多重选择性靶向肿瘤组织线粒体的药物设计、合成及活性研究

项目名称： 多重选择性靶向肿瘤组织线粒体的药物设计、合成及活性研究

项目编号： No.21472247

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 环境科学、安全科学

项目作者： 马大友

作者单位： 中南大学

项目金额： 88万元

中文摘要： 高选择性、特异性杀灭肿瘤组织一直是抗肿瘤药物研究的最高目标，本项目拟针对肿瘤组织细胞的自杀性武器库- - -线粒体，以氧化磷酸化抑制剂多杀菌素为切入点，结合RGD肽对肿瘤组织新生血管内皮细胞及肿瘤细胞表面高表达整合素αvβ3的选择性识别作用和亲脂性阳离子化合物对肿瘤细胞线粒体的选择性作用，并充分利用肿瘤组织酸性微环境的特点，设计、合成一类具有多重选择性的多杀菌素衍生物，研究其在体外、体内的抗肿瘤活性和构效关系，并通过实验来验证相关作用机制。我们希望通过本项目研究，能实现不同结构片段对肿瘤组织选择性的叠加作用，显著提高多杀菌素类化合物对肿瘤组织线粒体的靶向性，从而突破靶向线粒体的抗肿瘤药物研究选择性不高的瓶颈，研究开发出具有完全自主知识产权、高效低毒的多重选择性抗肿瘤药物分子。

中文关键词： 抗肿瘤药物；线粒体；整合素；多杀菌素；设计

英文摘要： High selectively or specifically targeting tumor tissue is the utmost goal in anti-tumor drug research. In current project, we will focus on the suicide weaponry, mitochondria, of cells in tumor tissue. Starting from the structure of spinosad, an oxidative phosphorization inhibitor, combining lipophilic cations which can selectively accumulate in the mitochondria matrix of tumor cells due to the elevated membrane potential and RGD peptide, which can be selectively recognized by the highly expressed integrin αvβ3 on the activated endothelial cells of tumor neovasculature and other tumor cells, furthermore, by utilizing the acidic micro environment of tumor tissues, a class of novel spinosyn derivatives with multiple selectivity to tumor tissue is designed. Synthesis and anti-tumor activity in vitro and vivo of the designed spinosad conjugates will be studied and their mechanism of action will be further explored. That, we aim to superimpose the selectivity of three different structure fragments to tumor tissue in order to enhance the selectivity of spinosad derivatives which we hope will be able to break the bottleneck of mitochondria targeting antitumor drug research, to produce an novel class of ideal muti-selective anti-tumor drug candidates.

英文关键词： antitumor;mitochondrion;integrin;spinosad;design