乏氧组织靶向苯胺喹唑啉类酪氨酸激酶抑制剂的设计与合成-药物化学专业论文.docx

中文摘要 目的：针对肿瘤中普遍存在的乏氧现象，通过结构修饰将硝基咪唑基团引入苯胺 喹唑啉类小分子酪氨酸激酶抑制剂分子结构中，以得到具有乏氧组织靶向功能的 新型EGFR/VEGFR-2酪氨酸激酶抑制剂。 方法：本文综合了肿瘤发生的分子生物学机制和乏氧对细胞信号传导通路的影响， 根据已有的苯胺喹唑啉类EGFR/VEGFR-2抑制剂和硝基咪唑类放射增敏剂的构 效关系，以凡德他尼为先导化合物，采用分子拼接和计算机辅助药物设计等方法 设计了目标分子，并对其进行化学合成、结构确证和生物活性筛选。 结果：本文合成了五大类共计37个未见文献报道的目标化合物，分子结构均经 1H-NMR和13C-NMR分析确证，分子量经质谱分析确证。药理活性筛选实验表明 部分目标化合物具有接近先导化合物的抗肿瘤活性，并对该类化合物的初步构效 关系进行了总结。 结论：本文合成的目标化合物不同程度地表现出肿瘤抑制活性，其中部分活性较 好的化合物可作为有潜力的乏氧组织靶向小分子酪氨酸激酶抑制剂候选药物，进 一步的结构修饰改造与药理筛选研究值得继续进行。 关键词：乏氧组织靶向；苯胺喹唑啉；酪氨酸激酶抑制剂；合成；生物活性筛 选 ABSTRACT Objective: Focusing on the hypoxia phenomenon in tumors, we introduced nitro-imidazole group to the structures of anilinoquinazoline small molecule tyrosine kinase inhibitors by structure modification to obtain new type of hypoxic tissue targeted EGFR/VEGFR-2 tyrosine kinase inhibitors . Methods: Considering the molecular biological mechanism for tumorigenisis and the influence of hypixia towards tumor cell signaling pathways, target compounds in this article were designed with Vandetanib as lead compound according to the exsiting structure-activity relationships of anilinoquinazoline EGFR/VEGFR-2 inhibitors and nitro-imidazole radiosensitizers through molecule splicing and computer-aided drug design methods. Synthesis, structure confirmation and biological activity test for these target compounds have also been completed. Results: In this paper, we have synthesized 37 unreported compounds of 5 types. Molecular structures of these compounds were comfirmed by 1H-NMR/13C-NMR and molecular weights were measured by mass spectrum. Biological activity test for target molecules indicated that some of them showed approximate anti-tumor activities with lead compound and we also have summerazied the preliminary structure-activity relationship for these target molecules. Conclusion: Target compounds synthesized in this paper showed anti-tumor activities in different degrees and some compounds with better tumor cell inhibition could become potential candidates of hypoxic tissue