新型多靶点激酶抑制剂的设计合成及生物活性研究
摘要
细胞信号转导通路的改变是导致癌症形成的重要因素之一。癌细胞中由基因突变引起高表达的蛋白激酶是导致其信号转导通路异常的主要原因之一。我们以与癌症密切相关的三种激酶——Aurora A、CDK2和FLT3激酶为靶点组合,以SB1317为先导化合物,采用计算机辅助药物设计方法研究配体与靶酶的相互作用关系,在此基础上开展多靶点激酶抑制的设计与合成,以期望得到同时对三种靶激酶具有抑制活性的新型多靶点激酶抑制剂。
首先,我们使用MOE分子设计软件对Aurora A、CDK2及FLT3激酶进行蛋白叠合,寻找三类激酶活性口袋的共性,发现Aurora A、CDK2及FLT3三种激酶在邻近铰链区的部位存在一共同的亲水表面,分别由Lys162、Glu12及Arg849氨基酸残基构成。以此为基础进一步研究配体分子SB1317与三类激酶活性口袋的相互作用关系,精确设计出目标化合物。然后,应用现代有机合成方法与检测手段(HPLC.1H-NMR、MS及HRMS等)进行目标化合物的合成研究。最后根据文献报道方法进行体外生物活性测试研究。
本课题开发了两条以不同的环合方法为关键步骤的制备具有大环结构目标化合物的合成路线,并依据所设计的路线合成了17个未见文献报道的全新化合物,验证了合成路线的可行性,为后续研究工作提供了重要的化学基础；目标化合物的体外抑酶活性实验结果显示,在10μM时,所合成的化合物对Aurora A、CDK2及FLT3激酶均有较强的抑制活性。这一结果为多靶点激酶抑制剂的后续研究奠定了重要基础。
Direct and indirect involvement of kinases in tumor growth, metastasis and apoptosis make them as most promising targets for anticancer drug discovery. However, clinical use of kinase inhibitors has led to the emergence of severe drug resistant tumors. Therefore, there is an emergent need to develop novel multikinase inhibitors.
Aurora A, CDK2 and FLT3 are over expressed in many tumors, and the active sites of them were identified. In this study, we present an alignment of catalytic domainamino acid sequences of Aurora A, CDK2 and FLT3. The results has revealed that they have shared a hydrophilic surface consists of Lys162, Glu12 and Arg849 residue near the hinge. Then the binding mode of SB1317 was analyzed. On the basis of the results from molecular docking, hydrophilic groups were designed to interact with the hydrophilic surface, and aliphatic chains were designed to link these hydrophobic groups to N atom of benzyl in SB1317.
In this study, we established two novel general procedure for the synthesis of macrocylic compounds of interesting, and 17 novel compounds were synthesized and the structure of them were confirmed by MS,'H-NMR and HRMS. Most of the compounds we synthesized showed potent Aurora A, CDK2 and FLT3 inhibitory activities, providing a useful guideline for the rational design of novle multikinase inhibitors.
首先,我们使用MOE分子设计软件对Aurora A、CDK2及FLT3激酶进行蛋白叠合,寻找三类激酶活性口袋的共性,发现Aurora A、CDK2及FLT3三种激酶在邻近铰链区的部位存在一共同的亲水表面,分别由Lys162、Glu12及Arg849氨基酸残基构成。以此为基础进一步研究配体分子SB1317与三类激酶活性口袋的相互作用关系,精确设计出目标化合物。然后,应用现代有机合成方法与检测手段(HPLC.1H-NMR、MS及HRMS等)进行目标化合物的合成研究。最后根据文献报道方法进行体外生物活性测试研究。
本课题开发了两条以不同的环合方法为关键步骤的制备具有大环结构目标化合物的合成路线,并依据所设计的路线合成了17个未见文献报道的全新化合物,验证了合成路线的可行性,为后续研究工作提供了重要的化学基础；目标化合物的体外抑酶活性实验结果显示,在10μM时,所合成的化合物对Aurora A、CDK2及FLT3激酶均有较强的抑制活性。这一结果为多靶点激酶抑制剂的后续研究奠定了重要基础。
Direct and indirect involvement of kinases in tumor growth, metastasis and apoptosis make them as most promising targets for anticancer drug discovery. However, clinical use of kinase inhibitors has led to the emergence of severe drug resistant tumors. Therefore, there is an emergent need to develop novel multikinase inhibitors.
Aurora A, CDK2 and FLT3 are over expressed in many tumors, and the active sites of them were identified. In this study, we present an alignment of catalytic domainamino acid sequences of Aurora A, CDK2 and FLT3. The results has revealed that they have shared a hydrophilic surface consists of Lys162, Glu12 and Arg849 residue near the hinge. Then the binding mode of SB1317 was analyzed. On the basis of the results from molecular docking, hydrophilic groups were designed to interact with the hydrophilic surface, and aliphatic chains were designed to link these hydrophobic groups to N atom of benzyl in SB1317.
In this study, we established two novel general procedure for the synthesis of macrocylic compounds of interesting, and 17 novel compounds were synthesized and the structure of them were confirmed by MS,'H-NMR and HRMS. Most of the compounds we synthesized showed potent Aurora A, CDK2 and FLT3 inhibitory activities, providing a useful guideline for the rational design of novle multikinase inhibitors.
引文
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