Design and synthesis of the ring-opened derivative of 3-n-butylphthalide-ferulic acid-glucose trihybrids as potential anti-ischemic agents |
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| Affiliation: | 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;1. College of Life Sciences, University of Chinese Academy of Science, Beijing 100049, China;2. Cardiovascular Division and Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA;1. Dipartimento di Chimica, Materiali e Ingegneria Chimica “Giulio Natta”, Politecnico di Milano, via Mancinelli 7, 20131 Milano, Italy;2. Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali, Via G. Giusti 9, 50121 Firenze, Italy;3. CNR-ISTM, Istituto di Scienze e Tecnologie Molecolari, via Golgi 19, 20133 Milano, Italy;4. Solvay Specialty Polymers, viale Lombardia 20, 20021 Bollate (MI), Italy;1. Department of Neurology, Hebei General Hospital, Shijiazhuang, 050051 Hebei Province, China;2. Department of Neurology, Hebei Medical University, Shijiazhuang, 050017 Hebei Province, China;1. Department of Neonatology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China;2. Department of Neonatology, Wenling Maternal and Child Health Care Hospital, Wenling, Zhejiang 317500, China;3. School of Nursing, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China;4. Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China;5. Department of Neonatology, Taizhou Maternal and Child Health Care Hospital of Wenzhou Medical University, Taizhou, Zhejiang 318000, China |
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| Abstract: | 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/R-induced 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. |
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| Keywords: | Ferulic acid Glucose Hybrids Ischemic Brain-blood barrier |
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