基于Sigma-1受体信号通路的化学小分子的设计合成及其抗癌活性研究

项目名称： 基于Sigma-1受体信号通路的化学小分子的设计合成及其抗癌活性研究

项目编号： No.21272229

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 数理科学和化学

项目作者： 卢晓霞

作者单位： 中国科学院成都生物研究所

项目金额： 80万元

中文摘要： Sigma-1(σ1)受体作为重要的药物作用靶点，其信号转导机制研究表明，σ1受体在肿瘤重大疾病中具有重要作用，其药理配体在肿瘤治疗中的作用一直是基础研究和国际制药领域的热点。然而目前具有高亲和力和选择性的σ1受体配体还较少，尤其是具有优良抗癌活性的σ1受体配体更是屈指可数，特别是我国对该领域的研究还甚少报道。因此，本项目针对σ1受体细胞凋亡信号通路，结合我们新发展起来的羰基1,4'-联哌啶醇类σ1受体配体的结构，通过合理药物设计及结构优化,发现在肿瘤重大疾病中具有重要功能的σ1受体信号通路抑制剂，鉴定具有重要生理功能的σ1受体配体，研究具有临床意义的新型化合物对相关σ1受体介导的信号通路的调控，结合肿瘤疾病动物模型，评价其药理效应，为肿瘤治疗提供新的先导化合物，为新药创制奠定基础。

中文关键词： 1;4-联哌啶醇；抗肿瘤活性；构效关系；；

英文摘要： Sigma-1 (σ1) receptor is the important drug target, and signal transduction pathways and mechanisms involved in the actions of σ1 receptor ligands in cancer biology suggested that σ1 receptor play important roles in cancer. the potential therapeutic contributions of their pharmacologic ligands in oncology have been a hot area of basic research and the international pharmaceutical. Unfortunately, this has been hampered due to the lack of σ1 receptor ligand with high affinity and selectivity besides excellent antitumor activity. Especially, research in this field has not been reported in China. Therefore, the project will be focus on discovering the σ1 receptor inhibitor based on apoptosis signaling pathway, combined with the structure of carbonyl 1,4 '- linked piperidine alcohol derivatives developed recently by us, through rational drug design and structural optimization. Furthermore the identification of important physiological functions of σ1 receptor ligands and evaluation pharmacologic effects of the novel compounds with the clinical significance including regulation of σ1 receptor signaling pathway with tumor disease animal models, lay the foundation to provide new lead compounds for new drug for cancer treatment.

英文关键词： Sigma receptors；1;4'-bipiperidinol；antitumor activity；Structure-activity relationship；