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

最近CDC报告说，他们发现了一名艾滋病患者，联合化疗对他完全无效。因此，艾滋病化疗中亟待解决的问题是开发抗HIV药物，防止耐药HIV的出现。本研究旨在开发抗HIV活性核苷，以防止耐药HIV-1变体的出现。对逆转录酶（RT）抑制性2 '，3'-双脱氧核苷（ddN）的抗性表明HIV可以获得区分ddN和生理性2 '-脱氧核苷（dN）和/或从前病毒DNA末端消除已经掺入的ddN的能力。通过考虑上述机制并基于以下基本原理（1）和（2），我们设计了4 ′-C-取代的-2 ′-脱氧核苷（4 ′ SdN），作为对各种HIV具有高活性并延迟或不允许抗性HIV出现的核苷。(1)4 SdN非常像dN，因为它具有dN的所有官能团，因此HIV很难区分它们。（2）4 ′-碳的三叔化使3 ′-OH变成一种非常不活泼的新戊基型仲醇，DNA的合成将在4 ′-SdN处终止，因此4 ′-SdN可能是RT反应的链终止剂。我们合成了各种4 'SdNs。它们中的一些对广泛的HIV病毒非常有效，但它们也非常有毒。最后，我们得到了4 ′-C-乙炔基-2 ′-脱氧-2-氟腺苷（2FA），它对所有HIV-1都具有前所未有的高效力，例如EC_<50>（IIIB）=0.2nM，（M184 V）= 3 nM，（MDR）=0.15nM，S.I=110.000。未观察到高达100 kg/kg的急性小鼠毒性。2FA目前正在临床研究中。

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.