Design and synthesis of the ring-opened derivative of 3-n-butylphthalide-ferulic acid-glucose trihybrids as potential anti-ischemic agents  

作　　者：Jianbing Wu Wei Yin Yinqiu Zhang Hui Ye Yunman Li Jide Tian Zhangjian Huang Yihua Zhang 

机构地区：[1]State Key Laboratory of Natural Medicines,Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases,Center of Drug Discovery,China Pharmaceutical University,Nanjing 210009,China [2]State Key Laboratory of Natural Medicines,Department of Physiology,China Pharmaceutical University,Nanjing 210009,China [3]Department of Molecular and Medical Pharmacology,University of California,Los Angeles,CA 90095,United States

出　　处：《Chinese Chemical Letters》2020年第7期1881-1886,共6页中国化学快报（英文版）

基　　金：the National Natural Science Foundation of China(Nos.81773573,81822041,21977116 and 81673305);National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”(No.2018ZX09711002006-013);the open project of State Key Laboratory of Natural Medicines(No.SKLNMZZCX201824);State Key Laboratory of Pathogenesis,Prevention and Treatment of High Incidence Diseases in Central Asia Fund(No.SKL-HIDCA-2018-1);Part of the work was supported by Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX18_0795)。

摘　　要：To improve aqueous solubility and anti-ischemic activity of 3-n-butylphthalide(NBP),we designed and synthesized the ring-opened derivative of NBP-ferulic acid-glucose trihybrids(S1-S8).These hybrids inhibited adenosine diphosphate(ADP)-or arachidonic acid(AA)-induced platelet aggregation,among them,S2 was 30-fold more water-soluble,and over 10-fold more potent in inhibition of platelet aggregation,as well as reduced ROS generation and protected primary neuronal cells from OGD/Rinduced damage,in comparison with NB P.Additionally,S2 was more active than its three moieties alone or in combination,suggesting that the activity of S2 may be attributed to the synergistic effects of these moieties.Importantly,in vivo studies indicated that S2 not only possessed good pharmacokinetic profile,but also improved NBP distribution in rodent brain,suggesting that the glucose moiety in S2 may be recognized by glucose transporter 1(GLUT1)on blood-brain barrier(BBB),promoting it to penetrate through BBB.Our findings suggest that S2 may be a promising candidate for the intervention of ischemic stroke,warranting further study.

关 键 词：3-N-BUTYLPHTHALIDE Ferulic acid GLUCOSE HYBRIDS ISCHEMIC Brain-blood barrier 

分 类 号：R914[医药卫生—药物化学]