【作者】 李家明；

【导师】 汪志勇；

【作者基本信息】 中国科学技术大学 ， 有机化学， 2006， 博士

【摘要】 论文由抗艾滋病毒药物研究进展的综述和另外五部分研究工作组成。 综述部分概述了自1981年第一例艾滋病患者被报道以来抗HIV药物的研究进展。N₁-（芳基）-1，3-丙二胺类HIV-1 Tat／PCAF BRD抑制剂的设计、合成及构效关系：（1）首次以HIV-1基因表达和转录过程中起关键作用的反式共激活因子PCAF中的特定区域BRD为靶点，设计、合成了18个N₁-（芳基）-（CH₂）_n-二胺盐酸盐类小分子化合物。（2）利用3D NMR技术测定了PCAF BRD／compound 2-2复合物三维结构。通过对三维结构进行分析，非常清楚地了解了化合物2-2与PCAF BRD疏水性口袋中关键氨基酸残基的作用方式。（3）通过ELISA检测法测定了所合成的18个小分子化合物的体外抑制活性(IC₅₀)，总结出了初步的构效关系（SAR）。 N₁-（缺电子芳基）-1，3-丙二胺类HIV-1 Tat／PCAF BRD抑制剂的新合成方法：（1）以等当量的三乙胺为碱，在无溶剂条件下加热到120℃可以实现缺电子基团取代的芳胺与N-（3-溴丙基）邻苯二甲酰亚胺的N-烷基化反应，得到较好收率的2-[3-（2-缺电子基团取代的芳胺基）-丙基]二氢异吲哚-1，3-二酮，然后将它们进行肼解，简便地合成了8个N₁-（缺电子基团取代的芳基）-1，3-丙二胺盐酸盐。该方法操作简便，收率较高，具有较好的适用范围。（2）通过ELISA检测法测定了所合成的3-9～3-11的体外抑制活性(IC₅₀)。测定结果进一步补充完善了N₁-（芳基）-（CH₂）_n-二胺盐酸盐类小分子化学抑制剂的构效关系（SAR）。 3-芳氧基-1-丙胺类HIV-1 Tat／PCAF BRD抑制剂的合成及生物活性：（1）以取代的2-硝基苯酚为起始原料，在常规加热和微波辐射加热下与1，3-二溴丙烷反应合成3-（2-硝基芳氧基）-1-溴丙烷，结果显示，微波辐射加热比常规加热下的反应速度明显加快，收率有所提高。3-（2-硝基芳氧基）-1-溴丙烷和邻苯二甲酰亚胺钾进行N-烷基化反应合成了2-[3-（芳氧基）-丙基]二氢异吲哚-1，3-二酮，再经肼解得到了6个3-芳氧基-1-丙胺盐酸盐。（2）ELISA检测法测定了它们体外抑制HIV-1 Tat／PCAF BRD的活性。与N₁-（2-硝基芳基）-1，3-丙二胺盐酸盐的体外抑制活性相比，有了明显的下降。利用Gaussian 98软件对化合物2-2和4-14的优势构象进行计算，对活性降低的原因进行了讨论。 N-[4-氨甲基-5-（4-甲基-2-硝基苯氨基）-戊基]-乙酰胺盐酸盐类HIV-1 Tat／PCAF BRD抑制剂的合成及生物活性：（1）以PCAF／compound 2-2和乙酰乙胺三重复合物的3D更多还原

【Abstract】 This thesis includes six parts: （1） A review described the progress in the studies of anti-HIV drugs since the first AIDS patient was reported in 1981; （2） Based on the 3D structure of the PCAF BRD which plays an important role in the gene expression and transcription of HIV-1, eighteen N₁-（nitroaryl）-propane-1,3- diamines derivatives were designed and synthesized as HIV-1 Tat/PCAF BRD association inhibitor for the first time. The interaction between compound 2-2 and the PCAF BRD was disclosed clearly by the 3D structure of PCAF BRD/compound 2-2 complex determined by NMR. Biological activities in vitro (IC₅₀) were determined by ELISA assay and the primary structure activity relationships were concluded; （3） The new methodology of N₁-（electron-drawing substituted aryl）-propane-1,3- diamines derivatives was studied. The 2-[3-（arylamino）-propyl]-isoindole-1,3-diones were synthesized from electron-drawing substituted anilines and N-（3-bromopropyl）phthalimide by N-alkylation under solvent-free condition. These intermediates were easily converted into N₁-（electron-drawing substituted aryl）-propane-1,3- diamines by hydrazinolysis, Biological activities in vitro (IC₅₀) of some new compounds were determined by ELISA assay and the results complement the primary structure activity relationships; （4） Six 3-aryloxy-1-propylamines were synthesized for studying the SAR of HIV-1 Tat/PCAF BRD inhibitors. Substituted 2-nitrophenol reacted with 1,3-dibromopropane to give 3-（2-nitroaryloxy）-1-propylbromides under common heating and microwave irradiation, the reaction rate was accelerated remarkably and the yields were increased under microwave irradiation in comparision with that under common heating. 3-（2-nitroaryloxy）-1-propylbromides were treated with potassium phthalimide to produce 2-[3-（aryloxy）-propyl]- -isoindoline-1, 3-dione. Hydrazinolysis of intermediates yielded target molecules. The inhibition of HIV-1 Tat/PCAF BRD interaction in vitro was determined by ELISA assay, and some influential factors of biological activity were discussed; （5） Based on the 3D structure of PCAF BRD/compound 2-2/ N-ethyl-acetamide triple complex, N₁- （4-methyl-2-nitro-phenyl）-2-acetaminoethyl更多还原