Murakami K, Shirasaka T, Yoshioka H, Kojima E, Aoki S, Ford H, Driscoll J S, Kelley J A, Mitsuya H
Research Laboratory of Bioresources, Sanyo-Kokusaku Pulp Company, Iwakuni, Japan.
J Med Chem. 1991 May;34(5):1606-12. doi: 10.1021/jm00109a012.
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 greater than 6-bromo, 2-amino-6-bromo greater than 6-chloro, 2-amino-6-chloro greater than 6-fluoro, 2-amino-6-fluoro much greater than ddG greater than 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 greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 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.
为提高这类抗人类免疫缺陷病毒（HIV）化合物的亲脂性，从而便于药物进入中枢神经系统，利用活的大肠杆菌酶促合成了一系列6-取代的2'，3'-二脱氧嘌呤核糖苷（ddP）。根据它们的正辛醇-水分配系数（P）定义，所有6-卤代取代的ddP比其未卤代的同系物2'，3'-二脱氧肌苷（ddI）或2'，3'-二脱氧鸟苷（ddG）的亲脂性要强得多。对于这类化合物，log P值在+0.5至 -1.2范围内，顺序如下：6-碘代、2-氨基-6-碘代大于6-溴代、2-氨基-6-溴代大于6-氯代、2-氨基-6-氯代大于6-氟代、2-氨基-6-氟代远大于ddG大于ddI。对这些化合物进行了体外评估，以检测其抑制HIV感染性、复制和细胞病变效应的能力。2-氨基-6-氟代、2-氨基-6-氯代和6-氟代-ddP对HIV表现出与ddI或ddG相当的强效活性，并且完全阻断了HIV的感染性，同时不影响靶细胞的生长。体外抗HIV活性的比较顺序为：2-氨基-6-氟代、2-氨基-6-氯代、6-氟代大于2-氨基-6-溴代大于2-氨基-6-碘代、6-氯代大于6-溴代大于6-碘代。这些化合物对HIV-2和3'-叠氮-3'-脱氧胸苷耐药的HIV-1变体也表现出强效的体外活性。所有2-氨基-6-卤代-ddP和6-卤代-ddP都是腺苷脱氨酶（ADA）的底物，分别被转化为ddG或ddI。在强效ADA抑制剂2'-脱氧助间型霉素存在的情况下，6-卤代取代的ddP未能发挥体外抗逆转录病毒作用。这些二脱氧嘌呤核苷类似物代表了一类新的ddG和ddI亲脂性前药，具有更有效治疗HIV引起的神经疾病的潜力。
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