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N6-Substituted 5′-N-Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation

Title
N6-Substituted 5′-N-Methylcarbamoyl-4′-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation
Authors
Yu J.Zhao L.X.Park J.Lee H.W.Sahu P.K.Cui M.Moss S.M.Hammes E.Warnick E.Gao Z.-G.Noh M.Choi S.Ahn H.-C.Choi J.Jacobson K.A.Jeong L.S.
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2017
Journal Title
Journal of Medicinal Chemistry
ISSN
0022-2623JCR Link
Citation
Journal of Medicinal Chemistry vol. 60, no. 8, pp. 3422 - 3437
Publisher
American Chemical Society
Indexed
SCI; SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
Potent and selective A3 adenosine receptor (AR) agonists were identified by the replacement of 4′-oxo- or 4′-thionucleosides with bioisosteric selenium. Unlike previous agonists, 4′-seleno analogues preferred a glycosidic syn conformation and South sugar puckering, as shown in the X-ray crystal structure of 5′-N-methylcarbamoyl derivative 3p. Among the compounds tested, N6-3-iodobenzyl analogue 3d was found to be the most potent A3AR full agonist (Ki = 0.57 nM), which was ≥800- and 1900-fold selective for A1AR and A2AAR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA3AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N9 isomers, but compound 3t lacked A3AR activation, appearing to be a weak antagonist. 2-Cl-N6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at ≤50 μM. This suggests the potential for the development of 4′-selenonucleoside A3AR agonists as novel antistroke agents. © 2017 American Chemical Society.
DOI
10.1021/acs.jmedchem.7b00241
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약학대학 > 약학과 > Journal papers
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