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.
- 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].
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.