TY - JOUR
T1 - Structure-activity relationship analysis of imidazoquinolines with toll-like receptors 7 and 8 selectivity and enhanced cytokine induction
AU - Schiaffo, Charles E.
AU - Shi, Ce
AU - Xiong, Zhengming
AU - Olin, Michael R
AU - Ohlfest, John R.
AU - Aldrich, Courtney
AU - Ferguson, David M
PY - 2014/1/23
Y1 - 2014/1/23
N2 - 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.
AB - 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.
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U2 - 10.1021/jm4004957
DO - 10.1021/jm4004957
M3 - Article
C2 - 24383475
AN - SCOPUS:84893110344
SN - 0022-2623
VL - 57
SP - 339
EP - 347
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 2
ER -