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Synthesis and evaluation of N?-substituted apioadenosines as potential adenosine A? receptor modulators.

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