靶向微管蛋白秋水仙碱位点的白藜芦醇-Combrestatin A-4类抑制剂的设计、合成及活性研究

Microtubules are cytoskeletal filaments consisting of α,β-tubulin heterodimers and are involved in a wide range of cellular functions that are critical to the life cycle of the cell. Tubulin inhibitors (TI) can cause cell death by cell cycle arrest. Therefore, microtubule is a potent target for screening antitumor drugs. A number of naturally occurring compounds, such as combretastatin A-4(CA-4), paclitaxel, vinblastine and podophyllotoxin, all exhibit their anticancer properties by interfering with the dynamics of tubulin polymerization or depolymerization, resulting in mitotic arrest. Resveratrol (RES), another famous natural product that is well-known for its cancer chemopreventive activity, was found to exhibit antitubulin activity in our group. According to the Combination Principle and the Structure-Based Drug Design, a novel class of tubulin inhibitor, RES-CA-4 (Resveratrol-combrestatin A-4) was designed by confusing Resveratrol and CA-4. Inhibitory activity of the combined molecule will be expected to significantly increase by means of the complementary binding of Resveratrol and CA-4 segments at the colchicine activie site. The structural optimization will be guided by QSAR and binding model; the pharmacological activity of the target molecules will be evaluated by in vitro and in vivo antitumor activity,acute toxicity,tubulin inhibitory and cell cycle arrest.One or two hits with high efficiency and low toxicity are expected to be found as antitumor drug candidates. This project will provide a new strategy for tubulin inhibitor discovery, and it very important to exploring a new drug for cancer treatment.

微管是细胞骨架的主要成分，微管蛋白抑制剂（TI）能通过抑制微管蛋白动力学使细胞分裂终止于G2/M期，诱导细胞凋亡。因此，微管（蛋白）是寻找抗肿瘤药物的一个有效靶点。本项目根据"拼合原理"和"基于结构的药物设计"理念，将具有良好抗肿瘤活性的天然产物白藜芦醇（Resveratrol,RES）和微管蛋白秋水仙碱位点抑制剂Combrestatin A-4(CA-4)杂合，创造性地设计出RES-CA-4型微管蛋白抑制剂。拟借助RES、CA-4两个片段在活性位点上的互补性来提高目标分子的活性；通过QSAR和结合模式的研究来指导结构优化；从体内外抗肿瘤活性、微管蛋白抑制活性、细胞周期阻滞、急性毒性等多个角度综合评价目标化合物的药理活性。力争获得高效低毒、低耐药性的新型微管蛋白抑制剂1-2个，为最终开发具有自主知识产权的抗肿瘤药物奠定基础。本项目将为TI研究提供新思路，对新型抗肿瘤药物的研究有重大意义。

微管是细胞骨架的基本组成部分，参与维持细胞形态、细胞内物质输送、信号传导、细胞分裂等重要过程。微管蛋白作为微管的基本单位，目前有多种微管蛋白抑制剂作为一线抗肿瘤药物应用于临床，在延长患者生存时间和提高生活质量方面发挥重要作用。微管蛋白上存在有三个作用位点：紫杉醇位点、长春碱位点及秋水仙碱位点，是抗肿瘤药物研究的重要靶点之一。本项目根据“拼合原理”和“基于结构的药物设计”理念，将具有良好抗肿瘤活性的天然产物白藜芦醇（Resveratrol，RES）和目前微管蛋白秋水仙碱位点作用最强的抑制剂Combrestatin-4（CA-4）杂合，设计合成系列衍生物。通过体外抗肿瘤活性、微管蛋白抑制活性、细胞周期阻滞综合评价目标化合物的抗肿瘤活性及作用机理。在此基础上，通过QSAR和结合模式的研究，进一步指导结构优化。通过本项目的实施，我们合成了白藜芦醇甲酰胺衍生物、白藜芦醇氰乙酰胺类衍生物、白藜芦醇硝基乙烯基衍生物及白藜芦醇香豆素类衍生物。活性测试结果显示，部分白藜芦醇甲酰胺衍生物、白藜芦醇氰乙酰胺类衍生物显示了良好的抗肿瘤活性。同时，我们意外地发现，虽然白藜芦醇香豆素型衍生物的抗肿瘤活性较弱，但这类衍生物对单胺氧化酶表现出了很强的选择性抑制作用，预示着这类化合物可能在治疗神经退行性疾病如帕金森症及阿尔茨海默症方面具有潜在的应用价值。