title: Exquisite selectivity for human toll-like receptor 8 in substituted furo[2,3-c]quinolines.
abstract: Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds may be promising candidate adjuvants. We synthesized and evaluated hitherto unexplored furo[2,3-c]quinolines and regioisomeric furo[3,2-c]quinolines derived via a tandem, one-pot Sonogashira coupling and intramolecular 5-endo-dig cyclization strategy in a panel of primary screens. We observed a pure TLR8-agonistic activity profile in select furo[2,3-c]quinolines, with maximal potency conferred by a C2-butyl group (EC50 = 1.6 μM); shorter, longer, or substituted homologues as well as compounds bearing C1 substitutions were inactive, which was rationalized by docking studies using the recently described crystal structure of human TLR8. The best-in-class compound displayed prominent proinflammatory cytokine induction (including interleukin-12 and interleukin-18), but was bereft of interferon-α inducing properties, confirming its high selectivity for human TLR8.
authors.affiliation: Department of Medicinal Chemistry and ‡Genomics Facility, University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Hari Prasad
authors.initials: HP
authors.lastname: Kokatla
authors.forename: Diptesh
authors.initials: D
authors.lastname: Sil
authors.forename: Subbalakshmi S
authors.initials: SS
authors.lastname: Malladi
authors.forename: Rajalakshmi
authors.initials: R
authors.lastname: Balakrishna
authors.forename: Alec R
authors.initials: AR
authors.lastname: Hermanson
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Fox
authors.forename: Xinkun
authors.initials: X
authors.lastname: Wang
authors.forename: Anshuman
authors.initials: A
authors.lastname: Dixit
authors.forename: Sunil A
authors.initials: SA
authors.lastname: David
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011804:Quinolines / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D051200:Toll-Like Receptor 8 / Q000187:drug effects*
chemical_list: D011804:Quinolines; D051200:Toll-Like Receptor 8
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