齐墩果酸类似物合成及其体外抗肿瘤活性研究

Synthesis of Oleanolic Acid Analogs and Their Anti-Cancer Biological Activities

采用计算机辅助设计,将尿激酶型纤溶酶原激活物受体与已知活性的化合物进行模拟分子对接,并采用对靶蛋白上具有活性作用的重要氨基酸残基进行解析的方法,确定能与活性位点结合的基团.以天然产物齐墩果酸为母体,在其2位上引入活性基团,同时对其C-28位羧基进行胍基化结构修饰,设计并合成一系列具有一定抗肿瘤活性的齐墩果酸类似物.采用MTT法进行初步的体外抗肿瘤活性筛选.采用FPIA法,对Ⅰ_(1)和Ⅰ_(3)进行尿激酶受体抑制试验.合成了5个新的齐墩果酸类似物,其结构经过NMR确证;活性测试表明化合物Ⅰ_(1)、Ⅰ_(3)与阳性对照药物相比表现更强的抑制作用.FPIA测试表明,化合物Ⅰ_(3)与尿激酶受体蛋白具有较好的结合能力.

Using computer-aided design,the urokinase type plasminogen activator receptor was docked with a compound with known activity,and the group that can bind to the active site was determined by analyzing the important amino acid residues on the target protein. Taking the natural product oleanolic acid as the parent,a series of oleanolic acid analogues with certain antitumor activity were designed and synthesized by introducing active groups at position 2 and modifying the carboxyl group at position C-28 with guanidine structure. MTT assay was used to screen the antitumor activity in vitro. Urokinase receptor inhibition tes was performed onⅠ_(1) andⅠ_(3) by FPIA method. Five new oleanolic acid analogues were synthesized and their structures were confirmed by NMR;Activity test showed that compoundsⅠ_(1) andⅠ_(3) showed stronger inhibitory effect than positive control drugs. FPIA test showed that compoundⅠ_(3) had good binding ability with urokinase receptor protein.