Development of 4'-C-ethynyl-2'-deoxy-2F-adenosine that is highly active against a multi-drug resistant HIV

最近，疾控中心报告说，他们发现了一名艾滋病患者，联合化疗对其完全无效。因此，艾滋病化疗中亟待解决的问题是开发抗艾滋病毒药物，以防止出现耐药艾滋病毒。这项研究旨在开发抗HIV活性核苷，以防止出现耐药的HIV-1变异体。对逆转录酶(RT)抑制的2‘，3’-双脱氧核苷(DDN)的抗性表明，HIVs可以获得区分DDN和生理性2‘-脱氧核苷(DN)的能力和/或从前病毒DNA末端消除已结合的DDN。考虑到上述机制，并基于(1)和(2)的基本原理，我们设计了4‘-C-取代-2’-脱氧核苷(4‘SDN)，作为一种可以高度有效地对抗各种HIV并延迟或不允许耐药HIV出现的药物。(1)4‘SDN非常类似于糖尿病肾病，因为它具有糖尿病肾病的所有官能团，因此艾滋病毒很难区分它们。(2)4‘-碳的季胺化反应使3’-羟基变成了不具活性的新戊基型仲醇，因此DNA生物合成将在4‘-SDN处停止，因此4’-SDN可能是RT反应的链终止剂。我们已经合成了各种4‘-SDN。它们中的一些对广泛的艾滋病毒具有高度的活性，但它们也具有很强的毒性。最后，我们得到了4‘-C-乙炔-2’-脱氧-2-氟腺苷(2FA)，它对所有的HIV-1都有前所未有的高效力，例如EC_&lt；50；(IIIB)=0.2 nM，(M184V)=3 nm，(Mdr)=0.15 nM，S.i=110.000。未发现100公斤/公斤以下的小鼠急性毒性。2FA目前正在进行临床应用研究。

Recently CDC reported that they identified an AIDS patient to whom the combined chemotherapy was not effective at all. Thus, the problem to be urgently solved in AIDS chemotherapy is the development of the anti-HIV drug that prevents the emergence of drug-resistant HIV. This study aims the development of anti-HIV active nucleosides that prevent the emergence of resistant HIV-1 variants. Resistance to reverse-transcrptase(RT)-inhibitory 2',3'-dideoxynucleoside (ddN) indicates that HIVs can acquire the ability to discriminate between ddN and physiologic 2'-deoxynucleoside(dN) and/or eliminate the already incorporated ddN from the proviral DNA terminus. By taking the above mechanism into account and based on the following rationale (1) and (2), we have designed 4'-C-substituted-2'-deoxynucleoside(4'SdN) as the one that could be highly active against various HIVs and delay or does not allow the emergence of resistant HIVs. (1)4'SdN is very much like dN because it has all the functional groups of dN and therefore it could be very difficult for HIV to discriminate between them. (2)Quaternarization of the 4'-carbon makes the 3'-OH into a very unreactive neopentyl type secondary alcohol, therefore DNA biosynthesis would stop at 4'SdN and thus 4'SdN could be the chain-terminator of RT reaction. We have synthesized various kind of 4'SdNs. Some of them are highly active against a wide spectrum of HIVs but they were very toxic, too. Finally, we have reached to 4'-C-ethynyl-2'-deoxy-2-fluoroadenosine(2FA), which turned out to be unprecedentedly highly potent against all HIV-1 ; e.g.EC_<50>(IIIB)=0.2nM, (M184V)=3nM, (MDR)=0.15nM, S.I=110.000. No acute mouse toxicity up to 100kg/kg has been seen. 2FA is now under study for clinical use.