Exquisite Selectivity for Human Toll-Like Receptor 8 in Substituted Furo[2,3-c]quinolines

• DOI: 10.1021/jm400694d
• Publication Date: 2013-07-30T15:17:09Z
• Authors: Hari Prasad Kokatla; Diptesh Sil; Subbalakshmi S. M...; Rajalakshmi Balak...; Alec R. Hermanson; Lauren M. Fox; Xinkun Wang; Anshuman Dixit; Sunil A. David
• Keywords: Innate immunity; 0301 basic medicine; Spectrometry, Mass, Electrospray Ionization; Magnetic Resonance Spectroscopy; Sonogashira coupling; Furoquinolines; 610; Vaccine adjuvants; 540; 3. Good health; TLR8 agonists; 03 medical and health sciences; HEK293 Cells; Toll-Like Receptor 8; Quinolines; Humans; TLR8

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.