新型芳基脲类VEGFR抑制剂的设计、合成及抗肿瘤活性研究

发布时间：2018-03-04 08:15

本文选题：抗肿瘤药物　切入点：芳基脲衍生物　出处：《广西医科大学》2016年硕士论文　论文类型：学位论文

【摘要】：恶性肿瘤是人类死亡的主要原因之一。近年来,我国的癌症发生率也呈现出快速增长的态势。蛋白激酶抑制剂是一种重要的分子靶向抗肿瘤药物,其中以受体酪氨酸激酶抑制剂研究最为广泛。在目前已知的各种血管生成因子中,血管内皮细胞生长因子(VEGF)活性最强、专属性最高。其受体VEGFR隶属于受体酪氨酸激酶超家族,主要有VEGFR-1、VEGFR-2、VEGFR-3三种亚型。VEGF/VEGFR参与调控机体的一系列生理病理效应,是促使新生血管形成的关键,与多种恶性肿瘤的生长、转移、预后关系密切。替沃扎尼(Tivozanib, KRN-951)是一种强效、特异的VEGFR抑制剂,口服有效,对VEGFR的三种主要亚型都表现出强抑制活性,肾细胞癌的III期临床显示其在无进展生存期、肿瘤反应率及耐药性方面均优于原有药物索拉非尼。替沃扎尼对其他肿瘤的治疗也有不错的进展。为了寻找活性更好的抗肿瘤药物,本课题以替沃扎尼为先导化合物,结合相关文献研究及实验室已有的工作基础,利用生物电子等排原理和拼接原理,重点对药物分子的疏水结合区和变构结合区的结构进行替换改造,进行了如下设计：1、保留其喹啉母核(A环)作为基本骨架结构以竞争性占据ATP腺嘌呤结合位点,保留芳基脲结构作为重要的活性结合单元；2、保留B环作为疏水结合基团,保留取代基C1原子的存在之外,也尝试替换为F原子,并变换取代基的位置,考察不同取代基及不同取代位置对药物分子活性的影响；3、在喹啉环的7-C位尝试两种设计方案：一种是保留甲氧基,另一种是替换为3-吗啉丙氧基,以此考察不同侧链对分子活性的影响；4、端基脲结构被寄望于占据变构口袋,增强药效和药物选择性,故此在端基成脲基团的选择上参考索拉非尼和乐伐替尼的结构,作以如下设计：①保留异恶唑结构,间位甲基提供大的位阻以期获得较高活性；②对接不同的取代苯基,间位三氟甲基提供大的位阻以期获得较高活性；③对接小分子烷基如环丙基和异丙基等；由此考察不同基团对活性的影响。依照上述新型芳基脲类VEGFR抑制剂的设计,我们以4-羟基-6-甲氧基-7苄氧基喹啉为原料,经过不同路线合成关键中间体Ⅰ-4a、Ⅰ-4b、Ⅰ-8a、 Ⅰ-8b、Ⅰ-8c,然后在中间体Ⅱ-1、Ⅱ-2、Ⅱ-3等的参与下合成终产物,实验中,我们探索了不同的合成路线,对部分反应条件进行了优化；合成了19个相关中间体,并完成了其中15个新目标化合物的合成,目标化合物的结构经1H-NMR鉴定。随后我们以A549人肺癌细胞株为受试对象,对化合物的体外抗肿瘤活性进行了初步研究。结果表明,化合物Ⅹ-01、Ⅹ-02、Ⅹ-06、Ⅹ-07、Ⅹ-09、 Ⅹ-10、Ⅹ-11、Ⅹ-13、Ⅹ-14、Ⅹ-15等多个化合物表现出显著的体外活性,甚至优于阳性对照药,提示可以开展进一步的研究。
[Abstract]:Malignant tumor is one of the main causes of human death. In recent years, China's cancer incidence rate is also showing a rapid growth trend. The protein kinase inhibitor is an important molecular targeted anti-tumor drugs, which to study the receptor tyrosine kinase inhibitors are most widely used. At present all known angiogenic factors, vascular endothelial cell growth factor (VEGF) activity was the strongest, the highest specificity. Its receptor VEGFR belongs to receptor tyrosine kinase superfamily, including VEGFR-1, VEGFR-2, a series of physiological and pathological effects of three subtypes of VEGFR-3.VEGF/VEGFR involved in the regulation of the body, is the key to promote angiogenesis, growth and metastasis, malignant tumor. The prognosis is closely related. For Vozani (Tivozanib, KRN-951) is a potent inhibitor of VEGFR, specific, effective oral VEGFR three major subtypes showed strong inhibitory activity, Renal cell carcinoma III clinical show in progression free survival, tumor response rate and drug resistance were better than that of the original drug sorafenib treatment for Vozani. For other tumors also have good progress. In order to find the better activity of antitumor drugs, this topic for Vozani as the lead compound, combined with basic research and laboratory previous work, using the bioisostere principle and the principle of combination of key hydrophobic drug molecule binding and the allosteric binding area structure to replace the transformation of design are as follows: 1, to retain the quinoline nucleus (A) as the basic framework to occupy the competitive ATP adenine binding sites, retention arylurea structure as an important activity of unit; 2, to retain the B ring as a hydrophobic binding group, retention of substituted C1 atoms exist, also try to replace F atoms, and transform from The position of substituted groups, the effects of different substituent groups and the effect of different substituted position of drug activity; 3, to two design schemes of the quinoline ring 7-C: one is the preservation of methoxy, another is substituted for 3- morpholine propoxy, so as to investigate the effects of different side chains of molecules; 4, the structure was expected to occupy the terminal urea allosteric pocket, enhance the efficacy and selectivity of drugs, so in the end to urea group selection of sorafenib and reference structure of icotinib, as in the following: 1. The design retains a methyl isoxazole structure, provided steric large in order to obtain higher activity; substituted phenyl the docking between three different, trifluoromethyl provided steric large high activity to the docking of small molecules such as; alkyl cyclopropyl and isopropyl; the effect of different groups on the activity. According to the above new aryl ureas VEGFR The formulation design, we use 4- hydroxy -6- methoxy -7 benzyloxyquinoline as raw material, through the different route of synthesis of the key intermediate of -4a, 1 -4b, 1 -8a, 1 -8b, 1 -8c, and then in the intermediate II -1 II -2 II in -3 under the synthesis of the final product in the experiment, we to explore the different synthesis routes, on the part of the reaction conditions were optimized; 19 intermediates were synthesized, and completed the synthesis of 15 new compounds, the structure of the target compound was identified by 1H-NMR. Then we use A549 human lung cancer cell lines as subjects, the antitumor activity of the compounds. In vitro were studied. The results showed that the compound x -01 x -02 x -06 x -07, -09 x, x, X -10, -11 x -13, -14 x, x, -15 and other compounds showed significant activity in vitro, even better than the positive control drug, that can be further studied.

【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R914;R96

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