Synthesis of novel 2-pyrrolidinone and pyrrolidine derivatives and study of their inhibitory activity against autotaxin enzyme |
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| Affiliation: | 1. Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece;2. Division of Immunology, Biomedical Sciences Research Center “Alexander Fleming”, Athens 16672, Greece;3. NovaMechanics Ltd, Nicosia 1065, Cyprus;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China;2. College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China;1. Graduate School of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan;2. Computer-aided Molecular Modeling Research Center, Kansai (CAMM-Kansai), 3-32-302, Tsuto-Otsuka, Nishinomiya 663-8241, Japan;3. Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan;4. Department of Pathobiochemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan;5. Faculty of Clinical Nutrition, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan;1. Center for Drug Discovery, RTI International, Research Triangle Park, NC 27709, United States;2. Center for Pulmonary Vascular Disease, Duke University Medical Center, Durham, NC 27710, United States;1. Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, 210037, Jiangsu, China;2. Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka, 533-0024, Japan;3. Oakwood Chemical, Inc, 730 Columbia Hwy. N, Estill, SC, 29918, USA;4. Department of Small Molecule Drug Discovery, Bristol Myers Squibb Research and Early Development, PO Box, 4000, Princeton, NJ, 08543 4000, United States;5. Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizábal 3, 20018, San Sebastián, Spain;6. IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013, Bilbao, Spain;1. Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, USA;2. Department of Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;3. Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA;4. Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN 46202, USA;5. Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599-3290, USA;1. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, F-59000 Lille, France;2. Laboratoire de Chimie Durable et Santé, Health & Environment Department, Team Sustainable Chemistry, Ecole des Hautes Etudes d’Ingénieur (HEI), Yncréa Hauts-de-France, 13 Rue de Toul, F-59046 Lille, France;3. UFR Pharmacie, Laboratoire de Chimie Analytique, BP 83, F-59006 Lille, France;4. ‘Alexandru Ioan Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania;5. Institut de Chimie Pharmaceutique Albert Lespagnol, 3 Rue du Professeur Laguesse, F-59000 Lille, France;6. Sorbonne University, Université de Technologie de Compiègne, ESCOM, EA 4297 TIMR, Centre de recherche Royallieu, CS 60319, 60203 Compiègne cedex, France |
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| Abstract: | Autotaxin (ATX), a glycoprotein (~125 kDa) isolated as an autocrine motility factor from melanoma cells, belongs to a seven-membered family of ectonucleotide pyrophosphatase/phosphodiesterase (ENPP), and exhibits lysophospholipase D activity. ATX is responsible for the hydrolysis of lysophosphatidylcholine (LPC) to produce the bioactive lipid lysophosphatidic acid (LPA), which is upregulated in a variety of pathological inflammatory conditions, including fibrosis, cancer, liver toxicity and thrombosis. Given its role in human disease, the ATX-LPA axis is an interesting target for therapy, and the development of novel potent ATX inhibitors is of great importance. In the present work a novel class of ATX inhibitors, optically active derivatives of 2-pyrrolidinone and pyrrolidine heterocycles were synthesized. Some of them exhibited interesting in vitro activity, namely the hydroxamic acid 16 (IC50 700 nM) and the carboxylic acid 40b (IC50 800 nM), while the boronic acid derivatives 3k (IC50 50 nM), 3l (IC50 120 nM), 3 m (IC50 180 nM) and 21 (IC50 35 nM) were found to be potent inhibitors of ATX. |
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| Keywords: | 2-pyrrolidinones Pyrrolidines Autotaxin Inhibitor DCU" },{" #name" :" keyword" ," $" :{" id" :" k0030" }," $$" :[{" #name" :" text" ," _" :" dicyclohexylurea DCC" },{" #name" :" keyword" ," $" :{" id" :" k0040" }," $$" :[{" #name" :" text" ," _" :" dicyclohexylcarbodiimide DMF" },{" #name" :" keyword" ," $" :{" id" :" k0050" }," $$" :[{" #name" :" text" ," _" :" dimethylformamide DMSO" },{" #name" :" keyword" ," $" :{" id" :" k0060" }," $$" :[{" #name" :" text" ," _" :" dimethyl sulfoxide DCM" },{" #name" :" keyword" ," $" :{" id" :" k0070" }," $$" :[{" #name" :" text" ," _" :" dichloromethane THF" },{" #name" :" keyword" ," $" :{" id" :" k0080" }," $$" :[{" #name" :" text" ," _" :" tetrahydrofuran TLC" },{" #name" :" keyword" ," $" :{" id" :" k0090" }," $$" :[{" #name" :" text" ," _" :" thin-layer chromatography EtOAc" },{" #name" :" keyword" ," $" :{" id" :" k0100" }," $$" :[{" #name" :" text" ," _" :" ethyl acetate EDC.HCl" },{" #name" :" keyword" ," $" :{" id" :" k0110" }," $$" :[{" #name" :" text" ," _" :" 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride HOBt" },{" #name" :" keyword" ," $" :{" id" :" k0120" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" __text__" ," _" :" 1" },{" #name" :" italic" ," _" :" -" },{" #name" :" __text__" ," _" :" hydroxybenzotriazole NHS" },{" #name" :" keyword" ," $" :{" id" :" k0130" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" N" },{" #name" :" __text__" ," _" :" -hydroxysuccinimide Boc" },{" #name" :" keyword" ," $" :{" id" :" k0140" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" t" },{" #name" :" __text__" ," _" :" -butoxycarbonyl Thr" },{" #name" :" keyword" ," $" :{" id" :" k0150" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" S-" },{" #name" :" __text__" ," _" :" threonine Asn" },{" #name" :" keyword" ," $" :{" id" :" k0160" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" S-" },{" #name" :" __text__" ," _" :" asparagine TBDMS" },{" #name" :" keyword" ," $" :{" id" :" k0170" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" t" },{" #name" :" __text__" ," _" :" -butyldimethylsilyl |
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