SYNTHESIS AND IN VITRO ANTI-HIV ACTIVITY OF LIPOPHILIC DIDEOXYNUCLEOSIDES

2-氨基-6-卤代-2‘，3’-二脱氧并呋喃核苷(6-Halo-DDGS) 卤代-DDPS(6-Halo-ddls)已被证明能抑制传染性， 艾滋病毒的复制和细胞病变效应(Shirasaka等人)。程序娜塔莉。 阿卡德。SCI。美国。87：9426-9430,1990)。2-氨基-6-氟-，2- 氨基-6-氯-和6-氟-DDPS显示出较强的抗HIV活性 与2‘，3’-二脱氧肌苷(DDL)或 2‘，3’-二脱氧鸟苷(DDG)，并完全阻断病毒的感染性。 在不影响靶细胞生长的情况下感染艾滋病毒。这些化合物具有 还显示出对HIV-2和耐AZT的HIV-1的有效活性 试管中的变种。几种含有6-卤素的DDP已经被 被发现有很强的亲脂性。亲脂性顺序 是：2-氨基-6-碘大于2-氨基-6-溴 2-氨基-6-氯大于2-氨基-6-氟 DDG大于DDI，对数P的范围从+0.5到-1.2。全部八个 腺苷脱氨酶(ADA)的底物为含6-卤素的DDPS。 在ADA抑制剂2‘-脱氧考福霉素存在下，ALL 含6-卤素的DDPS未能发挥其体外抗逆转录病毒作用 效果。

2-Amino-6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddGs) and 6- halo-ddPs (6-halo-ddls) have been shown to suppress the infectivity, replication and cytopathic effect of HIV (Shirasaka et al. Proc. Natl. Acad. Sci. USA. 87:9426-9430, 1990). 2-Amino-6-fluoro-, 2-- amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddl) or 2',3'-dideoxyguanosine (ddG), and completely blocked the infectivity of HIV without affecting the growth of target cells. These compounds have also shown a potent activity against HIV-2 and AZT-resistant HIV-1 variants in vitro. Several of the 6-halogen-containing ddPs have been found to have substantial lipophilic character. The lipophilicity order was: 2-amino-6-iodo is greater than 2-amino-6-bromo is greater than 2-amino-6-chloro is greater than 2-amino-6-fluoro is much greater than ddG is greater than ddI with a log P range from +0.5 to -1.2. All eight 6-halogen-containing ddPs were substrates for adenosine deaminase (ADA). In the presence of an ADA-inhibitor, 2'deoxycoformycin, all 6-halogen-containing ddPs failed to exert their in vitro antiretroviral effects.