Journal of Medicinal Chemistry p. 1606 - 1612 (1991)
Update date:2022-08-03
Topics:
Murakami
Shirasaka
Yoshioka
Kojima
Aoki
Ford Jr.
Driscoll
Kelley
Mitsuya
A series of 6-substituted 2',3'-dideoxypurine ribofuranosides (ddP) was enzymatically synthesized with live E. coli in an effort to enhance the lipophilicity of this class of anti-human immunodeficiency virus (HIV) compounds and thereby facilitate drug delivery into the central nervous system. All 6-halo-substituted ddPs were substantially more lipophilic, as defined by their octanol-water partition coefficient (P), than their nonhalogenated congeners 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG). For this class of compounds, log P's ranged from +0.5 to -1.2 in the following order: 6-iodo, 2-amino-6-iodo > 6-bromo, 2-amino-6-bromo > 6-chloro, 2-amino-6-chloro > 6-fluoro, 2-amino-6-fluoro >> ddG > ddI. These compounds were evaluated in vitro for ability to suppress the infectivity, replication, and cytopathic effect of HIV. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddP exhibited a potent activity against HIV comparable to that of ddI or ddG and completely blocked the infectivity of HIV without affecting the growth of target cells. The comparative order of in vitro anti-HIV activity was 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro > 2-amino-6-bromo > 2-amino-6-iodo, 6-chloro > 6-bromo > 6-iodo. These compounds also exhibited potent in vitro activity against HIV-2 and 3'-azido-3'-deoxythymidine-resistant HIV-1 variants. All 2-amino-6-halo-ddPs and 6-halo-ddPs were substrates for adenosine deaminase (ADA) and were converted to ddG or ddI, respectively. In the presence of the potent ADA inhibitor 2'-deoxycoformycin, 6-halo-substituted ddPs failed to exert an in vitro antiretroviral effect. These dideoxypurine nucleoside analogues represent a new class of lipophilic prodrugs of ddG and ddI that possess the potential for more effective therapy of HIV-induced neurologic disorders.
View MoreZhejiang Quzhou Jiancheng Silicone Co., Ltd.(Shanghai Jiancheng Industial and Trade Co, Ltd)
Contact:18957018777 +86-570-3888777
Address:The company production base address: Quzhou City, Zhejiang Province high-tech industrial park Nianhua Road 37
Dayang Chem (Hangzhou) Co.,Ltd.
website:http://www.dycnchem.com
Contact:+86-571-88938639
Address:9/F, Unit 2 Changdi Torch Building, 259# WenSan Road, Xihu District, Hangzhou City 310012, P.R.China
xi'an taima biological engineering co., ltd.
Contact:+8615619038117
Address:6 No,keji road xi'an city of china
Beijing Apis Biotechnology Co., Ltd.
Contact:86-010-67856775-8551
Address:NO.4PUHUANGYU ROAD,FENTAI DISTRICT, BEIJING, CHINA
website:http://www.mingchem.com/en/index
Contact:0519-85170101-802
Address:Fifth Floor,B of Beihua Buliding,520 Road of Science and Education City,Changwu middle road NO.801,Wujin District,Changzhou,Jiangsu province
Doi:10.1021/ol0256116
(2002)Doi:10.1246/cl.2011.967
(2011)Doi:10.1016/S0040-4020(01)00978-4
(2001)Doi:10.1016/S0957-4166(99)00484-X
(2000)Doi:10.1002/chem.200701679
(2008)Doi:10.1021/acs.inorgchem.9b02093
(2019)