title: Click modification in the N6 region of A3 adenosine receptor-selective carbocyclic nucleosides for dendrimeric tethering that preserves pharmacophore recognition.
abstract: Adenosine derivatives were modified with alkynyl groups on N(6) 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 A(3) adenosine receptor (AR) agonists: (5'-methyluronamides) or partial agonists (4'-truncated). Terminal alkynyl groups on a chain at the 3 position of a N(6)-benzyl group or simply through a N(6)-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 A(3)AR binding of distal, sterically bulky groups such as 1-adamantyl. Terminal 4-fluoro-3-nitrophenyl groups anticipated nucleophilic substitution for chain extension and (18)F radiolabeling. N(6)-(4-Fluoro-3-nitrophenyl)-triazolylmethyl derivative 32 displayed a K(i) of 9.1 nM at A(3)AR with ∼1000-fold subtype selectivity. Multivalent conjugates additionally containing click-linked water-solubilizing polyethylene glycol groups potently activated A(3)AR in the 5'-methyluronamide, but not 4' truncated series. N(6)-Benzyl nucleoside conjugate 43 (apparent K(i) 24 nM) maintained binding affinity of the monomer better than a N(6)-triazolylmethyl derivative. Thus, the N(6) region of 5'-methyluronamide derivatives, as modeled in receptor docking, is suitable for functionalization and tethering by click chemistry to achieve high A(3)AR agonist affinity and enhanced selectivity.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Khai
authors.initials: K
authors.lastname: Phan
authors.forename: Francesca
authors.initials: F
authors.lastname: Deflorian
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wei
authors.forename: Lena S
authors.initials: LS
authors.lastname: Yoo
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D057930:Click Chemistry; D050091:Dendrimers / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D009705:Nucleosides / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry*; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D050091:Dendrimers; D008024:Ligands; D009705:Nucleosides; C531249:Poly(amidoamine); D011073:Polyamines; D043684:Receptor, Adenosine A3; D011994:Recombinant Proteins; D000241:Adenosine