View : 593 Download: 0
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
- 최선
- Issue Date
- 2017
- Journal Title
- Journal of Medicinal Chemistry
- ISSN
- 0022-2623
- Citation
- Journal of Medicinal Chemistry vol. 60, no. 8, pp. 3422 - 3437
- Publisher
- American Chemical Society
- Indexed
- SCIE; 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
- Appears in Collections:
- 약학대학 > 약학과 > Journal papers
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML