Optimization of 8-oxoadenines with toll-like-receptor 7 and 8 activity
| Autor: | Hélène G. Bazin, Yufeng Li, David A. Johnson, Shannon M. Miller, Jay T. Evans, Mark T. Livesay, Van Cybulski, Laura S. Bess |
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| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_treatment
Clinical Biochemistry Pharmaceutical Science 01 natural sciences Biochemistry Article Structure-Activity Relationship Adjuvants Immunologic Drug Discovery medicine Humans Potency Receptor Molecular Biology Toll-like receptor 010405 organic chemistry Chemistry Adenine Organic Chemistry virus diseases TLR7 TLR8 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cytokine Toll-Like Receptor 7 Toll-Like Receptor 8 Leukocytes Mononuclear Quinolines Cytokines Molecular Medicine Selectivity Linker |
| Zdroj: | Bioorg Med Chem Lett |
| ISSN: | 0960-894X |
| DOI: | 10.1016/j.bmcl.2020.126984 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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