Synthesis/Biological evaluation of Anti-HIV Nucleosides

描述(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效果，新药发现 寻找毒性较低且无交叉耐药的现有抗HIV药物 目前迫切需要特工。人们非常关注的是，一些艾滋病毒 接受HAART的患者对目前可用的药物没有反应。因此， 患者需要额外的药物进行抢救治疗。以前，在 对这笔赠款的支持我们发现了几个艾滋病毒的临床候选者 (DAPD；Amdoxovir)和癌症(L-OddC；曲西他滨)。尤其是，国土安全部是 对艾滋病毒感染的治疗非常有希望，因为它降低了 在LM期临床研究期间患者的显著病毒载量(1.9log) 那些未能通过联合治疗的患者。因此，DAPD可能对以下方面有潜在的帮助 HAART失败患者的抢救治疗和额外的II期研究 DAPD目前正在进行中。 为了发现具有独特抗药性的新型抗HIV核苷 简介，在目前的资助期内，我们一直在综合各种 化合物的类别。通过这些努力，我们开发出了几个优雅的 未来结构-活性研究的综合方法学，此外，我们 发现了几类新的具有生物前景的化合物，包括 D&L-2‘-或3’-F-取代的2‘，3’-不饱和核苷。在.期间 在下一个资金周期，我们建议扩大那些已经证明 有望在体外发挥抗艾滋病毒的活性，并进行深入的生物学研究 为了评估这些化合物作为临床候选化合物的全部潜力，作为我们的 小组此前曾对在我们的 实验室，如美国国防部。 鉴于有趣的化学和生物活性，在这 应用我们将继续专注于2‘-或3’-F的合成 取代不饱和核苷的综合构效关系 研究内容包括：1)D-和L-3‘-F-2’，3‘-不饱和化合物的合成 核苷(3‘-F-d4N，第11类)，2)D-和L-2’-F-2‘，3’-不饱和化合物的合成 4‘-S-核苷(2’-F-Sd4N7Ⅲ类)，3)D-和L-3‘-F-2’，3‘- 不饱和4‘-S核苷(3’-F-S-d4N7类N)4)对映体的合成 D&L-2‘-F-2’，3‘-不饱和碳环核苷(2’-F-C-d4N7 V类)，5) D-和L-3‘-F-2’，3‘-不饱和碳环的对映体合成 核苷(3‘-F-C-d4N，VI类)分子模拟研究。最近，我们 研究了核苷耐药的分子机制并发现 相对结合能和相对结合能之间存在质的相关性 抗艾滋病病毒的活动。这是第一次这样的研究证明了 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.