新型舒林酸衍生物的设计，合成及与核受体tRXRα相关的抗癌活性研究

Sulindac, one of the nonsteroidal anti-inflammatory drugs (NSAIDs), is currently used for treating pain and inflammation. The discovery that regular use of aspirin reduced the incidence of colon cancer has provided the impetus to develop NSAIDs for cancer prevention and treatment. NSAIDs are known to inhibit the activities of cyclooxygenases (COXs). Unfortunately, the proven anti-cancer activities of NSAIDs are overshadowed by concomitantly emerging side effects associated with their COX-2 inhibition, including increased cardiovascular risk. Although NSAIDs and selective inhibitors of COX-2 can exert their anti-cancer activities through their inhibition of COX-2, compelling evidence however has also shown that NSAIDs can function through COX-2-independent mechanisms. The adverse side effects of NSAIDs have impeded the exploitation of their proven anti-tumor potential, underscoring the importance for the identification of non-COX-2 targets, which may lead to new strategies for developing improved anti-cancer drugs. Recently, we reported that Sulindac induces apoptosis of cancer cells by binding to N-terminally truncated retinoid X receptor-alpha (tRXRalpha) through COX-2-independent mechanism. When combined with TNFalpha, Sulindac inhibited TNFalpha-induced tRXRalpha/p85alpha interaction and activation of PI3K/AKT signaling pathway, leading to activation of the death receptor-mediated apoptotic pathway. The goal of this project is to design, synthesize, and evaluate Sulindac derivatives with improved tRXRalpha-binding activity and reduced COX inhibitory effect. We will first design Sulindac derivatives for binding to tRXRalpha using computer-aided drug design (CADD). Depending on the result of CADD, 50-100 compounds will be synthesized by chemical modification of Sulindac, which will be evaluated for their tRXRalpha and COX binding. The anticancer （breast） activity of Sulindac derivatives will be examined by studying their inhibitory effect on TNFalpha-induced tRXRalpha/p85alpha interaction and PI3K/AKT activation. The structure-activity relationship of Sulindac derivatives will be studied, and the optimal 1-3 analogs will be evaluated for their anti-cancer effect in animals. Results from this project will lead to identification of improved Sulindac derivatives for dissecting the newly identified tRXRalpha pathways and for future development of Sulindac-based anti-cancer therapeutics.

舒林酸，作为传统的非甾体类抗炎药，通过抑制环氧化酶(COX)活性发挥解热镇痛的效果；由于舒林酸有很强的抗肿瘤活性而成为抗癌药物开发的热门对象，但抑制环氧化酶活性可产生严重的药物不良反应。最近研究表明舒林酸存在着环氧化酶非依赖性的抗癌机理，本课题组新近发现舒林酸可通过结合核受体tRXRα从而引起肿瘤细胞凋亡的新机制，因此针对tRXRα靶点，本项目将运用"计算虚拟组合化学+小量有机合成"的手段对舒林酸进行结构优化与化学合成，进一步降低其环氧化酶抑制活性，并提高其tRXRα的靶向性，并研究这些衍生物如何抑制tRXRα参与介导的TNFα/PI3K/AKT的肿瘤细胞生存信号转导通路，诱导乳腺肿瘤细胞凋亡。通过构效层面的研究，对优势的化合物，我们将进行抗癌动物模型的研究。这些衍生物最终可能开发为特异性靶向核受体tRXRα的先导化合物或者抗癌候选新药。

舒林酸，作为传统的非甾体类抗炎药，通过抑制环氧化酶(COX)活性发挥解热镇痛的效果；由于舒林酸有很强的抗肿瘤活性而成为抗癌药物开发的热门对象，本课题组新近发现舒林酸可通过结合核受体tRXRα从而引起肿瘤细胞凋亡的新机制，因此针对此靶点，本项目通过对核受体RXRα的靶点结构研究，经过理论设计并通过多步骤反应合成了舒林酸两类衍生物,K3与K8衍生物共62个化合物，通过与RXRα的结合实验以及转录活性实验研究发现，两个K3衍生物（XS121，XS127）优于K-80003衍生物，并对XS127展开乳腺癌小鼠实验研究，结果表明其具有较好的抗乳腺癌作用；四个K8衍生物对RXRα具有较好的转录抑制活性。此外，在时间跟经费允许的情况下，我们通过计算机虚拟筛选结合实验研究发现，除了舒林酸，还有四个老药（匹伐他汀钙、氟伐他汀钠、多潘立酮和马来酸罗格列酮）对核受体RXRα的转录活性具有调节作用；发现了一类新的具有自主知识产权的核受体RXRα的配体-硝基烯类化合物具有很好的抗肿瘤以及治疗白血病的作用。本项目研究成果目前在一区期刊（cancer research跟oncotarget）发表2篇，在Bioorganic & Medicinal Chemistry Letters期刊发表1篇。