苯并咪唑-2-甲酰胺和1，4-二氢异喹啉-3-酮类衍生物的设计合成和抗肿瘤活性筛选
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摘要
受体酪氨酸激酶RTKs是一类具有酪氨酸激酶活性的受体,他们受配体如胰岛素、生长因子或者细胞因子等的刺激后自身磷酸化结构中的酪氨酸残基,召集并磷酸化下游信号蛋白分子,传递胞外信号至细胞质。RTKs可以激活多条重要的细胞信号传递传导通路,从而调节细胞的增殖、分化、迁移、代谢等过程。此外,酪氨酸激酶的异常表达还与肿瘤的侵袭和转移,肿瘤的血管生成,肿瘤的化疗抗药性密切相关。因此,以受体酪氨酸激酶为靶点进行药物研究成为国际上抗肿瘤药物研究的热点。本论文第一章介绍了RTKs及其抑制剂。
基于RTKs抑制剂的基础及对RTKs信号转导途径的了解,本文从多靶点抑制剂的角度考虑,设计合成了一类含有苯并咪唑-2-甲酰胺的拟肽类化合物,共136个,其中48个化合物经过MS和1HNMR表征,并对合成的苯并咪唑-2-甲酰胺拟肽类化合物进行了细胞水平抗肿瘤生物活性测试。测试结果发现,在30μmol/L浓度下,化合物对HepG2肿瘤细胞有一定的选择性抑制作用。其中6个化合物表现出较好的抑制活性,化合物4.3.7的活性最好,对HepG2的抑制率为35.6%，对KB细胞株的抑制率为12.5%以上。构效关系显示,当中间连接氨基酸为侧链有取代或芳环取代的氨基酸对细胞的抑制活性较强,第二位点以含N杂原子的芳香酸取代时活性最优。
异喹啉酮是一类很重要的母核结构和药物中间体,它出现在多类具有抗肿瘤活性、抗微生物活性及抗疟原虫活性的天然化合物和药物中；同时,它还是合成谷氨酸类亚型非竞争性抑制剂的重要中间体。对异喹啉母核生物活性的研究促使研究者们去寻找更多简便高效的方法来制备此类化合物,本文介绍了利用分子内Heck关环反应高效简便地合成一类具有高度区域和空间选择性的1,4-二氢异喹啉-3-酮衍生物。同时,对该类化合物进行抗肿瘤活性筛选,筛选结果表明绝大部分化合物都具有良好的抗肿瘤活性。
The Receptor tyrosine kinases (RTKs) are a class of receptors with tyrosine kinase activities, which can be activated by corresponding ligands such as insulin, growth factors or cytokines. When stimulated by these ligands, RTKs self-phosphorylate tyrosine residues of their own, and then, they transfer extracellular signal to the cytoplasm by followed convening and phosphorylating of downstream signaling proteins. RTKs can mediate sevaral important cellular signal trasction pathways to regulate cell proliferation, differentiation, migration, metabolism and other processes. Furthermore, it is confirmed that tumor invasion, metastasis, angiogenesis, resistance to chemotherapy are closely related to the abnormal expression of RTKs. Therefore, RTKs are considered as significant anti-cancer drug targets. The first chapter of this thesis reviewed on the RTKs and their inhibitors.
Based on the knowledgement of RTKs and the signal transduction pathways mediated by them, we designed and synthesized a class of benzoimidazol-2-formamide peptide-like inhibitors from the perspective of multi-target inhibitors to RTKs. We synthesized a total number of 136 benzoimidazol-2-formamides,48 of which have been characterized by MS and 1H NMR. Furthermore, they were used for the biological evaluation in vitro. The biological evaluation results indicated that most synthesized compounds showed a slightly selective inhibition to HepG2 tumor cells on the concentration of 30μmol/L. Six of the tested compounds showed good antiproliferative activities, compound 4.3.7 was found to have the most potent cytotoxicity against HepG2 and KB with inhibition values of 35.6% and 12.5%. Structure-activity relationship showed that when there were aromatic amino acids on R1 position, compounds showed better inhibition to tumor cells, while heterocycle acids on the R2 position proved to be more favorable substitute groups.
The isoquinolinone is an important heterocyclic scaffold widely found in many natural alkaloids and pharmaceuticals that exhibit antitumor, antimicrobial, antiplasmodial activity and noncompetitive inhibition to AMPA receptor. The wide range of biological and pharmacological importance of isoquinolinones promoted us to prepare new derivatives of these compounds utilizing a simple and efficient method. We reported an efficient method for the synthesis of 4-substituted-1,4-dihydro isoquinolin-3-ones employing an intramolecular Heck reaction, providing full regio-and stereoselectivity. Most of the synthesized compounds showed potent antiproliferative activities against tumor cell lines.
基于RTKs抑制剂的基础及对RTKs信号转导途径的了解,本文从多靶点抑制剂的角度考虑,设计合成了一类含有苯并咪唑-2-甲酰胺的拟肽类化合物,共136个,其中48个化合物经过MS和1HNMR表征,并对合成的苯并咪唑-2-甲酰胺拟肽类化合物进行了细胞水平抗肿瘤生物活性测试。测试结果发现,在30μmol/L浓度下,化合物对HepG2肿瘤细胞有一定的选择性抑制作用。其中6个化合物表现出较好的抑制活性,化合物4.3.7的活性最好,对HepG2的抑制率为35.6%，对KB细胞株的抑制率为12.5%以上。构效关系显示,当中间连接氨基酸为侧链有取代或芳环取代的氨基酸对细胞的抑制活性较强,第二位点以含N杂原子的芳香酸取代时活性最优。
异喹啉酮是一类很重要的母核结构和药物中间体,它出现在多类具有抗肿瘤活性、抗微生物活性及抗疟原虫活性的天然化合物和药物中；同时,它还是合成谷氨酸类亚型非竞争性抑制剂的重要中间体。对异喹啉母核生物活性的研究促使研究者们去寻找更多简便高效的方法来制备此类化合物,本文介绍了利用分子内Heck关环反应高效简便地合成一类具有高度区域和空间选择性的1,4-二氢异喹啉-3-酮衍生物。同时,对该类化合物进行抗肿瘤活性筛选,筛选结果表明绝大部分化合物都具有良好的抗肿瘤活性。
The Receptor tyrosine kinases (RTKs) are a class of receptors with tyrosine kinase activities, which can be activated by corresponding ligands such as insulin, growth factors or cytokines. When stimulated by these ligands, RTKs self-phosphorylate tyrosine residues of their own, and then, they transfer extracellular signal to the cytoplasm by followed convening and phosphorylating of downstream signaling proteins. RTKs can mediate sevaral important cellular signal trasction pathways to regulate cell proliferation, differentiation, migration, metabolism and other processes. Furthermore, it is confirmed that tumor invasion, metastasis, angiogenesis, resistance to chemotherapy are closely related to the abnormal expression of RTKs. Therefore, RTKs are considered as significant anti-cancer drug targets. The first chapter of this thesis reviewed on the RTKs and their inhibitors.
Based on the knowledgement of RTKs and the signal transduction pathways mediated by them, we designed and synthesized a class of benzoimidazol-2-formamide peptide-like inhibitors from the perspective of multi-target inhibitors to RTKs. We synthesized a total number of 136 benzoimidazol-2-formamides,48 of which have been characterized by MS and 1H NMR. Furthermore, they were used for the biological evaluation in vitro. The biological evaluation results indicated that most synthesized compounds showed a slightly selective inhibition to HepG2 tumor cells on the concentration of 30μmol/L. Six of the tested compounds showed good antiproliferative activities, compound 4.3.7 was found to have the most potent cytotoxicity against HepG2 and KB with inhibition values of 35.6% and 12.5%. Structure-activity relationship showed that when there were aromatic amino acids on R1 position, compounds showed better inhibition to tumor cells, while heterocycle acids on the R2 position proved to be more favorable substitute groups.
The isoquinolinone is an important heterocyclic scaffold widely found in many natural alkaloids and pharmaceuticals that exhibit antitumor, antimicrobial, antiplasmodial activity and noncompetitive inhibition to AMPA receptor. The wide range of biological and pharmacological importance of isoquinolinones promoted us to prepare new derivatives of these compounds utilizing a simple and efficient method. We reported an efficient method for the synthesis of 4-substituted-1,4-dihydro isoquinolin-3-ones employing an intramolecular Heck reaction, providing full regio-and stereoselectivity. Most of the synthesized compounds showed potent antiproliferative activities against tumor cell lines.
引文
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