Design, efficient synthesis, and anti-HIV activity of 4′-C-cyano- and 4′-C-ethynyl-2′-deoxy purine nucleosides
Design, efficient synthesis, and anti-HIV activity of 4′-C-cyano- and 4′-C-ethynyl-2′-deoxy purine nucleosides
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DOI：
10.1081/ncn-120037508
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发表时间：
2004-04-01
影响因子：
1.3
通讯作者：
Ohrui, H
中科院分区：
文献类型：
--
作者：
Kohgo, S;Yamada, K;Ohrui, H
4 '-C-取代基为甲基、乙基、乙炔基等的2'-脱氧核苷中，4 '-C-乙炔基-2'-脱氧嘌呤核苷具有最强的抗HIV活性，我们推测，4 '-C-乙炔基-2'-脱氧嘌呤核苷的4'-C-取代基越小，其生物活性越强。因此，取代基小于乙炔基的4 ′-C-氰基-2 ′-脱氧嘌呤核苷将具有更有效的抗病毒活性。为了证明我们的假设，我们计划开发4 '-C-氰基-2'-脱氧嘌呤核苷（4 '-CNdN）和4'-C-乙炔基-2 '-脱氧嘌呤核苷（4'-EdN）的有效合成。因此，我们成功地开发了一种由2 ′-脱氧腺苷和2，6-二氨基嘌呤2 ′-脱氧核苷在糖部分的C-4 ′位带有氰基或乙炔基的6个2 ′-脱氧嘌呤核苷的有效合成方法。不幸的是，4 '-C-氰基衍生物显示出较低的抗HIV-1活性，并且两种4'-C-乙炔基衍生物显示出体内高毒性。
Some 4'-C-ethynyl-2'-deoxy purine nucleosides showed the most potent anti-HIV activity among the series of 4'-C-substituted 2'-deoxynucleosides whose 4'-C-substituents were methyl, ethyl, ethynyl and so on. Our hypothesis is that the smaller the substituent at the C-4' position they have, the more acceptable biological activity they show. Thus, 4'-C-cyano-2'-deoxy purine nucleosides, whose substituent is smaller than the ethynyl group, will have more potent antiviral activity. To prove our hypothesis, we planned to develop an efficient synthesis of 4'-C-cyano-2'-deoxy purine nucleosides (4'-CNdNs) and 4'-C-ethynyl-2'-deoxy purine nucleosides (4'-EdNs). Consequently, we succeeded in developing an efficient synthesis of six 2'-deoxy purine nucleosides bearing either a cyano or an ethynyl group at the C-4' position of the sugar moiety from 2'-deoxyadenosine and 2,6-diaminopurine 2'-deoxyriboside. Unfortunately, 4'-C-cyano derivatives showed lower activity against HIV-1, and two 4'-C-ethynyl derivatives suggested high toxicity in vivo.