Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.

Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity.
Bioorg Med Chem Lett. 2020 Jan 22;:126984
Authors: Bazin HG, Bess LS, Livesay MT, Li Y, Cybulski V, Miller SM, Johnson DA, Evans JT
Abstract
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.
PMID: 32001135 [PubMed - as supplied by publisher]

Source: Bioorganic and Medicinal Chemistry Letters - January 21, 2020 Category: Chemistry Authors: Bazin HG, Bess LS, Livesay MT, Li Y, Cybulski V, Miller SM, Johnson DA, Evans JT Tags: Bioorg Med Chem Lett Source Type: research