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

Hélène G Bazin, Laura S Bess, Mark T Livesay, Yufeng Li, Van Cybulski, Shannon M Miller, David A Johnson, Jay T Evans

Bioorganic & medicinal chemistry letters 2020 Mar 15

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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. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Hélène G Bazin, Laura S Bess, Mark T Livesay, Yufeng Li, Van Cybulski, Shannon M Miller, David A Johnson, Jay T Evans. Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity. Bioorganic & medicinal chemistry letters. 2020 Mar 15;30(6):126984