苯并咪唑并氮杂糖的设计、合成及其糖苷酶抑制活性

Design and Synthesis of Benzimidazole-Iminosugars and Their Inhibitory Activities against Glycosidases

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10μmol/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11.7μmol/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.

Based on our previous studies that benzimidazole-fused tricyclic iminosugars 1 and 2 derived from D-ribose inhibitedβ-glucosidase significantly,a series of novel tricyclic iminosugars 6a~6c and 7a~7c derived from L-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 28b againstα-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 10μmol/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 IC50 values of 10.5 and 11.7μmol/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.