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

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.

SUBMITTER: Toti KS

PROVIDER: S-EPMC4128473 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Toti Kiran S KS Moss Steven M SM Paoletta Silvia S Gao Zhan-Guo ZG Jacobson Kenneth A KA Van Calenbergh Serge S

Bioorganic & medicinal chemistry 20140523 15

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 ...[more]

PMID: 24931275

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