Synthesis/Biological evaluation of Anti-HIV Nucleosides

描述（由申请人提供）：由于耐药性和副作用 目前使用的抗艾滋病毒药物的方式的影响，新的药物发现， 寻找毒性较小和与现有抗艾滋病毒药物无交叉耐药性的药物 代理商是非常需要的。令人担忧的是，一些艾滋病毒 接受HAART治疗的患者对目前可用的药物没有反应。因此，在本发明中， 患者需要额外的药物进行挽救治疗。此前，根据 在这项资助的支持下，我们发现了几个HIV临床候选者 (DAPD; Amdoxovir）和癌症（L-OddC; Troxicitabine）。特别是，DAPD是 对于治疗艾滋病病毒感染是很有希望的，因为它降低了 Lm期临床研究期间患者中的显著病毒载量（1.9 log） 联合治疗失败的人因此，DAPD可能对以下方面潜在有用： HAART失败患者的挽救治疗和其他II期研究， DAPD目前正在进行中。 为了发现具有独特抗性的新型抗HIV核苷 在当前的资助期间，我们一直在综合各种 化合物的种类。通过这些努力，我们开发了几种优雅的 为今后的结构-活性研究的合成方法，此外，我们 发现了几种新的具有生物学前景的化合物，包括 D-和L-2 ′-或3 ′-F-取代的2 ′，3 ′-不饱和核苷。期间 下一个供资周期，我们建议扩大这些化合物， 有希望的体外抗艾滋病毒活性，并进行深入的生物学研究 评估这些化合物作为临床候选药物的全部潜力， 该小组以前曾对我们发现的其他化合物进行过研究。 实验室，如DAPD。 鉴于有趣的化学和生物活性，在此 在应用中，我们将继续关注2 '-或3 '-F的合成 用于综合结构-活性的取代的不饱和核苷 1）D- & L-3 '-F-2'，3 '-不饱和脂肪酸的合成 2）D- & L-2 '-F-2'，3 '-不饱和核苷（3'-F-d4 N，类别11）的合成 4 '-S-核苷（2'-F-Sd 4 N7 III类），3）D- & L-3 '-F-2'，3 '- 不饱和4 '-S-核苷（3'-F-S-d4 N7 N类）4）对映体合成 D- & L-2 '-F-2'，3 '-不饱和碳环核苷（2'-F-C-d4 N7 V类），5） D- & L-3 '-F-2'，3 '-不饱和碳环化合物的对映体合成 核苷（3 '-F-C-d4 N，VI类）分子模拟研究。最近我们 研究了核苷类药物耐药的分子机制， 在相对结合能和 抗艾滋病毒活性。这是第一次这样的研究表明， 这种分子建模方法的潜力。

DESCRIPTION (provided by applicant): Due to the drug resistance and side effects of currently used modalities of anti-HIV agents, new drug discovery in search of less toxic and non-cross resistant drugs with existing anti-HIV agents are critically needed. There is a great concern that a number of HIV patients under HAART fail to respond to the current available drugs. Thus, Patients need additional drugs for salvage therapy. Previously, under the support of this grant we have discovered several clinical candidates for HIV (DAPD; Amdoxovir) and cancer (L-OddC; Troxicitabine). Particularly, DAPD is quite promising for the treatment of HIV infection in that it lowered a significant viral load (1.9 log) in patients during Phase Lm clinical studies who fail the combination therapy. Thus, DAPD may be potentially useful for salvage therapy to patients who fail HAART and additional Phase II studies for DAPD are currently in progress. In order to discover novel anti-HIV nucleosides with unique resistance profiles, during the current funding period we have been synthesizing a various classes of compounds. From these efforts we have developed several elegant synthetic methodology for future structure-activity studies, and furthermore we discovered several novel classes of biologically promising compounds, including the D- & L-2'- or 3'-F-substituted 2',3'-unsaturated nucleosides. During the next funding cycle, we propose to scale-up those compounds which demonstrated promising anti-HIV activity in vitro and to pursue in-depth biological studies to assess the full potential of those compounds as clinical candidates, as our group has previously conducted for other compounds discovered in our laboratories, such as DAPD. In view of the interesting chemistry and biological activity, in this application we will continue to focus on the synthesis of 2'- or 3 '-F substituted unsaturated nucleosides for comprehensive structure-activity studies, which include: 1) Synthesis of D- & L-3'-F-2',3'-unsaturated nucleosides (3'-F-d4N, Class 11), 2) Synthesis of D- & L-2'-F-2',3'-unsaturated 4'-S-nucleosides (2'-F-Sd4N7 Class III), 3) Synthesis of D- & L-3'-F-2',3'- unsaturated 4'-S-nucleosides (3'-F-S-d4N7 Class N) 4) Enantiomeric synthesis of D- & L-2'-F-2',3'-unsaturated carbocyclic nucleosides (2'-F-C-d4N7 Class V), 5) Enantiomeric synthesis of D- & L-3 '-F-2',3'-unsaturated carbocyclic nucleosides (3 '-F-C-d4N, Class VI) molecular modeling studies. Recently, we have studied molecular mechanism of nucleoside drug resistance and discovered that there is a qualitative correlation between the relative binding energy and the anti-HIV activity. This is the first such studies demonstrating the potential of this molecular modeling approach.