p53激活剂RITA及其类似物的设计、合成及抗肿瘤活性研究

项目名称： p53激活剂RITA及其类似物的设计、合成及抗肿瘤活性研究

项目编号： No.21272134

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： 蒋宇扬

作者单位： 清华大学

项目金额： 80万元

中文摘要： 恶性肿瘤是严重威胁人类健康的常见多发病，人类近50%恶性肿瘤发生了抑癌基因的p53的突变或失活，通过激活p53来抗肿瘤已成为近年来抗肿瘤药物研发的热点之一。三环噻吩类似物RITA具有良好的抗肿瘤功能，在p53(wt)肿瘤细胞中，它可重新激活p53，调控其下游诸多的调控因子，最终引起肿瘤细胞周期阻滞和凋亡；本项目以RITA为先导化合物，探索实用且高效合成RITA及其类似物的新路线，设计并合成一系列RITA的类似物，并筛选其抗肿瘤的生物活性，研究其构效关系；通过优化RITA的类似物结构，获得结构新颖、毒副作用小，选择性好且抗肿瘤活性较RITA好的化合物；深入研究RITA及其类似物抗肿瘤作用，以期发现其抗肿瘤作用的新机制。同时探究RITA及其类似物的药效学与药动学性质，进行这类化合物的临床前研究。本项目的成功研发，将为以p53为靶点性抗肿瘤药物的研发提供新的研究思路和实验依据。

中文关键词： p53；RITA；抗肿瘤；凋亡；

英文摘要： Cancer is a common frequently-occurring disease threat to human health, tumor suppressor genes p53 was mutated or deactivated in nearly 50% human cance. p53-based Anti-cancer therapies have become one of the hot spots in the research and development.of antitumor drugs in recent years. Tricyclic thiophene derivative RITA rescues p53 function by blocking p53-Mdm2 interaction, resulting in tumor apoptosis, cell-cycle arrest or senescence in p53 (wt) cancer cells. In this project, RTIA was selected as a lead compound to explore a new efficient and effective route to synthesis RITA and its analogues, and a series of substituted tricyclic α-heteroaryl (funan/thiophene) derivatives were designed, synthesized and screened, and their structure activity relationship (SAR) was studied. New RITA analogues with little side effect, good selectivity, stronger antitumor effect were gained through the optimization of their structure.The new mechanism of their anti-tumor effect will be achieved by further study their antitumor function. The exploration of RITA and their analogues of pharmacokinetic and pharmacodynamic properties will be convenient for clinical research. The success of this project will provide new research ideas and experimental evidence to antitumor drugs research and development and prospects for p53-based canc

英文关键词： p53；RITA；antitumor；apoptosis；