噻吩嘧啶论文芳亚甲基(氧代噻吩嘧啶基)乙酰腙类化合物的合成及其抗肿瘤活性研究.docVIP

噻吩嘧啶论文： -芳亚甲基（氧代噻吩嘧啶基）乙酰腙类化合物的合成及其抗肿瘤活性研究 【中文摘要】尽管当前各类分子靶向的药物发现技术不断涌现,基于细胞水平的随机体外筛选仍然是发现抗肿瘤药物先导化合物的有效和实用手段。基于课题组前期随机筛选发现的一个抗肿瘤活性先导化合物A01结构,为了提高A01的抗肿瘤活性,我们共设计合成了38个衍生物(A02-A39)。对所有设计合成的38个衍生物,选取3种常见肿瘤细胞株(A549、Hela和MDA-MB-231),进行了抗肿瘤细胞增殖活性测试。共发现5个衍生物(A14、A23、A25、A27和A35)对3种肿瘤细胞株表现出微摩尔水平的抑制活性(IC50=6-40μM),其中3个最强的化合物(A25、A27和A35)的抑制活性介于10-20μM之间。此外,这些化合物对正常细胞HEK-293T没有明显的抑制效果,显示出对肿瘤细胞的选择性作用。选取发现的5个强效抗肿瘤活性化合物,开展了初步的抗肿瘤作用机制研究。流式细胞检测结果表明,本论文目标物(A23、A27和A35)能够有效诱导HeLa细胞的凋亡,进一步Western Blot实验发现,这3个目标物可以诱导HeLa细胞中caspase-3蛋白的活化,引起PARP蛋白降解,表现出caspase-3蛋白依赖的细胞凋亡的典型特征。这些初步的结果说明本论文化合物是通过诱导细胞凋亡来发挥抗肿瘤作用。基于抗肿瘤活性结果,总结归纳了N’-芳亚甲基-2-(4-氧代噻吩嘧啶-3-基)乙酰腙类化合物(A01-A39)的构效关系(SARs),这些SARs结果为今后进一步设计开发新型抗肿瘤药物提供了结构基础。 【英文摘要】The discovery and development of effective anti-cancer therapies has been accelerated in recent years by various molecular targeted techniques and strategies. Nevertheless, in vitro random screening with tumor cell lines is still an essential approach to the identification of compounds with desired potency. The lead compound (A01) was discovered in a cell-based random screening to have noticeable cytotoxicity on several tumor cell lines. For improving anti-cancer activity of compoumd A01, a total of 38 derivatives (A02-A39) of this compound were and designed and synthesized. These compounds were tested in standard MTT assays on three selected tumor cell lines, including A549 (human alveolar epithelial cell), HeLa (human cervical tumor cell), and MBA-MD-231 (human breast tumor cell), and five derivatives (A14, A23, A25, A27, and A35) exhibited improved anti-cancer activities at micro-molar level (IC50 =6-40μM), the three most potent compounds (A25, A27, and A35) have IC50 values of 10-20μM. In addition, these compounds do not have obvious effect on a normal cell line HEK-293T, demonstrating the desired selectivity against tumor cells. The pro-apoptotic activity of the five most potent derivatives identified in our MTT assays were further examined in a flow cytometry assay. Flow