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以1,2,3,6-四氢吡啶为起始原料,通过胺基保护、双键环氧化、胺化和去保护4步反应合成了8个羰基1,4’-联哌啶醇类σ_1受体配体,在锂盐催化作用下成功实现了环氧化合物的4位区域选择性胺化开环。体外活性筛选发现,羰基1,4’-联哌啶醇类σ_1受体配体对乳腺癌MCF-7细胞具有较好的抑制作用,IC_(50)值(半数抑制浓度)在52.68~176.79μmol/L内。进一步构效关系研究表明,与母体1,4’-联哌啶醇上4位相连的芳香环上的电子效应对抗肿瘤活性有影响,供电子取代基团将增强其抗肿瘤活性,而吸电子取代基团则减弱抗肿瘤活性;而与母体1,4’-联哌啶醇上4’位相连的芳香环上的给或吸电子基团取代,都将减弱其抗肿瘤活性;与母体1,4’-联哌啶醇上4’位直接相连的芳杂环吡啶基团由于对σ_1受体较低的亲和力而活性最低,表明影响活性的因素不再是电子密度而是立体位阻。
Tetrahydropyridine was used as the starting material to synthesize 8 carbonyl 1,4’-piperidinols through 4-step reaction of amine protection, double bond epoxidation, amination and deprotection Class σ 1 receptor ligands, the 4-site selective aminated ring opening of epoxy compounds has been successfully achieved under the catalysis of lithium salts. In vitro activity screening showed that carbonyl 1, 4-piperidinyl alcohol sigma 1 receptor ligand MCF-7 breast cancer cells have a good inhibitory effect, IC 50 values ?? (half inhibitory concentration) in 52.68 ~ 176.79μmol / L inside. Further structure-activity relationship studies have shown that the electronic effect on the aromatic ring attached to the 4 position of the parent 1,4’-piperidinol has an influence on the antitumor activity, and the electron donating group will enhance its antitumor activity, while the electron-withdrawing Substituent group weakened anti-tumor activity; Substitution with the donor or electron-withdrawing group on the aromatic ring attached to the 4 ’position of the parent 1,4’-piperidinol would reduce the antitumor activity; , The 4 ’direct coupling of the 4’ bipyridyl aromatic heterocyclic pyridyl group due to the lower affinity for sigma 1 receptor activity and the lowest, indicating that the factors that affect the activity is no longer the electron density but steric hindrance.