Citation: Shi Yongheng, Zhou Chunmei, Zhang Panlong, Liu Jiping, Zhao Guilong, Wang Yuli. Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2016, 36(3): 604-612. doi: 10.6023/cjoc201508003 shu

Design, Synthesis and Hypoglycemic Activity of Cyclopropane-Bearing C-Glucosides as Sodium-Glucose Cotransporter 2 Inhibitors

a.
College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046
b.
Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193

Corresponding author: Shi Yongheng, shiyongheng1986@aliyun.com
Received Date: 5 August 2015
Revised Date: 1 November 2015

Fund Project: the National Natural Science Fundation of China 21302141the Scientific Research Projects of Shaanxi Education Department 15JK1203the Natural Science Foundation of Shandong Province ZR2015BM028

Figures(3)

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.
- cyclopropane,
- C-glucoside,
- SGLT2 inhibitor,
- synthesis,
- hypoglycemic activity
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沈阳化工大学材料科学与工程学院沈阳 110142