1309944-03-3Relevant academic research and scientific papers
Click modification in the N 6 region of A3 adenosine receptor-selective carbocyclic nucleosides for dendrimeric tethering that preserves pharmacophore recognition
Tosh, Dilip K.,Phan, Khai,Deflorian, Francesca,Wei, Qiang,Yoo, Lena S.,Gao, Zhan-Guo,Jacobson, Kenneth A.
, p. 232 - 247 (2012)
Adenosine derivatives were modified with alkynyl groups on N6 substituents for linkage to carriers using Cu(I)-catalyzed click chemistry. Two parallel series, both containing a rigid North-methanocarba (bicyclo[3.1.0] hexane) ring system in place of ribose, behaved as A3 adenosine receptor (AR) agonists: (5′-methyluronamides) or partial agonists (4′-truncated). Terminal alkynyl groups on a chain at the 3 position of a N6-benzyl group or simply through a N6-propargyl group were coupled to azido derivatives, which included both small molecules and G4 (fourth-generation) multivalent poly(amidoamine) (PAMAM) dendrimers, to form 1,2,3-triazolyl linkers. The small molecular triazoles probed the tolerance in A3AR binding of distal, sterically bulky groups such as 1-adamantyl. Terminal 4-fluoro-3-nitrophenyl groups anticipated nucleophilic substitution for chain extension and 18F radiolabeling. N6-(4-Fluoro-3- nitrophenyl)-triazolylmethyl derivative 32 displayed a Ki of 9.1 nM at A3AR with ～1000-fold subtype selectivity. Multivalent conjugates additionally containing click-linked water-solubilizing polyethylene glycol groups potently activated A3AR in the 5′- methyluronamide, but not 4′ truncated series. N6-Benzyl nucleoside conjugate 43 (apparent Ki 24 nM) maintained binding affinity of the monomer better than a N6-triazolylmethyl derivative. Thus, the N6 region of 5′-methyluronamide derivatives, as modeled in receptor docking, is suitable for functionalization and tethering by click chemistry to achieve high A3AR agonist affinity and enhanced selectivity. This article not subject to U.S. Copyright. Published 2011 by the American Chemical Society.
METHANOCARBA ADENOSINE DERIVATIVES AND DENDRIMER CONJUGATES THEREOF
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Page/Page column 49-50, (2011/06/25)
Disclosed are (N)-methanocarba adenine nucleosides, e.g., of the formula (I): as A3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein A, a, R2, and
