【作者】 史海波；

【导师】 裴文； 胡惟孝；

【作者基本信息】 浙江工业大学 ， 工业催化， 2011， 博士

【摘要】 以酪氨酸激酶为靶点进行药物研发成为国际上抗肿瘤药物研究的热点。已有多个单抗和小分子抑制剂己先后上市,超过100个药物分子正在进行临床研究。文献表明,2-氨基噻唑类化合物是一类显著的Src家族酪氨酸蛋白激酶抑制剂。本论文以2-氨基噻唑为母体结构,在2-位,4-位,5-位引入不同的含氮杂环及其他活性基团,构建具有多功能团取代的新型噻唑类化合物,其结构用包括X-单晶衍射等方法确定,并进行抗肿瘤活性的筛选,部分化合物进行了体内抗肿瘤活性的测定。具体研究内容如下:1、按Hantzsch反应合成重要的原料2-芳胺基-4-甲基-5-乙酰基-噻唑,并研究发现得到异构体2-亚胺-3-芳基-4-甲基-5-乙酰基-2,3-二氢噻唑共计18个,并通过IR、MS、1HNMR和HRMS表征结构。探讨研究了该反应的反应条件,明确了反应的温度和溶剂对异构体含量的影响规律,在极性溶剂中主要产物是2-3结构,而在非极性溶剂中主要得到2-4结构。推测反应机理并通过实验确证氢溴酸能促进2-4结构的生成。2、按Claisen-Schmidt缩合反应在噻唑环5-位上的乙酰基引入查尔酮结构,合成了 37个(E)-1-(4’-甲基-2’-芳胺基-噻唑-5’-基)-3-芳基-丙-2-烯-1-酮和4个(E)-1-(2’-亚胺基-3’-芳基-4’-甲基-2’-噻唑啉-5’-基)-3-芳基-丙-2-烯-1-酮,其结构用IR、MS、1HNMR和EA表征。初步体外抗肿瘤活性测试实验结果表明,在其5位引入查尔酮结构有利于活性提高,最好的结果为:化合物3-26对BGC-823和NCI-H460两种肿瘤细胞株有较好的增殖抑制活性,其IC50分别为5.40和6.32μM;化合物3-41对BGC-823和NCI-H460两种肿瘤细胞株有较好的增殖抑制活性,其IC50分别为9.70和6.31 μM。化合物3-10和3-41对ICR小鼠S180移植瘤抑制活性进行了测定,结果为两化合物高剂量组的抑瘤率相当。3、以2-芳胺基-4-甲基-5-乙醜基-噻唑为原料通过Bredereck嘧啶缩合法引入芳氨基-嘧啶环合成得到37个目标产物{4-[2-(芳基-甲基胺)-4-甲基-噻唑-5]-嘧啶-2}-芳胺,其结构用IR、MS、1HNMR和EA表征,其中三个化合物培养成晶体用X-单晶衍射仪进一步确证结构。初步体外抗肿瘤活性测试实验结果表明,引入芳氨基-嘧啶环能明显提高活性提高,化合物4-9对肿瘤细胞Ishikawa和A549有较强的抑制作用,其IC50分别为1.99和2.90μM,化合物4-30对肿瘤细胞A549有较强的抑制作用,其IC50为1.52μM。更多还原

【Abstract】 During the past few years,the role of Protein tyrosine kinases(PTKs)playing in the malignant Proliferation of tumour cell has been studied and revealed,and consequently the PTKs has been an important target to find a new drug.Many effective drugs of PTKs inhibitor have appeared on the market while much more drug molecules are ongoing clinical trials.2-aminothiazole has been proved a remarkably effect of Src family kinase inhibitor.We attempt to investigate whether introduction of methyl group,imino group,arylamino group,pyrimidine ring and aryl ring into thiazole at 2-,4-,or 5-position could enhance their anticancer activities or not.Thus,we constructed the basic structure of thiazole,and synthesized two series of novel thiazole-chalcones and thiazole-pyrimidines.These compounds were tested for their cytotoxic activity against several human tumor cell lines.It may be summarized as follows:1.According to the method of Hantzsch,eighteen 5-acetyl-4-methyl-2-arylamino-thiazole and isomer were prepared by arylthioureas and 3-bromo-acetylacetone under refluxing solvents.The structures of these compounds were confirmed by IR,1H NMR,MS and HRMS.The reaction conditions have been studied and influence of different temperatures and solvents on the ratio of isomers were discussed.The final ratio of aminothiazoles 2-3 and iminodihydrothiazoles 2-4 was depended on the equilibrium of intermediates,which might probably affected by the nature of solvents and in situ released hydrobromic acid might accelerate the formation of compounds 4.It could be speculated that non-polar solvents might enhance the yields of iminodihydrothiazoles 4 and the predominant aminothiazoles 2-3 in polar solvents.A plausible mechanism involving solvent effect was proposed.2.Based on the common structural features of chalcones reported in the literature,especially in the antitumor activities and we introduced the chalcones structure into thiazole at 5-position via Claisen-Schmidt condensation reaction.The total 37 compounds of(E)-1-(4-methyl-2-arylaminothiazol-5-yl)-3-arylprop-2-en-1-ones and(E)-1-(2-Imino-4-methyl-3-aryl-2,3-dihydro-thiazol-5-yl)-3-arylprop-2-en-1-ones were synthesized and tested for their cytotoxic activity against several human tumor cell lines in vitro.The structures of these compounds were confirmed by IR,1H NMR,MS and elemental analysis or HRMS.Primary SAR study indicated that utilizing of chalcones moiety as the linker was more beneficial for the activities.The most potent compound 3-26 exhibited significant activity against BGC-823 and NCI-H460 with IC50 of 9.70 and 6.31μM,respectively.The compounds 3-10 and 3-40 showed strong potential inhibitory in vitro and were further evaluated their antitumor activity in vivo in ICR mice bearing sarcoma 180 cells.The results showed that compound 3-10 and 3-40 through ig administration at dose of 50 mg/kg,exhibited moderate experimental therapeutic efficacy by 25%.3、The novel thirty-seven compounds of thiazol-pyrimidines were synthesized by the general pyrimidine condensation of Bredereck and tested for their cytotoxic activity against several human tumor cell lines in vitro by MTT.The structures of these compounds were confirmed by IR,1H NMR,MS and elemental analysis.Primary SAR study indicated that introduction of arylamino group and pyrimidine group into thiazole could enhance their anticancer activities.The compounds 4-9(IC50 1.99 and 2.99μM)and 4-30(IC50 7.98 and 1.52μM)showed strong potential inhibitory against Ishikawa and A549 with.The structure of compounds 4-15,4-23 and 4-35 were further confirmed by X-Ray Single Crystal Diffraction.更多还原