新型非甾体类AR拮抗剂的设计合成及生物活性评价

项目名称： 新型非甾体类AR拮抗剂的设计合成及生物活性评价

项目编号： No.21272140

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： 赵桂森

作者单位： 山东大学

项目金额： 80万元

中文摘要： 1.研究内容：以雄激素受体（Androgen Receptor,AR）为靶标，设计合成系列新颖的非甾体类AR拮抗剂，测定化合物对AR的相对亲和力、对AR的激动和拮抗作用以及对前列腺癌细胞的生长抑制作用，探讨构效关系，通过测定化合物对激素依赖型和激素非依赖型以及AR高表达前列腺癌细胞的生长抑制作用，筛选对去势抵抗型前列腺癌有潜在活性的AR拮抗剂。2.研究意义：AR的扩增及突变是前列腺癌发生和发展的基本特征及根本动力，激素依赖型及激素非依赖型前列腺癌的发生、发展都依赖于AR的激活，因此，以AR为靶标，研究开发新型的非甾体类 AR 拮抗剂，发现对野生型和突变型AR均具有高亲和力的AR拮抗剂，具有重要的临床意义。

中文关键词： 前列腺癌；雄激素受体；拮抗剂；；

英文摘要： Androgen receptor (AR) plays a pivotal role in prostate cancer, primarily by regulating different gene expression programs elicited by androgen, which is important for cancer cell proliferation, survival, and differentiation. Androgen ablation via surgical or medical castration in combination with an AR antagonist (eg. bicalutamide) is currently the treatment of choice for advanced prostate cancer. Unfortunately, a decrease in efficacy was observed after a period of time of treatment. Recent advances in the field have shown that reactivation of the AR signaling pathway is the root cause for the development of androgen independent prostate cancer. AR mutations are also suggested to result in the ability of anti-androgens to exhibit agonist activity. In this project, a series of novel nonsteroidal AR antagonists will be designed and synthesized. Their biological activities, i.e., AR binding affinity, AR antagonism, and effect on proliferation of prostate cancer cell lines, will be evaluated. The structure-activity relationships will also be explored in order to discover new AR antagonists that bind tightly to the AR and function as antagonists to the wild-type and the mutant isoforms of the AR.

英文关键词： Prostate cancer；androgen receptor；antagonists；；