Cristalli G, Vittori S, Eleuteri A, Volpini R, Camaioni E, Lupidi G, Mahmood N, Bevilacqua F, Palù G
Dipartimento di Scienze Chimiche, Università di Camerino, Italy.
J Med Chem. 1995 Sep 29;38(20):4019-25. doi: 10.1021/jm00020a017.
A series of 1-deazaadenine nucleosides with the N6 nitrogen unsubstituted or bearing methyl or cycloalkyl substituents, with or without a chloro group in the 2-position, and with the glycosylic moiety being ribose (1-16), 2'-deoxyribose (17-32), or 2', 3'-dideoxyribose (33-48) were designed and synthesized starting from 5,7-dichloro-3H-imidazo[4,5-b] pyridine (50). These compounds were evaluated for their in vitro activity against human immunodeficiency virus type-1 (HIV-1) and herpes simplex virus type-1 (HSV-1). In addition they were tested for their ability to inhibit adenosine deaminase (ADA) from calf intestine. While the parent compounds 1-deazaadenosine (9), 2'-deoxy-1-deazaadenosine (25), and 2',3'-dideoxy-1- deazaadenosine (41) and the corresponding 2-chloro derivatives were inactive, nucleosides bearing cycloalkyl substituents on N6 exhibited moderate to good anti-HIV-1 activity, compared to 2',3'-dideoxyadenosine, with the degree and pattern of improvement depending on the structure of the sugar moiety. In general, 2'-deoxy- and 2',3'-dideoxy derivatives were more potent compounds than the corresponding ribose nucleosides. Compounds bearing a 6-cycloheptyl or cyclooctylamine were the most active in every series. The presence of a chloro group in the 2-position improved both activity and therapeutic index in every series, the most active compound being 2'-deoxy-2-chloro-N6-cycloheptyl-1-deazaadenosine (23; ED50 = 0.2 microM). On the other hand, most of these derivatives were inactive as anti-HSV-1 agents, showing a high degree of virus selectivity. The 1-deazaadenine derivatives were not substrates of adenosine deaminase, and some of them proved to be good inhibitors of the enzyme. However, the ADA inhibitory activity does not account for the antiviral potency since increased lipophilicity and steric hindrance of substituents resulted in derivatives much less active than the parent compounds.
从5,7 - 二氯 - 3H - 咪唑并[4,5 - b]吡啶（50）出发，设计并合成了一系列1 - 脱氮腺嘌呤核苷，其N6氮未被取代或带有甲基或环烷基取代基，2 - 位有或没有氯原子，糖部分为核糖（1 - 16）、2'- 脱氧核糖（17 - 32）或2',3'- 二脱氧核糖（33 - 48）。对这些化合物进行了抗1型人类免疫缺陷病毒（HIV - 1）和1型单纯疱疹病毒（HSV - 1）的体外活性评估。此外，还测试了它们抑制小牛肠腺苷脱氨酶（ADA）的能力。虽然母体化合物1 - 脱氮腺苷（9）、2'- 脱氧 - 1 - 脱氮腺苷（25）和2',3'- 二脱氧 - 1 - 脱氮腺苷（41）以及相应的2 - 氯衍生物无活性，但与2',3'- 二脱氧腺苷相比，N6带有环烷基取代基的核苷表现出中度至良好的抗HIV - 1活性，改善的程度和模式取决于糖部分的结构。一般来说，2'- 脱氧和2',3'- 二脱氧衍生物比相应的核糖核苷更具活性。带有6 - 环庚基或环辛基胺的化合物在每个系列中活性最高。2 - 位氯原子的存在提高了每个系列的活性和治疗指数，活性最高的化合物是2'- 脱氧 - 2 - 氯 - N6 - 环庚基 - 1 - 脱氮腺苷（23；ED50 = 0.2 microM）。另一方面，这些衍生物大多作为抗HSV - 1药物无活性，表现出高度的病毒选择性。1 - 脱氮腺嘌呤衍生物不是腺苷脱氨酶的底物，其中一些被证明是该酶的良好抑制剂。然而，ADA抑制活性并不能解释抗病毒效力，因为取代基亲脂性增加和空间位阻导致衍生物的活性比母体化合物低得多。
