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J Med Chem. 2017 Apr 27;60(8):3422-3437. doi: 10.1021/acs.jmedchem.7b00241. Epub 2017 Apr 19.

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

Author information

1
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
2
College of Chemistry and Chemical Engineering, Liaoning Normal University , Dalian 116-029, China.
3
College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Korea.
4
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, and Digestive and Kidney Disease, National Institutes of Health , Bethesda, Maryland 20892, United States.
5
College of Pharmacy, Dongguk University , Goyang, Gyeonggi-do 410-820, Korea.
6
Department of Chemistry, The University of Suwon , Hwaseong, Gyeonggi-do 445-743, Korea.

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.

PMID:
28380296
PMCID:
PMC5479327
DOI:
10.1021/acs.jmedchem.7b00241
[Indexed for MEDLINE]
Free PMC Article

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