基于葛根素结构的SGLT2抑制剂的设计、合成与体外生物活性研究
收稿日期: 2018-04-16
修回日期: 2018-05-22
网络出版日期: 2018-06-29
基金资助
陕西省高校科协青年人才托举计划（No.20160227）和国家级大学生创新创业训练计划（No.201710716008）资助项目.
Design, Synthesis and In vitro Biological Activity of SGLT2 Inhibitors Based on the Molecule Structure of Puerarin
Received date: 2018-04-16
Revised date: 2018-05-22
Online published: 2018-06-29
Supported by
Project supported by the Young Talent Fund of University Association for Science and Technology in Shaanxi Province (No. 20160227) ane the National Students' Training Program for Innovation and Entrepreneurship (No. 201710716008).
合成了一系列葛根素衍生物，采用稳定表达钠-葡萄糖协同转运蛋白2（human sodium-dependent glucose cotransporter 2，hSGLT2）的中国仓鼠卵巢细胞（Chinese hamster ovary，CHO）和14C-甲基葡萄糖苷为底物评价衍生物体外抑制SGLT2的活性.葛根素衍生物具有显著的抑制SGLT2的活性，部分葛根素双取代衍生物的IC50（hSGLT2）可达20~30 nmol·L-1，是葛根素活性的40~60倍.单取代衍生物如正己基葛根素（1i）、正辛基葛根素（1j）、对甲基苄基葛根素（1l）和对甲氧基苄基葛根素（1m）也表现出很强的抑制SGLT2活性，且保留了7-OH结构，可能保留了母核葛根素抗氧化、调血脂的药理活性，这对糖尿病及其心血管并发症的治疗是有利的.
史永恒 , 白黎明 , 马丽 , 陈宇阳 , 刘继平 , 张恩户 . 基于葛根素结构的SGLT2抑制剂的设计、合成与体外生物活性研究[J]. 有机化学, 2018 , 38(8) : 1963 -1971 . DOI: 10.6023/cjoc201804032
A new class of mild sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors with glucosyl isoflavone structure were prepared from puerarin. The in vitro biological activity was performed on Chinese hamster ovary (CHO) cells stably expressing human SGLT2 while taking[14C]-methyl-D-glucopyranoside ([14C]-AMG) as the substrate. Some derivatives exhibited potent activity against SGLT2 with IC50 among 20~30 nmol/L. The inhibitory activities of derivatives with more lipophilic substitutents were more potent. The compounds whose 4'-OH and 7-OH were both protected with alkyl or benzyl are more active than those with only the 4'-OH being protected. The inhibitory activity of some homologues has no great difference. 4'-O-n-Hexylpuerarin (1i), 4'-O-n-octylpuerarin (1j), 4'-O-(4-methylbenzyl)puerarin (1l), 4'-O-(4-methoxylbenzyl)-puerarin (1m) with moderate inhibitory activity against SGLT2 may have anti-oxidant and anti-atherosclerotic properties due to the presence of Ar-OH in the molecule structure, which will be very useful to treat diabetic disease and cardiovascular complications.
Key words： puerarin; derivative; SGLT2 inhibitor; diabetes; in vitro biological
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