靶向K-Ras突變的抗癌小分子化合物的設(shè)計(jì)、合成與活性研究
發(fā)布時(shí)間：2018-09-18 06:30
【摘要】：癌癥嚴(yán)重威脅著人類的健康,而Ras信號(hào)通路在癌癥的發(fā)生、發(fā)展過程中起到著很重要的作用。Ras蛋白家族是一類低分子量的GTP結(jié)合蛋白,其主要分為H-Ras、N-Ras和K-Ras。在人類已發(fā)現(xiàn)的腫瘤中,RAS突變類型腫瘤約占全部腫瘤30%,其中K-Ras的突變更是占全部RAS突變的70%左右。經(jīng)研究表明,苯并三氮唑類小分子,在治療疾病方面有著很好的應(yīng)用,例如抗癌、抗真菌、抗炎癥等。因此,苯并三氮唑是一類具有優(yōu)勢(shì)的藥物化學(xué)骨架,可以應(yīng)用在藥物研發(fā)中。1,500多個(gè)化合物通過在T29/T9KT1P兩種細(xì)胞系上進(jìn)行差異性篩選,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濃度下,能夠選擇性的抑制T29KT1P細(xì)胞增殖。本文以07B11作為陽性化合物,通過合理的藥物設(shè)計(jì),設(shè)計(jì)合成了一系列的苯并三氮唑類小分子。通過T29細(xì)胞系和T29KT1P細(xì)胞系抗增殖實(shí)驗(yàn)驗(yàn)證,實(shí)驗(yàn)結(jié)果表明有一批在1-5 μM濃度下選擇性的抑制T29KT1P增殖的小分子化合物42,43,67,70和71。通過構(gòu)效關(guān)系分析,表明在苯并三氮唑這一優(yōu)勢(shì)化學(xué)骨架中,在5-氨基位點(diǎn)引入溴代或者氯代乙�；鶗r(shí),其在T29KT1P細(xì)胞系上的抗增殖活性最好；對(duì)于2-苯基上的修飾,苯基的4號(hào)位氯取代和甲氧基取代對(duì)于保持小分子抗增殖活性是最好的。綜合對(duì)比小分子化合物42,43,67,70和71在T29KT1P/T29實(shí)驗(yàn)數(shù)據(jù),化合物67較其他化合物能夠更好的選擇性抑制T29KT1P細(xì)胞增殖�；衔�67在人源正常細(xì)胞系、K-Ras野生型和K-Ras突變型癌細(xì)胞系上進(jìn)行細(xì)胞增殖實(shí)驗(yàn),發(fā)現(xiàn)其在5 μM時(shí)候,能夠選擇性的抑制K-Ras突變癌細(xì)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.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：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.
【學(xué)位授予單位】：華東師范大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R91;R914.5
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