Click Modification in the N6 Region of A3 Adenosine Receptor-Selective Carbocyclic Nucleosides for Dendrimeric Tethering that Preserves Pharmacophore Recognition

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• 作者：Dilip K. Tosh ; Khai Phan ; Francesca Deflorian ; Qiang Wei ; Lena S. Yoo ; Zhan-Guo Gao ; Kenneth A. Jacobson
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：February 15, 2012
• 年：2012
• 卷：23
• 期：2
• 页码：232-247
• 全文大小：568K
• 年卷期：v.23,no.2(February 15, 2012)
• ISSN：1520-4812

文摘

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鈥?methyluronamides) or partial agonists (4鈥?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 K_i 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鈥?methyluronamide, but not 4鈥?truncated series. N⁶-Benzyl nucleoside conjugate 43 (apparent K_i 24 nM) maintained binding affinity of the monomer better than a N⁶-triazolylmethyl derivative. Thus, the N⁶ region of 5鈥?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.