氮芥缀合4-氨基喹唑啉衍生物双化疗协同作用抗肿瘤药物的构建及体外活性分析

发布时间：2018-05-03 10:50

本文选题：4-氨基喹唑啉 + EGFR　；参考：《遵义医学院》2017年硕士论文

【摘要】：目的:构建具有抗肿瘤活性和EGFR抑制剂活性的双化疗协同作用的单一药物分子,并对其药效学进行初步研究。方法:以2-氰基-4-硝基苯胺和DMF-DMA为起始原料微波一步合成4-硝基喹唑啉衍生物,随后用钯碳(Pd/C,10%)或铁粉还原转化成相应的氨基喹唑啉衍生物,通过亲核加成与芳香氮芥缩合得到目标前药分子。通过1H-NMR,13C-NMR、HRMS、FT-IR及单晶衍射等现代分析手段对中间体及目标前药分子进行结构和组成表征。采用MTT比色法对中间体及目标化合物进行了细胞毒性实验,初步评价目标前药的体外抗肿瘤活性,并采用ELISA法评估目标化合物的EGFR的抑制活性。结果:成功探寻出了经济、环保、高效的微波辅助“一锅”合成关键中间体4-氨基喹唑啉的低碳绿色合成方法,并考察了该法的条件和底物适应性。以此为基础,成功还原了三个4-氨基喹唑啉衍生物并合成了三个目标分子,经1H NMR、13C NMR、FT-IR、HRMS和单晶衍射等确认为预期结构目标分子。MTT法结果表明:化合物对SMMC-7721及Hep G2肿瘤细胞株表现出了优于临床上使用的抗肿瘤药物Gefitinib阳性对照抗肿瘤活性,且具有良好的EGFR的抑制活性。结论:在探寻出的喹唑啉药物关键中间体—4-氨基喹唑啉的低碳绿色合成途径之上,构建的目标前药分子初步表现出抗肿瘤活性和EGFR抑制剂活性双化疗协同联用性能,这对于发展多功能前药具有十分重要的意义。
[Abstract]:Aim: to construct a single drug molecule with two chemotherapeutic synergistic effects of antitumor activity and EGFR inhibitor activity, and to study its pharmacodynamics. Methods: 4-nitroquinazoline derivatives were synthesized by microwave with 2-cyano-4-nitroaniline and DMF-DMA as starting materials, and then reduced to corresponding aminoquinazoline derivatives by palladium carboxyl PD / c1010) or iron powder. The target prodrug molecules were obtained by nucleophilic addition and condensation of aromatic nitrogen mustard. The structure and composition of intermediates and target prodrug molecules were characterized by 1H-NMR-13C-NMR-HRMSFT-IR and single crystal diffraction. The cytotoxicity of intermediates and target compounds was tested by MTT colorimetry. The antitumor activity of target prodrug in vitro was preliminarily evaluated, and the inhibitory activity of EGFR was evaluated by ELISA method. Results: a low carbon green synthesis method of 4-aminoquinazoline, a key intermediate in "one pot" synthesis, was successfully developed, and the conditions and substrate adaptability of the method were investigated. On this basis, three 4-aminoquinazoline derivatives were successfully reduced and three target molecules were synthesized. By 1H NMR-13C NMR-FT-IRMS and single crystal diffraction, the results showed that the compounds exhibited better antitumor activity against SMMC-7721 and Hep G2 tumor cell lines than the clinical use of Gefitinib positive control. And has good inhibitory activity of EGFR. Conclusion: on the basis of exploring the low carbon green synthesis pathway of quinazoline key intermediate -4-aminoquinazoline, the target prodrug molecule has the ability of combining anti-tumor activity with EGFR inhibitor activity in combination with chemotherapy. This is of great significance for the development of multifunctional prodrug.
【学位授予单位】：遵义医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914;R96

【相似文献】