LIPOPHILIC DIDEOXYNUCLEOSIDE DERIVATIVES ACTIVE AGAINST HIV IN VITRO

4个2-氨基-6-卤代和4个6-卤代-2'，3'-二脱氧嘌呤呋喃核糖苷 (ddP)合成并测试体外活性以抑制 感染性、细胞病变效应、gag蛋白表达和DNA合成 艾滋病病毒。八种化合物体外抗HIV活性的比较顺序 6-卤代-ddPs为：2-氨基-6-氟，2-氨基-6-氯，6-氟，2-氨基- 6-溴> 2-氨基-6-碘，6-氯> 6-溴> 6-碘。2-氨基-6-氟-， 2-氨基-6-氯-和6-氟-DDP显示出有效的抗HIV活性 与2 '，3'-双脱氧肌苷（ddI）或2'，3'-双脱氧鸟苷- (ddG)，并完全阻断了艾滋病毒的传染性，而不影响 靶细胞的生长。亲脂性顺序为：2-氨基-6-碘> 2-氨基-6-碘 氨基-6-溴> 2-氨基-6-氯> 2-氨基-6-氟>> ddG> ddl。所有八 6-卤代-DDP是腺苷脱氨酶（ADA）的底物。的相对 ADA的水解速率为：ddA，2-氨基-6-氟>> 2-氨基-6-氯， 2-氨基-6-溴> 2-氨基-6-碘。在ADA抑制剂的存在下， 2'-脱氧coformycin，所有2-氨基-6-卤代-和6-卤代-ddp均未能发挥 它们的体外抗逆转录病毒作用。总之，这些化合物可以 代表ddl和ddG的一类新的亲脂性前药，并且还可以 提供了一种新的策略， 理想的亲脂性。

Four 2-amino-6-halo- and four 6-halo-2',3'-dideoxypurine ribofuranosides (ddP) were synthesized and tested for in vitro activity to suppress the infectivity, cytopathic effect, gag protein expression, and DNA synthesis of HIV. The comparative order of in vitro anti-HIV activity of the eight 6-halo-ddPs 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. 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 (ddI) or 2',3'-dideoxyguanosine- (ddG), and completely blocked the infectivity of HIV without affecting the growth of target cells. The lipophilicity order was : 2-amino-6-iodo > 2- amino-6-bromo > 2-amino-6-chloro > 2-amino-6-fluoro >> ddG > ddl. All eight 6-halo-ddPs were substrates for adenosine deaminase (ADA). The relative rate of hydrolysis by ADA was : ddA, 2-amino-6-fluoro >> 2-amino-6-chloro, 2-amino-6-bromo > 2-amino-6-iodo. In the presence of an ADA-inhibitor, 2'-deoxycoformycin, all 2-amino-6-halo- and 6-halo-ddPs failed to exert their in vitro antiretroviral effect. Taken together, these compounds may represent a new class of lipophilic prodrugs for ddl and ddG, and may also provide a new strategy for endowing therapeutic purine nucleosides with desirable lipophilicity.