Discovery of imidazoquinolines with toll-like receptor 7/8 independent cytokine induction

Ce Shi, Zhengming Xiong, Padmaja Chittepu, Courtney Aldrich, John R. Ohlfest, David M Ferguson

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34 Scopus citations


Toll-like receptors (TLRs) are key targets in the design of immunomodulating agents for use as vaccine adjuvants and anticancer treatments. The imidazoquinolines, imiquimod and resiquimod, have been shown to activate TLR-7 and -8, which in turn induce cytokine production as part of the innate immune response. Herein, we report the synthesis and discovery of a C7-methoxycarbonyl derivative of imiquimod that stimulates cytokine production but is devoid of TLR-7/8 activity. Data are presented that shows that this analogue not only induces IL-12p40 and TNF production, similar to that of imiquimod and resiquimod, but greatly enhances the production of IL-1β, a key cytokine involved in the activation of CD4 T cells. It is further demonstrated that TLR-7/8 activation can be recovered by the addition of a C2-alkyl substituent to this newly discovered analogue. The results support the existence of an alternative mechanism of action by which imidazoquinolines can stimulate cytokine production.

Original languageEnglish (US)
Pages (from-to)501-504
Number of pages4
JournalACS Medicinal Chemistry Letters
Issue number6
StatePublished - May 14 2012


  • cytokine induction
  • imidazoquinolines
  • toll-like receptor 7/8


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