新型细胞周期蛋白依赖性激酶1抑制剂的设计、合成、活性评价及定量构效关系研究

The occurrence and development of malignant tumor have related to deregulation of cell cycle. CDK1 is the only essential cell cycle CDK, because CDK1 is able to execute all the required events to drive cell division even in the absence of other CDKs. So CDK1 was regarded as a potential target for bolcking cell cycle or inducing apoptosis for anti-cancer agents discovery. Baicalein belongs to flavonoid. It was found that Baicalein could inhibit the proliferation of some kinds of tumor cells. The mechanism maybe that it could downregulate the expression of CDK1 and CDK2, which could induce the cell cycle arrest or apoptosis. In this research, CDK1 was taken as target and Baicalein as lead. First, Baicalein was docked to the active site of homology modeling CDK1. In this process, activition required functional groups could be confirmed. Then, the other parts of Baicalein were modified to enhance the CDK1 inhibitory activity. The structures of final compounds were determined by UV, NMR and MS. And then the final compounds will be assayed for their anti-CDK1 activity. Finally, according to the structure and activity data, quantitative structure activity relationship (QSAR) model can be bulit by utilizing computer-assisted drug design software. The QSAR model could be used for the future compound modification. This research can afford basis for new selective CDK1 inhibitors development.

恶性肿瘤的发生、发展与细胞周期调节机制紊乱有密切关系。其中，细胞周期蛋白依赖性激酶1（CDK1）在整个细胞周期过程中起到不可或缺的作用，在其它CDKs缺失的情况下，仍能催化底物磷酸化，推动细胞完成分裂进程。因而，开发选择性CDK1抑制剂成为抗肿瘤药物研究的热点。黄芩素(Baicalein)具有抑制肿瘤细胞增殖的活性，其抗肿瘤的主要作用机制主要是下调CDK1、CDK2等激酶的表达，使细胞周期停滞或诱导细胞凋亡。本课题以CDK1为靶点，以黄芩素为先导，先将黄芩素与同源模建的CDK1活性中心进行对接，确定活性必需的官能团，然后对其他位置进行结构修饰，旨在提高黄芩素衍生物的CDK1抑制活性，合成的目标化合物确定结构后，进行生物活性评价，最后利用计算机辅助药物设计软件研究化合物的结构与活性的关系，建立定量构效关系模型，为开发新型选择性CDK1抑制剂奠定基础。

恶性肿瘤的发生、发展与细胞周期调节机制紊乱有密切关系。其中，细胞周期蛋白依赖性激酶1（CDK1）在整个细胞周期过程中起到不可或缺的作用，在其他CDKs缺失的情况下，仍能催化底物磷酸化，推动细胞完成分裂进程。因而，开发选择性CDK1抑制剂成为抗肿瘤药物研究得热点。本课题以CDK1为靶点，利用合理药物设计的原理方法，对黄芩素的A、B环进行结构改造，并对得到的关键中间体和目标化合物进行生物活性评价和构效关系分析。最终合成关键中间体7个，黄芩素的酯衍生物（A系列）30个，黄芩素的醚衍生物（B系列）3个，共计40个化合物，结构经核磁、质谱等确定。抗MCF-7肿瘤细胞增殖实验结果表明，CDKI010超过了阳性对照CPG74514A和flavoplrldol，CDKI022，CDKI009，CDKI016，CDKI026活性与阳性对照flavoplrldol相当。化合物对CDK1/ Cyclin B 激酶的IC50值，与对MAC-7细胞的IC50值的呈正相关，可初步判断化合物的抗肿瘤活性与CDK1有关。8位连接N-甲基哌嗪甲基和硫代吗啉亚甲基，6位连接肉桂酸和α-甲基丙烯酸的化合物活性较好，B系列化合物活性优于A系列化合物。由于B系列化合物数量较少，应在完成全部B系列化合物后，进一步研究其构效关系。