中文版 | English
题名

HIF-2α抑制剂的设计、合成及其构效关系的研究

其他题名
DESIGN,SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIP SUTDY OF HIF-2α INHIBITORS
姓名
姓名拼音
LI Chao
学号
12032106
学位类型
硕士
学位专业
085602 化学工程
学科门类/专业学位类别
0856 材料与化工
导师
李迎君
导师单位
前沿与交叉科学研究院
论文答辩日期
2022-05-14
论文提交日期
2022-06-21
学位授予单位
南方科技大学
学位授予地点
深圳
摘要

缺氧诱导因子HIF是一重要的氧敏感转录因子。HIF通路的过表达与实体瘤如肾细胞癌相关;HIF通路的抑制与炎症、贫血和其他缺氧缺血性疾病相关。HIF有三种亚基:HIF-1αHIF-2αHIF-3α已有的证据表明,HIF-2α亚基在肾透明细胞癌ccRCC中比其他两个亚基起到了更为关键的作用。利用HIF-2α的小分子抑制剂,阻断了ccRCC中肿瘤细胞的生长和肿瘤血管的生成已然成为治疗肾癌的一个新的途径。

20218月,默沙东Belzutifan(原PT2977)被美国FDA批准上市。然而,Belzutifan合成复杂,导致成本较高。因此,研发出选择性更好、价格更便宜的HIF-2α小分子抑制剂仍然是国际研究的热点。本研究通过高通量筛选获得了全新的先导化合物HST3782并基于结构的药物化学优化改造策略,得到了多个结构新颖的HIF-2α制剂,共合成了30个化合物。其后采用luciferase实验验证化合物32IC500.017 μM与阳性分子PT2385活性相当。而在qPCR实验中,所合成化合物对于VEGFHIF-2αEPO均表现出较好抑制活性而在斑马鱼体内的血管生成实验中HST3782表现了较好的抗血管生成效用。

综上所述,本研究成功获得了对HIF-2α具有选择性抑制作用的化合物,这些化合物作为HIF-2α靶向抑制剂,可以进行更进一步的研究和探讨。

 

关键词
语种
中文
培养类别
独立培养
入学年份
2020
学位授予年份
2022-07
参考文献列表

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