Design and Synthesis of N1-Modified Imidazoquinoline Agonists for Selective Activation of Toll-like Receptors 7 and 8

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18 Scopus citations

Abstract

A series of N1-modified imidazoquinolines were synthesized and screened for Toll-like receptors (TLR) 7 and 8 activities to identify recognition elements that confer high affinity binding and selectivity. These receptors are key targets in the development of immunomodulatory agents that signal the NF-κB mediated transcription of pro-inflammatory chemokines and cytokines. Results are presented showing both TLR7/8 activations are highly correlated to N1-substitution, with TLR8 selectivity achieved through inclusion of an ethyl-, propyl-, or butylamino group at this position. While the structure-activity relationship analysis indicates TLR7 activity is less sensitive to N1-modification, extension of the aminoalkyl chain length to pentyl and p-methylbenzyl elicited high affinity TLR7 binding. Cytokine profiles are also reported that show the pure TLR8 agonist [4-amino-2-butyl-1-(2-aminoethyl)-7-methoxycarbonyl-1H-imidazo[4,5-c]quinoline] induces higher levels of IL-1β, IL-12, and IFNγ when compared with TLR7 selective or mixed TLR7/8 agonists. The results are consistent with previous work suggesting TLR8 agonists are Th1 polarizing and may help promote cell-mediated immunity.

Original languageEnglish (US)
Pages (from-to)1148-1152
Number of pages5
JournalACS Medicinal Chemistry Letters
Volume8
Issue number11
DOIs
StatePublished - Nov 9 2017

Bibliographical note

Funding Information:
*Tel: 612-626-2601. E-mail: ferguson@umn.edu. ORCID David M. Ferguson: 0000-0001-6294-8057 Funding Support for this study, in part, was provided by the Masonic Cancer Center, University of Minnesota (to T.S.G.) and the Randy Shaver Cancer Research & Community Fund (to T.S.G.). Notes The authors declare no competing financial interest.

Publisher Copyright:
© 2017 American Chemical Society.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

Keywords

  • SAR
  • TLR7
  • TLR8
  • Toll-like receptor
  • cytokine
  • imidazoquinoline

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