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

(2014) BIOORGANIC & MEDICINAL CHEMISTRY. 22(15). p.4257-4268
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Abstract
Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A(3)AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of beta-D-apio-D-furano- and alpha-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N-6 of beta-D-apio-D-furanoadenosine afforded an A(3)AR antagonist (10c, K = 0.98 mu M), while a similar modification of an alpha-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, K-i = 3.07 mu M). The structural basis for this difference was examined by docking to an A(3)AR model; the antagonist lacked a crucial interaction with Thr94.
Keywords
Apionucleosides, Adenosine A(3) receptor, G protein-coupled receptor, A(3)-ADENOSINE RECEPTOR, NUCLEOSIDES, 2-ARYLETHYNYL, SUBSTITUTIONS, PHARMACOLOGY, EFFICACY, AGONISTS, ANALOGS, DESIGN

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Citation

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Chicago
Toti, Kiran, Steven M Moss, Silvia Paoletta, Zhan-Guo Gao, Kenneth A Jacobson, and Serge Van Calenbergh. 2014. “Synthesis and Evaluation of N6-substituted Apioadenosines as Potential Adenosine A₃ Receptor Modulators.” Bioorganic & Medicinal Chemistry 22 (15): 4257–4268.
APA
Toti, K., Moss, S. M., Paoletta, S., Gao, Z.-G., Jacobson, K. A., & Van Calenbergh, S. (2014). Synthesis and evaluation of N6-substituted apioadenosines as potential adenosine A₃ receptor modulators. BIOORGANIC & MEDICINAL CHEMISTRY, 22(15), 4257–4268.
Vancouver
1.
Toti K, Moss SM, Paoletta S, Gao Z-G, Jacobson KA, Van Calenbergh S. Synthesis and evaluation of N6-substituted apioadenosines as potential adenosine A₃ receptor modulators. BIOORGANIC & MEDICINAL CHEMISTRY. 2014;22(15):4257–68.
MLA
Toti, Kiran, Steven M Moss, Silvia Paoletta, et al. “Synthesis and Evaluation of N6-substituted Apioadenosines as Potential Adenosine A₃ Receptor Modulators.” BIOORGANIC & MEDICINAL CHEMISTRY 22.15 (2014): 4257–4268. Print.
@article{5797297,
  abstract     = {Adenosine receptors (ARs) trigger signal transduction pathways inside the cell when activated by extracellular adenosine. Selective modulation of the A(3)AR subtype may be beneficial in controlling diseases such as colorectal cancer and rheumatoid arthritis. Here, we report the synthesis and evaluation of beta-D-apio-D-furano- and alpha-D-apio-L-furanoadenosines and derivatives thereof. Introduction of a 2-methoxy-5-chlorobenzyl group at N-6 of beta-D-apio-D-furanoadenosine afforded an A(3)AR antagonist (10c, K = 0.98 mu M), while a similar modification of an alpha-D-apio-L-furanoadenosine gave rise to a partial agonist (11c, K-i = 3.07 mu M). The structural basis for this difference was examined by docking to an A(3)AR model; the antagonist lacked a crucial interaction with Thr94.},
  author       = {Toti, Kiran and Moss, Steven M and Paoletta, Silvia and Gao, Zhan-Guo and Jacobson, Kenneth A and Van Calenbergh, Serge},
  issn         = {0968-0896},
  journal      = {BIOORGANIC \& MEDICINAL CHEMISTRY},
  keyword      = {Apionucleosides,Adenosine A(3) receptor,G protein-coupled receptor,A(3)-ADENOSINE RECEPTOR,NUCLEOSIDES,2-ARYLETHYNYL,SUBSTITUTIONS,PHARMACOLOGY,EFFICACY,AGONISTS,ANALOGS,DESIGN},
  language     = {eng},
  number       = {15},
  pages        = {4257--4268},
  title        = {Synthesis and evaluation of N\unmatched{2076}-substituted apioadenosines as potential adenosine A\unmatched{2083} receptor modulators},
  url          = {http://dx.doi.org/10.1016/j.bmc.2014.05.036},
  volume       = {22},
  year         = {2014},
}

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