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N-6-Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation
- N-6-Substituted 5'-N-Methylcarbamoyl-4'-selenoadenosines as Potent and Selective A3 Adenosine Receptor Agonists with Unusual Sugar Puckering and Nucleobase Orientation
- Yu, Jinha; Zhao, Long Xuan; Park, Jongmi; Lee, Hyuk Woo; Sahu, Pramod K.; Cui, Minghua; Moss, Steven M.; Hammes, Eva; Warnick, Eugene; Gao, Zhan-Guo; Noh, Minsoo; Choi, Sun; Ahn, Hee-Chul; Choi, Jungwon; Jacobson, Kenneth A.; Jeong, Lak Shin
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- JOURNAL OF MEDICINAL CHEMISTRY
- 0022-2623; 1520-4804
- vol. 60, no. 8, pp. 3422 - 3437
- AMER CHEMICAL SOC
- SCI; SCIE; SCOPUS
- 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 Xray crystal structure of 5'-N-methylcarbamoyl derivative 3p. Among the compounds tested, N-6-3-iodobenzyl analogue 3d was found to be the most potent A(3)AR full agonist (K-i = 0.57 nM), which was >= 800- and 1900-fold selective for AIAR and A(2A)AR, respectively. In the N6-cycloalkyl series, 2-Cl analogues generally exhibited better hA(3)AR affinity than 2-H analogues, whereas 2-H > 2-Cl in the N-6-3-halobenzyl series. N7 isomers 3t and 3u were much weaker in binding than corresponding N-9 isomers, but compound 3t lacked A(3)AR activation, appearing to be a weak antagonist. 2-Cl-N-6-3-iodobenzyl analogue 3p inhibited chemoattractant-induced migration of microglia/monocytes without inducing cell death at <50 mu M. This suggests the potential for the development of 4'-selenonucleoside A(3)AR agonists as novel antistroke agents.
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