Design and synthesis of N6-substituted-4′-thioadenosine-5′-uronamides as potent and selective human A3 adenosine receptor agonists

Won Jun Choi, Hyuk Woo Lee, Hea Ok Kim, Moshe Chinn, Zhan Guo Gao, Amit Patel, Kenneth A. Jacobson, Hyung Ryong Moon, Young Hoon Jung, Lak Shin Jeong

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

On the basis of a bioisosteric rationale, 4′-thionucleoside analogues of IB-MECA (N6-(3-Iodo-benzyl)-9-(5′-methylaminocarbonyl-β-d- ribofuranosyl)adenine), which is a potent and selective A3 adenosine receptor (AR) agonist, were synthesized from d-gulonic acid γ-lactone. The 4′-thio analogue (5h) of IB-MECA showed extremely high binding affinity (Ki = 0.25 nM) at the human A3AR and was more potent than IB-MECA (Ki = 1.4 nM). Bulky substituents at the 5′-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A3AR binding, although small alkyl analogues were more potent.

Original languageEnglish
Pages (from-to)8003-8011
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number23
DOIs
StatePublished - 1 Dec 2009

Keywords

  • 4′-Thionucleosides
  • A adenosine receptor
  • Agonist
  • Binding affinity

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