含环丙烷结构的C-葡萄糖苷类钠-葡萄糖共转运子2抑制剂的设计、合成与降血糖活性研究
收稿日期: 2015-08-05
修回日期: 2015-11-01
网络出版日期: 2015-11-06
基金资助
陕西省教育厅专项科研(No. 15JK1203)、国家自然科学基金(No. 21302141)和山东省自然科学基金(No. ZR2015BM028)资助项目.
Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors
Received date: 2015-08-05
Revised date: 2015-11-01
Online published: 2015-11-06
Supported by
Project supported by the Scientific Research Projects of Shaanxi Education Department (No. 15JK1203), the National Natural Science Fundation of China (No. 21302141) and the Natural Science Foundation of Shandong Province (No. ZR2015BM028).
研究设计并以取代的苯甲酸为原料成功合成了一系列含有环丙烷结构的C-葡萄糖苷类钠-葡萄糖共转运子2 (SGLT2)抑制剂, 并对环丙烷部分的合成方法进行了研究, 对所有化合物的结构经过了1H NMR和HR-MS的表征. 大鼠尿糖排泄(UGE)实验显示, 所合成的7个含有环丙烷结构的C-葡萄糖苷类化合物1a~1g均显示较强的降血糖活性, 其中(1S)-1-脱氧-1-{4-氯-3-[1-(4-乙氧基苯基)环丙-1-基]苯基}-D-葡萄糖(1e)的活性最强, 但是仍比dapagliflozin低, 显示出dapagliflozin的结构改造不能耐受环丙烷结构, 且dapagliflozin中Cl原子的位置在类似物中是最优的.
史永恒 , 周春梅 , 张盼龙 , 刘继平 , 赵桂龙 , 王玉丽 . 含环丙烷结构的C-葡萄糖苷类钠-葡萄糖共转运子2抑制剂的设计、合成与降血糖活性研究[J]. 有机化学, 2016 , 36(3) : 604 -612 . DOI: 10.6023/cjoc201508003
A novel series of cyclopropane-bearing C-glucosides were designed and synthesized as sodium-glucose cotransporter 2 (SGLT2) inhibitors starting from the substituted bromobenzoic acids. The reaction condition for the construction of the cyclopropane moiety was studied, and a more economical synthetic route was established. All the synthesized compounds were characterized by 1H NMR and HR-MS. In vivo evaluation of these compounds by rat urinary glucose excretion (UGE) test revealed that all the synthesized seven cyclopropane-bearing C-glucosides 1a~1g exhibited potent hypoglycemic activity, among which (1S)-1-deoxy-1-{4-chloro-3-[1-(4-ethoxyphenyl)cyclopropyl-1-yl]-phenyl}-D-glucopyranose (1e) was the most potent one but still exhibited lower hypoglycemic activity to dapagliflozin, demonstrating that the cyclopropane moiety can not be well tolerated in dapagliflozin molecule and the position of the Cl atom in dapagliflozin is the best among the analogues.
Key words： cyclopropane; C-glucoside; SGLT2 inhibitor; synthesis; hypoglycemic activity
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