Citation: Wu Jianbing, Yin Wei, Zhang Yinqiu, Ye Hui, Li Yunman, Tian Jide, Huang Zhangjian, Zhang Yihua. Design and synthesis of the ring-opened derivative of 3-n-butylphthalide-ferulic acid-glucose trihybrids as potential anti-ischemic agents[J]. Chinese Chemical Letters, ;2020, 31(7): 1881-1886. doi: 10.1016/j.cclet.2020.02.031 shu

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

Wu Jianbing ^a ,
Yin Wei ^a ,
Zhang Yinqiu ^a ,
Ye Hui ^a ,
Li Yunman ^b,*, ,
Tian Jide ^c ,
Huang Zhangjian ^a,*, ,
Zhang Yihua ^a,*,

a.
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
b.
State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, China
c.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, United States

liyunman@cpu.edu.cn

zhangjianhuang@cpu.edu.cn

zyhtgd@163.com

Received Date: 22 December 2019
Revised Date: 15 February 2020
Accepted Date: 17 February 2020
Available Online: 18 February 2020

Figures(5)

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 NBP. 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.
- 3-n-Butylphthalide,
- Ferulic acid,
- Glucose,
- Hybrids,
- Ischemic,
- Brain-blood barrier
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