Journal of Medicinal Chemistry p. 2195 - 2201 (1992)
Update date:2022-08-05
Topics:
Siddiqui
Driscoll
Marquez
Roth
Shirasaka
Mitsuya
Barchi Jr.
Kelley
The synthesis, chemistry, biochemistry, and anti-HIV activity of a series of 1-(2,3-dideoxy-2-fluoro-β-D-threo-pentofuranosyl)pyrimidines have been studied in an attempt to find useful anti-AIDS drugs. Synthesis is carried out via a 2,3-dideoxyribose intermediate which facilitates the preparation of analogues by removing the sugar 3'-hydroxyl group prior to, rather than after, condensation with a uracil or cytosine aglycon. The 2'-F-dd-uridine analogues 7a-d (with H, F, Cl, and CH3 substitution in the 5-position) as well as the 4-deoxy compound (12b) are nonprotective to ATH8 or CEM cells infected with HIV-1. In the corresponding cytidine series, the 5-chloro analogue (11) is inactive. However, 2'-fluoro-2',3'- dideoxyarabinosylcytosine, 10a, and its 5-fluoro analogue, 10b, are both active. While neither compound is as potent as ddC or 5-F-ddC (2b), 10b gives complete protection against the cytopathic effects of HIV in both host cell lines. 2'-Fluoro substitution confers increased chemical and enzymatic stability on dideoxynucleosides. Even though dideoxy pyrimidine nucleosides are inherently more stable than the corresponding purine analogues toward acid-catalyzed cleavage of the glycosidic bond, 2'-fluoro substitution (10a) still increases stabilization relative to ddC (2b). No detectable deamination by partially purified cytidine deaminase is observed with the 2'-fluoro compounds 10a, 10b, or 11 under conditions which rapidly deaminate cytidine. A small amount of 2'-F-dd-ara-U (7a) is formed from 10a in monkey plasma after >24 h of exposure. The octanol-water partition coefficients for the dideoxynucleosides in this study indicate their hydrophilic character, with log P values varying from -0.28 to -1.18.
View MoreTaizhou Chenyi chemical co. LTD,
Contact:13736652831
Address:NO.273 SHANGHAI SOUTH STREET,LUQIAO DISTRICT,ZHEJIANG PROVINCE,CHINA.
Qingdao Pana-Life Biochem Co.,Ltd.
Contact:86-532-87683902
Address:No.967 Dalao Road, Licang Zone, Qingdao City,Shandong, China 266021
Wuhan Better Organic Technology Inc.
Contact:13307163183
Address:Wuhan Economic&Technology Development Zone, Hubei
JIAXING SUNS INTERNATIONAL TRADE CO LTD
Contact:18367306858
Address:No.123,Huixin Avenue,Huimin Dist
Contact:86-21-50966856
Address:Building 5,300 Chuanzhan Road,Pudong New District,Shanghai
Doi:10.1016/j.tetlet.2006.08.020
(2006)Doi:10.1021/ja064460p
(2006)Doi:10.1007/BF00513848
(1984)Doi:10.1080/00397911.2018.1434205
(2018)Doi:10.1246/bcsj.57.1058
(1984)Doi:10.3390/11020148
(2006)