抗HIV-1活性分子“二苯胺酯”结构改造、构效关系及作用机制研究

AIDS is one of the major diseases，which greatly affects on human health and social stability. Due to the lack of an effective vaccine against AIDS and the appears of clinical drug resistance, the research and development of anti-AIDS drugs with new mechanisms or new targets have become the hot topic in the anti-AID drug research. Due to the structural diversity characteristics of natural products, they are considered to be an important source for searching bioactive leading-molecules in anti-AIDS drug development.. Project group found a series of dibenzocyclooctadiene lignans from natural source in previous work, which showed significant anti-AIDS activity. However, the biphenyl derivatives derived from the basic structure unit of biphenyl in dibenzocyclooctadiene lignans showed better anti-HIV bioactivity. Further structural modifications and structure-activity relationship analysis led to the finding of a nitrogen-containing biphenyl compound, named as "Erbenanzhi", which showed potent anti-HIV bioactivity. Its mechanism research indicates that this compound can specially inhibit the synthesis of (+) DNA chain of HIV virus, which hint that it possesses new function mechanism. This finding has not only obtained the protections of Chinese patent and USA patent. Its total synthetic route for large scale production has been optimized and prepared a number of samples for furture research. The current project aims at using "Erbenanzhi" as a template molecule to synthesize a series of structural analogues. The structure-activity relationships and function mechanism will also be studied for selected bioactive compounds. This work will provide the foundations for the new anti-AIDS drug development with China's own intellectual property rights.

艾滋病是影响人类健康、社会稳定的重大疾病之一，由于缺乏有效预防艾滋病的疫苗且临床药物易产生耐药性的不足，因此研发具有新作用机制、新靶点的抗艾滋病药物成为当前的研究热点。天然产物由于具有结构多样性的特点，被认为是抗艾滋病新药研发中寻找活性先导分子的重要途径。. 项目组前期发现系列天然产物联苯环辛二烯木脂素具有显著的抗艾滋病活性，且源于其联苯结构单元的衍生物具有更强的活性；进一步结构改造及构效关系分析，发现含氮的联苯结构活性显著增加，并获得活性分子“二苯胺酯”；机制研究表明其特异性地抑制HIV正链DNA合成，具有新的作用机制；该发现已得到中国专利和美国专利的保护；完成了其放大生产全合成路线的优化。本项目拟基于“二苯胺酯”分子的结构特征，合成系列结构类似物，并进行构效关系及作用机制研究，优选出强活性的抗艾滋病候选药物分子，为开发具有我国自主知识产权的新型抗艾滋病药物打下基础。

“二苯胺酯”（SJP-L-5）是一类含氮联苯类化合物，具有良好的抗HIV活性，是一种新型的非核苷类抗HIV逆转录酶抑制剂。与传统NNRTIs不同，它具有全新的机制，仅针对病毒由负链DNA合成DNA的过程进行抑制。. 在该项目的实施过程中，我们以SJP-L-5为先导化合物设计合成了两个系列共100余个衍生物并对其抗HIV活性进行了测试。其中，活性最好的化合物5b IC50值为0.06±0.01μM，治疗指数TI为1660.63，较SJP-L-5（IC50=4.59±0.63μM; TI>43.55）其抗HIV活性有了大幅提升。选取活性最好的三个化合物5b, 5c, 5r进行了深入的机制研究，发现三个化合物对临床分离株、蛋白酶抑制剂耐药株、融合抑制剂耐药株、核苷类逆转录酶抑制剂耐药株复制均有很好的抑制作用，同时对PBMC的毒性较小。化合物5r出现了和SJP-L-5类似的机制，即仅针对HIV病毒由负链DNA合成DNA的过程进行抑制，这有别于已上市的HIV非核苷类逆转录酶抑制剂。我们还建立了化合物数据库，通过构效关系寻找结构与活性之间的规律，找到优势的改造位点和基团，对今后的设计合成提供了重要的指导意义。此外，我们还对该类化合物进行了活性拓展，发现该类化合物也具有良好的抗肝癌活性，个别化合物的抑制效果甚至还要高于阳性对照药依诺沙星。对其机制进一步研究发现它是一类新型的TRBP调控剂。