新型酪氨酸激酶抑制剂合成及活性评价及新型抗辐射分子的合成研究

发布时间：2018-03-27 06:18

本文选题：蛋白酪氨酸激酶抑制剂　切入点：L029衍生物　出处：《安徽医科大学》2017年硕士论文

【摘要】：本文工作分为两部分:第一部分是新型蛋白酪氨酸激酶抑制剂的设计合成研究。蛋白酪氨酸激酶(PTK)与肿瘤信号传导关系密切,已被作为抗肿瘤药物的靶点。c-Met作为小分子抑制剂与受体肝细胞生长因子(HGF)结合激活酪氨酸激酶,诱导细胞发生一系列生物学效应。HGF的特异性膜受体是原癌基因c-Met的表达产物。在多种肿瘤组织中发现HGF/c-Met信号通路异常活化,这种异常活化参与并调控这些肿瘤的发生、发展或转移,阻断HGF/c-Met信号途径可有效抑制肿瘤细胞生长、侵袭和转移。SU5416是HGF的高效抑制剂,其能阻断HGF诱导的Hep G2肝癌细胞侵袭和转移。本课题组前期对SU5416进行结构改造研究,从一系列化合物中发现了对c-Met酪氨酸激酶抑制活性佳且成药性好的新化合物L029。本文针对L029溶解性差等不足,通过还原在其活泼H等位点接入侧链3-二甲基氨基-1-丙烷、乙酸甲酯、丙酸甲酯等基团,设计合成了一系列L029衍生物。对目标化合物进行酪氨酸激酶活性初步筛选发现,在100mM的浓度下,化合物TM03、TM04、TM08、TM10、TM15、TM11K(TM11的钾盐)具有比较明显的抑制活性,其中TM11K对PTK的抑制作用强于L029;在1m M浓度下,化合物TM03、TM04、TM08、TM10、TM15、TM11Na也具有比较明显的抑制活性。第二部分是新型抗辐射分子DBIBB合成路线优化及其卤代衍生物的合成。LPA_2是一类G蛋白偶联受体,该受体的非脂类激动剂具有治疗急性放射病的作用。DBIBB作为一类特异性LPA_2激动剂具有降低急性放射性骨髓损伤和胃肠损伤的作用,这两个系统是高剂量放射暴露最敏感的器官。本文合成了DBIBB,并对其原合成路线进行了优化,缩短了反应的加热时间,避免了浓硫酸的使用,提高了产率,新的合成路线未见文献报道。为其规模化生产奠定了基础。文献报道DBIBB氟代衍生物及氯代衍生物活性远高于DBIBB,本文对此二者的合成方法进行改进,有望实现放大制备,为后期开展此类新型抗辐射分子的进一步研究奠定了基础。综上所述,本文以L029为先导化合物设计合成了12个新化合物,并筛选出几个酪氨酸激酶抑制活性良好的化合物,为此类化合物进一步结构优化提供了重要参考。同时,制备了DBIBB及其氟代、氯代衍生物,并对三者的合成路线进行了改进,为进一步开展新型抗辐射分子的研究奠定了基础。
[Abstract]:This paper is divided into two parts: the first part is the design and synthesis of novel protein tyrosine kinase inhibitors. C-Met has been used as a target of anti-tumor drugs to activate tyrosine kinase by binding to the receptor hepatocyte growth factor (HGF) as a small molecule inhibitor. A series of biological effects were induced. The specific membrane receptor of HGF was the expression product of proto-oncogene c-Met. Abnormal activation of HGF/c-Met signaling pathway was found in various tumor tissues, and this abnormal activation was involved in and regulated the occurrence of these tumors. Development or metastasis, blocking HGF/c-Met signaling pathway can effectively inhibit the growth of tumor cells. Invasion and metastasis. SU5416 is an efficient inhibitor of HGF, which can block the invasion and metastasis of Hep G2 hepatoma cells induced by HGF. A new compound L029, which has good inhibitory activity to c-Met tyrosine kinase and good drug properties, was found from a series of compounds. In this paper, due to the poor solubility of L029, 3-Dimethylamino-1-propane was inserted into the side chain of L029 at its active H sites. A series of L029 derivatives were designed and synthesized with methyl acetate and methyl propionate groups. Tyrosine kinase activity of the target compound was preliminarily screened. It was found that the potassium salt of TM03N, TM04, TM08, TM010, TM15 and TM11KN TM11 had obvious inhibitory activity at the concentration of 100mM. The inhibitory effect of TM11K on PTK was stronger than that on L029. The second part is the optimization of synthesis route of new anti-radiation molecule DBIBB and the synthesis of halogenated derivatives. The non-lipid agonist of the receptor has the effect of treating acute radiation sickness. As a specific LPA_2 agonist, DBIBB can reduce acute radiation-induced bone marrow injury and gastrointestinal injury. These two systems are the most sensitive organs for high dose radiation exposure. DBIBB was synthesized, and its original synthesis route was optimized to shorten the heating time of the reaction, avoid the use of concentrated sulfuric acid, and increase the yield. The new synthesis route has not been reported in literature, which lays a foundation for its large-scale production. It is reported in the literature that the activity of DBIBB fluorinated derivatives and chlorinated derivatives is much higher than that of DBB. In this paper, 12 new compounds were designed and synthesized with L029 as the lead compound, and several compounds with good inhibitory activity of tyrosine kinase were screened out. At the same time, DBIBB and its fluorinated and chlorinated derivatives were prepared, and their synthesis routes were improved, which laid a foundation for the further study of new radiation-resistant molecules.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

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