2. Academic Validation
  3. Synthesis and evaluation of N⁶-substituted apioadenosines as potential adenosine A₃ receptor modulators

Synthesis and evaluation of N⁶-substituted apioadenosines as potential adenosine A₃ receptor modulators

  • Bioorg Med Chem. 2014 Aug 1;22(15):4257-68. doi: 10.1016/j.bmc.2014.05.036.
Kiran S Toti 1,  Steven M Moss 2,  Silvia Paoletta 2,  Zhan-Guo Gao 2,  Kenneth A Jacobson 2,  Serge Van Calenbergh 3
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium.
  • 2 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Gent, Belgium. Electronic address: [email protected].
PMID: 24931275 DOI: 10.1016/j.bmc.2014.05.036
Abstract

Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A₃AR subtype may be beneficial in controlling diseases such as colorectal Cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of β-D-apio-D-furano- and α-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N(6) of β-D-apio-D-furanoadenosine afforded an A₃AR antagonist (10c, Ki=0.98 μM), while a similar modification of an α-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, Ki=3.07 μM). The structural basis for this difference was examined by docking to an A₃AR model; the antagonist lacked a crucial interaction with Thr94.

Keywords

Adenosine A(3) receptor; Apionucleosides; G protein-coupled receptor.

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