Structure-activity relationship analysis of imidazoquinolines with toll-like receptors 7 and 8 selectivity and enhanced cytokine induction

Charles E. Schiaffo, Ce Shi, Zhengming Xiong, Michael R Olin, John R. Ohlfest, Courtney Aldrich, David M Ferguson

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Toll-like receptors 7 and 8 (TLRs) have emerged as key targets in the design of small molecule adjuvants and stimulants for use in immunotherapies. This study examines the structure-activity relationship of a series of C2- and N1-substituted C7-methoxycarbonylimidazoquinolines to gain insight to the structural basis to TLR-7 and -8 selective activity. The analysis is further applied to evaluate the induction of multiple cytokines, including IL-10, IL-12, IL-1β, TNF-α, IFN-α, and IFN-γ, using murine BMDCs and human PBMCs. The results show TLR-7/8 activity is correlated to the C2-alkyl chain length, with peak activity occurring for the butyl (TLR-7) and pentyl (TLR-8) derivatives. A similar SAR is identified in the production of IL-1β, IL-12, and IFN-γ, which are shown to depend on both the C2-alkyl chain length and substitution to the N1-position. The compounds were also potent stimulators of IFN-α and IL-10 production but with less pronounced structure-based correlations.

Original languageEnglish (US)
Pages (from-to)339-347
Number of pages9
JournalJournal of medicinal chemistry
Volume57
Issue number2
DOIs
StatePublished - Jan 23 2014

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