Discovery of novel (6S/12aS)-heptachpyridone capable of inhibiting thrombosis in vivo |
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| Institution: | 1. Department of Pharmacology, Chungnam National University College of Pharmacy, Daejeon 305-764, Republic of Korea;2. Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea;3. Institute of Drug Research & Development, Chungnam National University, Daejeon 305-764, Republic of Korea;4. Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology (VAST), 18 Hoang Quoc Viet St., Caugiay, Hanoi, Viet Nam;5. Department of Natural Product Chemistry, Chungnam National University College of Pharmacy, Daejeon 305-764, Republic of Korea;6. College of Pharmacy, Research Center for Bioresource and Health, Chungbuk National University, Cheongju 361-763, Republic of Korea;1. Faculty of Sciences of Bizerte, University of Carthage, Zarzouna, Bizerte, Tunisia;2. UR06/SP14 Disorders of Embryo-Fetal and Placental Development, Service of Embryo-Fetopathology, Center for Maternity and Neonatology of Tunis, Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia;3. UR05/08-08, LR99ES11, Department of Biochemistry, Rabta Hospital, Faculty of Medicine, Tunis El Manar University, Jebbari, Tunis, Tunisia;4. Laboratory of Human Genetics, Immunology and Pathology, Faculty of Sciences, Tunis El Manar University, Tunis, Tunisia |
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| Abstract: | The in vitro conversion of (1S,3S)-1-dimethoxylethyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid, (1S,3S)-DCCA, in rat plasma is monitored by HPLC-FT-ICR-MS. We show that the in vitro conversion of (1S,3S)-DCCA in rat plasma for 1 h leads to forming (6S/12aS)-bisdimethoxyethylheptachpyridone, reflecting intermolecular condensation of (1S,3S)-DCCA, and the in vitro conversion of (6S/12aS)-bisdimethoxyethylheptachpyridone in rat plasma for 1 h leads to forming (6S/12aS)-heptachpyridone, reflecting hydrolysis of (6S/12aS)-bisdimethoxyethylheptachpyridone. At a dose of 1.0 μmol/kg (6S/12aS)-heptachpyridone orally inhibits venous thrombosis and arterial thrombosis in vivo. Bleeding time, clotting time and international normalized ratio show that at this dose (6S/12aS)-heptachpyridone has no bleeding risk, does not lengthen clotting time and does not change the exogenous coagulation pathway. We also show that the reactions promoted by rat plasma are easy to practice by chemical synthesis. Thus our findings build a bridge across the in vivo conversion and the application. |
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| Keywords: | Metabolism Venous thrombosis Arterial thrombosis Bleeding HPLC-MS |
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