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

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Issue Date
2013-09-12Author
Kokatla, Hari Prasad
Sil, Diptesh
Malladi, Subbalakshmi S.
Balakrishna, Rajalakshmi
Hermanson, Alec R.
Fox, Lauren M.
Wang, Xinkun
Dixit, Anshuman
David, Sunil A.
Publisher
American Chemical Society
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm400694d.
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Show full item recordAbstract
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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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
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