摘要/Abstract

鉴于前期研究发现的源于D-核糖的苯并咪唑并氮杂糖1和2具有良好的β-葡萄糖糖苷酶抑制活性, 通过关键的Mitsunobu反应, 设计合成了系列新型L-核糖源和2-脱氧-D-核糖源的苯并咪唑并氮杂糖衍生物6a~6c和7a~7c; 并依据电子等排的药物设计方法, 设计了系列新的糖环上2位氨基取代的稠合三环氮杂糖13a、13b和17a~17e; 以及4位烷氧基取代的氮杂糖28a和28b. 化合物13a和13b通过苄胺对甲磺酰化的羟基(OMs)取代合成, 化合物17a~17e通过氨基对三元环氧中间体15的开环制备, 化合物28a和28b通过4-羟基对卤代烃的亲核取代合成. 测试了化合物6a~6c、7a~7c、13a、13b、15、17a~17e、19、28a和28b对α-葡萄糖糖苷酶(黑曲霉)、β-葡萄糖糖苷酶(杏仁)和α-半乳糖糖苷酶(咖啡豆)的抑制活性, 结果显示所测化合物在10 μmol/L时对α-葡萄糖糖苷酶和α-半乳糖糖苷酶没有或微弱的抑制活性, 部分化合物表现出较好的β-葡萄糖糖苷酶抑制活性, 其中环氧中间体15和2-氨基化合物17a活性最好, IC₅₀值分别为10.5和11.7 μmol/L, 但均低于阳性对照品1的活性. 结果表明该类稠合三环氮杂糖是一类良好的选择性β-葡萄糖苷酶抑制剂.
关键词: 稠合三环氮杂糖, Mitsunobu反应, 糖苷酶抑制剂, 苯并咪唑, 环氧中间体
Based on our previous studies that benzimidazole-fused tricyclic iminosugars 1 and 2derived fromD-ribose inhibitedβ-glucosidase significantly, a series of novel tricyclic iminosugars 6a~6c and 7a~7c derived fromL -ribose and 2-deoxy-D-ribose, respectively, were designed and synthesized through the key Mitsunobu reaction. Additionally, based on the drug design method of isosterism, a series of tricyclic iminosugars derivitives 13a,13b and 17a~17e containing amino group on C-2 position, and 28a and 28b with alkoxyl group on C-4 position on sugar ring were designed. Compounds 13a and 13b were synthesized through substitution reaction of benzylamine and methylsulfonide hydroxy (OMs), while compounds 17a~17e were prepared through ring opened reaction of amine and the three-membered epoxy intermediate 15, compounds 28a and 28b were synthesized through nucleophilic substitution reaction of 4-OH and halohydrocarbon. The inhibitory activities of compounds 6a~6c,7a~7c,13a,13b,15,17a~17e,19,28a and 28bagainstα-glucosidase (Aspergillus niger),β-glucosidase (almonds) andα-galatosidase (coffee beans) were tested. The results showed that the tested compounds exhibited no or weakα-glucosidase andα-galatosidase inhibitory activities at 10 μmol/L. Some compounds exhibited good inhibitory activities againstβ-glucosidase. Among them, the epoxy intermediate 15 and compound 17a(2-amino) were the best ones with IC₅₀values of 10.5 and 11.7 μmol/L, respectively, but lower than that of the positive control 1. The results further suggested that such fused tricyclic iminosugars were the excellent and specific inhibitors againstβ-glucosidase.
Key words: fused tricyclic iminosugar, Mitsunobu reaction, glycosidase inhibitors, benzimidazole, epoxy intermediate


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