Guanosine analog in the pyrido[2,3-d]pyrimidine ring system as a potential toll-like receptor agonist.
The synthesis of a guanosine analog in the pyrido[2,3-d]pyrimidine ring system has been accomplished by glycosylation of the preformed aromatic heterocyclic base, which was prepared in 2 steps by condensation of methyl acrylate with guanidine carbonate and methyl cyanoacetate in the presence of sodium methoxide, followed by dehydrogenation. The analog was evaluated in vitro for its ability to modulate the innate immune response by acting as an agonist or as an antagonist of Toll-like receptor (TLR) signaling by measuring cytokine induction or inhibition of induction, respectively, in mouse bone marrow-derived macrophages. Despite its structural similarity to 7-thia-8-oxoguanosine, a known TLR7 agonist, the analog was found to antagonize TLR7-induced cytokine induction in this cell-based assay.
Jin
Guangyi
G
Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0820, USA.
Wu
Christina C N
CC
Carson
Dennis A
DA
Cottam
Howard B
HB
D000085:Acetates / Q000737:chemistry; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002254:Carbonates / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D005269:Femur / Q000378:metabolism; D019791:Guanidine / Q000737:chemistry*; D006151:Guanosine / Q000031:analogs & derivatives*; D008264:Macrophages / Q000166:cytology; D000432:Methanol / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000737:chemistry*; D013977:Tibia / Q000378:metabolism; D051193:Toll-Like Receptors / Q000819:agonists*
D000085:Acetates; D002254:Carbonates; D016207:Cytokines; C115711:PD 173074; D011743:Pyrimidines; D051193:Toll-Like Receptors; D006151:Guanosine; D019791:Guanidine; D000432:Methanol