title: Structure-activity relationship analysis of imidazoquinolines with Toll-like receptors 7 and 8 selectivity and enhanced cytokine induction.
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.
authors.affiliation: Center for Drug Design, University of Minnesota , 516 Delaware Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Schiaffo
authors.forename: Ce
authors.initials: C
authors.lastname: Shi
authors.forename: Zhengming
authors.initials: Z
authors.lastname: Xiong
authors.forename: Michael
authors.initials: M
authors.lastname: Olin
authors.forename: John R
authors.initials: JR
authors.lastname: Ohlfest
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
authors.forename: David M
authors.initials: DM
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D007093:Imidazoles; D011804:Quinolines; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8