靶向K-Ras突变的抗癌小分子化合物的设计、合成与活性研究
发布时间：2018-09-18 06:30
【摘要】：癌症严重威胁着人类的健康,而Ras信号通路在癌症的发生、发展过程中起到着很重要的作用。Ras蛋白家族是一类低分子量的GTP结合蛋白,其主要分为H-Ras、N-Ras和K-Ras。在人类已发现的肿瘤中,RAS突变类型肿瘤约占全部肿瘤30%,其中K-Ras的突变更是占全部RAS突变的70%左右。经研究表明,苯并三氮唑类小分子,在治疗疾病方面有着很好的应用,例如抗癌、抗真菌、抗炎症等。因此,苯并三氮唑是一类具有优势的药物化学骨架,可以应用在药物研发中。1,500多个化合物通过在T29/T9KT1P两种细胞系上进行差异性筛选,得到小分子化合物07B11(5-溴呋喃-2-羧酸[2-(4-甲氧基苯基)-2H-苯并三唑-5-氨基]-酰胺),其在10μM浓度下,能够选择性的抑制T29KT1P细胞增殖。本文以07B11作为阳性化合物,通过合理的药物设计,设计合成了一系列的苯并三氮唑类小分子。通过T29细胞系和T29KT1P细胞系抗增殖实验验证,实验结果表明有一批在1-5 μM浓度下选择性的抑制T29KT1P增殖的小分子化合物42,43,67,70和71。通过构效关系分析,表明在苯并三氮唑这一优势化学骨架中,在5-氨基位点引入溴代或者氯代乙酰基时,其在T29KT1P细胞系上的抗增殖活性最好；对于2-苯基上的修饰,苯基的4号位氯取代和甲氧基取代对于保持小分子抗增殖活性是最好的。综合对比小分子化合物42,43,67,70和71在T29KT1P/T29实验数据,化合物67较其他化合物能够更好的选择性抑制T29KT1P细胞增殖。化合物67在人源正常细胞系、K-Ras野生型和K-Ras突变型癌细胞系上进行细胞增殖实验,发现其在5 μM时候,能够选择性的抑制K-Ras突变癌细胞系的增殖。
[Abstract]:Cancer is a serious threat to human health, and Ras signaling pathway plays an important role in the occurrence and development of cancer. Ras protein family is a class of low molecular weight GTP binding proteins, which are mainly divided into H-Rasn N-Ras and K-Ras. Ras mutations account for about 30% of all human tumors, and K-Ras mutations account for about 70% of all RAS mutations. Studies have shown that benzotriazole small molecules have a good application in the treatment of diseases, such as cancer, antifungal, anti-inflammatory, and so on. Therefore, benzotriazole is a kind of superior pharmacokinetic skeleton, which can be used in drug research and development. More than 1, 500 compounds can be screened by differential screening on two T29/T9KT1P cell lines. A small molecule compound 07B11 (5- (4-methoxyphenyl) -2H-benztriazole-5-amino-amide) was obtained, which could selectively inhibit the proliferation of T29KT1P cells at a concentration of 10 渭 M. In this paper, a series of benzotriazole small molecules were designed and synthesized with 07B11 as positive compound. The anti-proliferation experiments of T29 cell line and T29KT1P cell line were carried out. The results showed that there were a number of small molecular compounds 42O43C67H70 and 71which selectively inhibited the proliferation of T29KT1P at 1-5 渭 M concentration. The results of structure-activity analysis showed that benztriazole had the best antiproliferative activity in T29KT1P cell line when brominated or chlorinated acetyl group was introduced at 5- amino site in the dominant chemical skeleton. Chlorination and methoxy substitutions at position 4 of phenyl are the best to maintain the anti-proliferative activity of small molecules. Compared with the experimental data of T29KT1P/T29, compound 67 was more selective than other compounds in inhibiting the proliferation of T29KT1P cells. Compound 67 could selectively inhibit the proliferation of K-Ras mutant cancer cells at 5 渭 M by cell proliferation assay on human normal cell lines, wild type K-Ras and K-Ras mutant cancer cells.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91;R914.5
[Abstract]:Cancer is a serious threat to human health, and Ras signaling pathway plays an important role in the occurrence and development of cancer. Ras protein family is a class of low molecular weight GTP binding proteins, which are mainly divided into H-Rasn N-Ras and K-Ras. Ras mutations account for about 30% of all human tumors, and K-Ras mutations account for about 70% of all RAS mutations. Studies have shown that benzotriazole small molecules have a good application in the treatment of diseases, such as cancer, antifungal, anti-inflammatory, and so on. Therefore, benzotriazole is a kind of superior pharmacokinetic skeleton, which can be used in drug research and development. More than 1, 500 compounds can be screened by differential screening on two T29/T9KT1P cell lines. A small molecule compound 07B11 (5- (4-methoxyphenyl) -2H-benztriazole-5-amino-amide) was obtained, which could selectively inhibit the proliferation of T29KT1P cells at a concentration of 10 渭 M. In this paper, a series of benzotriazole small molecules were designed and synthesized with 07B11 as positive compound. The anti-proliferation experiments of T29 cell line and T29KT1P cell line were carried out. The results showed that there were a number of small molecular compounds 42O43C67H70 and 71which selectively inhibited the proliferation of T29KT1P at 1-5 渭 M concentration. The results of structure-activity analysis showed that benztriazole had the best antiproliferative activity in T29KT1P cell line when brominated or chlorinated acetyl group was introduced at 5- amino site in the dominant chemical skeleton. Chlorination and methoxy substitutions at position 4 of phenyl are the best to maintain the anti-proliferative activity of small molecules. Compared with the experimental data of T29KT1P/T29, compound 67 was more selective than other compounds in inhibiting the proliferation of T29KT1P cells. Compound 67 could selectively inhibit the proliferation of K-Ras mutant cancer cells at 5 渭 M by cell proliferation assay on human normal cell lines, wild type K-Ras and K-Ras mutant cancer cells.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R91;R914.5
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