-c) using NaB(OAc)(3)H afforded the target 4-[1-(2-deoxy-beta-D-ribofuranosyl)]-derivatives of the respective 2-substituted-5-fluoroaniline (6a-c). The deoxycytidine mimic, 3-fluoro-4-[1-(2-deoxy-beta-D-ribofuranosyl)]aniline (6a), in which the cytosine ring of deoxycytidine is replaced by a 4-(3-fluoroaniline) ring system, was inactive as an anticancer agent against a variety of tumor cell lines, and as an antihuman immunodeficiency virus (HIV-1, HIV-2) agent. The failure of this unnatural deoxycytidine mimic (6a) to exhibit anticancer-antiviral activity may be due to its inability to undergo phosphorylation by host cell- and virus-induced kinases.
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页码:1081 / 1088
页数:8
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