取代2H-苯并吡喃-3-甲酰苯胺化合物的合成及抗辐射活性评价

Synthesis and anti⁃radiation activity evaluation of substituted 2H⁃benzopyran⁃3⁃formylaniline compounds

目的发现新结构的活性分子,为抗辐射药物研究提供候选化合物。方法使用构象固定和官能团转换策略对Ex-RAD进行结构改造,设计并合成取代2H-苯并吡喃-3-甲酰苯胺化合物。通过照射细胞存活模型进行抗辐射活性筛选,并考察活性化合物的细胞毒性。优选活性化合物进行Western印迹实验,考察对照射细胞凋亡相关蛋白表达的影响,并通过照射小鼠模型评价其抗辐射活性。结果合成目标化合物21个,通过筛选发现8个化合物可以显著提高照射细胞的存活,选择4个化合物进行复筛和细胞毒性评价。优选化合物D19进行Western印迹实验,发现D19可以影响照射AHH-1细胞凋亡相关蛋白的表达。与辐射组相比,D19可以使全身8.6 Gy照射小鼠30 d存活率提高70%。D19对非致死剂量照射小鼠的血液系统具有保护作用。结论新结构的化合物D19具有明确的抗辐射活性,值得进一步深入研究。

Objective To discover new⁃structure active molecules in order to provide candidate compounds for anti⁃radiation drug research.Methods Conformational fixation and functional group conversion strategies were used to modify the structure of Ex⁃RAD before substituted 2H⁃benzopyran⁃3⁃formylaniline compounds were designed and synthesized.The anti⁃radiation activities of the synthesized compounds were screened via irradiated cell survival models and the cytotoxicity of the active compounds was examined.Western blotting assay was used to investigate the effects of the optimal compound on the expressions of apoptosis related proteins in irradiated cells.The anti⁃radiation activity of the optimal compound was evaluated through irradiated mice models.Results Twenty⁃one target compounds were synthesized,eight of which were found to significantly improve the survival of irradiated cells.Four compounds were selected for re⁃screening and cytotoxicity evaluation.Compound D19 was determined as the optimal compound that could affect the expressions of apoptosis related proteins in irradiated AHH⁃1 cells by Western blotting assay.Compared with the radiation group,the 30⁃day survival rate of D19 treated mice irradiated with 8.6 Gy of whole⁃body radiation increased by 70%.D19 showed protective effect on the blood system of non⁃lethal dose irradiated mice.Conclusion The novel compound D19 has shown strong anti⁃radiation activity and deserves more research.