Synthesis and evaluation of N6-substituted apioadenosines as potential adenosine A3 receptor modulators |
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| Institution: | 1. Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium;2. Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;1. Center for Technologies Against Cancer, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan;2. Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510, Japan;3. Department of Radiological Science, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan;4. Department of Radiation Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima-shi, Hiroshima, Japan;5. Radiation Risk Reduction Research Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan;1. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany;2. CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A., Chemin du Foriest, 1420 Braine l’Alleud, Belgium;1. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019 Sesto Fiorentino, Italy;2. Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy;3. Scuola di Scienze del Farmaco e dei Prodotti della Salute, Università degli Studi di Camerino, via S.Agostino 1, 62032 Camerino (MC), Italy;1. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy;2. Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Università di Ferrara, Via Fossato di Mortara 17-19, 44121 Ferrara, Italy;3. Molecular Modeling Section (MMS), Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy;1. Department of Pharmacy, Faculty of Science, National University of Singapore, 3 Science Drive 2, Singapore;2. Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34128 Trieste, Italy;3. Institut für Pharmakologie und Toxikologie, Universität Würzburg, D-97078 Würzburg, Germany;4. Pharmaceutical Chemistry Division, School of Advance Science, Vellore Institute of Technology University, Vellore 632014, Tamilnadu, India;1. Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Sezione di Farmaceutica e Nutraceutica, Università degli Studi di Firenze, Via Ugo Schiff, 6, 50019, Sesto Fiorentino, Italy;2. Dipartimento di Scienze Mediche, Sezione di Farmacologia, Università degli Studi di Ferrara, Via Fossato di Mortara 17-19, 44121, Ferrara, Italy |
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| Abstract: | Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A3AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of β-d-apio-d-furano- and α-d-apio-l-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N6 of β-d-apio-d-furanoadenosine afforded an A3AR antagonist (10c, Ki = 0.98 μM), while a similar modification of an α-d-apio-l-furanoadenosine gave rise to a partial agonist (11c, Ki = 3.07 μM). The structural basis for this difference was examined by docking to an A3AR model; the antagonist lacked a crucial interaction with Thr94. |
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| Keywords: | G protein-coupled receptor Apionucleosides |
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