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Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines
Kokatla, Hari Prasad Sil, Diptesh Malladi, Subbalakshmi S. Balakrishna, Rajalakshmi Hermanson, Alec R. Fox, Lauren M. Wang, Xinkun Dixit, Anshuman David, Sunil A.
Kokatla, Hari Prasad
Sil, Diptesh
Malladi, Subbalakshmi S.
Balakrishna, Rajalakshmi
Hermanson, Alec R.
Fox, Lauren M.
Wang, Xinkun
Dixit, Anshuman
David, Sunil A.
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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 its 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.
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Date
2013-09-12
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American Chemical Society
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Keywords
TLR8, TLR8 agonists, Vaccine adjuvants, Innate immunity, Furoquinolines, Sonogashira coupling
Citation
Kokatla, H. P., Sil, D., Malladi, S. S., Balakrishna, R., Hermanson, A. R., Fox, L. M., … David, S. A. (2013). Exquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolines. Journal of Medicinal Chemistry, 56(17), 6871–6885. http://doi.org/10.1021/jm400694d