biostudies-literatureBazin HGNIAID NIH HHSUniversity of MontanaNIAID126984https://www.ebi.ac.uk/biostudies/studies/S-EPMC7050994biostudies-literatureUnknown30(6)Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased pBioorganic & medicinal chemistry lettersOptimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.PMC7050994HHSN272200900036CMiller SMLivesay MTLi YBess LSCybulski VBazin HGJohnson DAEvans JTfalseOptimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.Toll-like receptors 7 and 8 (TLR7/8) agonists are potent immunostimulants that are attracting considerable interest as vaccine adjuvants. We recently reported the synthesis of a new series of 2-O-butyl-8-oxoadenines substituted at the 9-position with various linkers and N-heterocycles, and showed that TLR7/8 selectivity, potency and cytokine induction could be modulated by varying the alkyl linker length and the N-heterocyclic ring. In the present study, we further optimized the oxoadenine scaffold by investigating the effect of different substituents at the 2-position of the oxoadenine on TLR7/8 potency/selectivity, cytokine induction and DC maturation in human PBMCs. The results show that introducing a 1-(S)-methylbutoxy group at the 2-position of the oxoadenine significantly increased p2020-01-01T00:00:00Z2020 Mar2026-05-07T18:46:11.47Z2026-04-07T23:11:56.939ZS-EPMC70509943200113510.1016/j.bmcl.2020.126984