title: N6-Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A3Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation.
abstract: Potent and selective A3adenosine 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. N7isomers 3t and 3u were much weaker in binding than corresponding N9isomers, 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.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Jinha
authors.initials: J
authors.lastname: Yu
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.|College of Chemistry and Chemical Engineering, Liaoning Normal University , Dalian 116-029, China.
authors.forename: Long Xuan
authors.initials: LX
authors.lastname: Zhao
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Korea.
authors.forename: Jongmi
authors.initials: J
authors.lastname: Park
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Sahu
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Korea.
authors.forename: Minghua
authors.initials: M
authors.lastname: Cui
authors.affiliation: 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.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Moss
authors.affiliation: 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.
authors.forename: Eva
authors.initials: E
authors.lastname: Hammes
authors.affiliation: 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.
authors.forename: Eugene
authors.initials: E
authors.lastname: Warnick
authors.affiliation: 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.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Minsoo
authors.initials: M
authors.lastname: Noh
authors.affiliation: College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University , Seoul 03760, Korea.
authors.forename: Sun
authors.identifier: 0000-0002-7669-7954
authors.initials: S
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Dongguk University , Goyang, Gyeonggi-do 410-820, Korea.
authors.forename: Hee-Chul
authors.initials: HC
authors.lastname: Ahn
authors.affiliation: Department of Chemistry, The University of Suwon , Hwaseong, Gyeonggi-do 445-743, Korea.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Kenneth A
authors.identifier: 0000-0001-8104-1493
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.
authors.forename: Lak Shin
authors.identifier: 0000-0002-3441-707X
authors.initials: LS
authors.lastname: Jeong
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D058909:Adenosine A3 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D016566:Organoselenium Compounds / Q000737:chemistry*; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: C531224:4'-selenoadenosine; D058909:Adenosine A3 Receptor Agonists; D016566:Organoselenium Compounds; D000241:Adenosine