Na^+依赖性葡萄糖共转运体2抑制剂分子中糖片段上脱氧构效关系普遍性的研究  

Generality of Structure-Activity Relationship of Deoxylations of the Sugar Moiety in SGLT2 Inhibitors

作　　者：姜琳琳[1] 王玉丽[2] 刘钰强 谢亚非[2] 徐为人[2] 汤立达[2] 尹玲[1] 高志刚[2] 赵桂龙[2] 

机构地区：[1]济宁学院化学与化工系,山东曲阜273155 [2]天津药物研究院有限公司天津市新药设计与发现重点实验室,天津300193

出　　处：《中国药学杂志》2015年第22期1946-1953,共8页Chinese Pharmaceutical Journal

基　　金：国家自然科学基金资金项目(21302141);天津市应用基础与前言技术研究计划(14JCQNJC12900;14JCZDJC33500)

摘　　要：目的研究Na+依赖性葡萄糖共转运体2(SGLT2)抑制剂分子中糖片段上3-OH和6-OH脱氧构效关系的普遍性。方法在前期研究的基础上,进一步设计并合成了3-脱氧canagliflozin 5、6-脱氧ipragliflozin 6、6-脱氧empagliflozin 7和3-脱氧empagliflozin 8,并测试了它们体外抑制h SGLT2和h SGLT1的活性。结果利用各自的芳基卤化物9a^9c和3-脱氧/6-脱氧的苄基保护的葡萄糖酸内酯11a^11b作为原料,经过5步反应制备了上述设计的4个脱氧SGLT2抑制剂,体外活性测试表明化合物5和8几乎没有SGLT2抑制活性,而化合物6和7则具有与其各自母体结构基本一样的SGLT2抑制活性。结论 SGLT2抑制剂分子中葡萄糖片段上的6-OH脱去后对活性基本没有影响的结论具有一定的普遍性,但是3-OH脱去后对活性的影响则与母体分子相关,似乎没有普遍规律。OBJECTIVE To study the generality of the structure-activity relationships（ SARs） of 3-deoxylation and 6-deoxylation of the sugar moiety in SGLT2 inhibitors. METHODS Based on the earlier study,3-deoxycanagliflozin（ compound 5）,6-deoxyipragliflozin（ compound 6）,6-deoxyempagliflozin（ compound 7） and 3-deoxyempagliflozin（ compound 8） were synthesized and evaluated by in vitro h SGLT2 and h SGLT1 inhibitory assay. RESULTS The deoxylated SGLT2 inhibitors were synthesized from their corresponding aryl halides 9a- 9c and 3-/6-deoxylated perbenzylated gluconolactones 11a- 11 b. In vitro h SGLT2 and h SGLT1 inhibitory assay showed that compounds 5 and 8 almost lost SGLT2 inhibitory activity,while compounds 6 and 7 exhibited similar activities to their corresponding parent compounds. CONCLUSION It seems a general rule that 6-deoxylation of the sugar moiety in SGLT2 inhibitors has no effect on the SGLT2 inhibitory activity,whereas the effect of 3-deoxylation on SGLT2 inhibitory activity depends on the structures of the specific SGLT2 inhibitors,which does not show a universal rule.

关 键 词：SGLT2抑制剂 3-脱氧糖苷 6-脱氧糖苷 构效关系 合成 

分 类 号：R284[医药卫生—中药学]