Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity
- Bioorg Med Chem Lett. 2020 Mar 15;30(6):126984. doi: 10.1016/j.bmcl.2020.126984.
- 1. Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States. Electronic address: [email protected].
- 2. Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.
- 3. GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.
- 4. Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Division of Biological Sciences, University of Montana, Missoula, MT 59812, United States; GSK Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, United States.
- 5. Center for Translational Medicine, University of Montana, Missoula, MT 59812, United States; Division of Biological Sciences, University of Montana, Missoula, MT 59812, United States.
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 potency for TLR7/8 activity, cytokine induction and DC maturation.