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

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• 作者：Hari Prasad Kokatla ; Diptesh Sil ; Subbalakshmi S. Malladi ; Rajalakshmi Balakrishna ; Alec R. Hermanson ; Lauren M. Fox ; Xinkun Wang ; Anshuman Dixit ; Sunil A. David
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 12, 2013
• 年：2013
• 卷：56
• 期：17
• 页码：6871-6885
• 全文大小：622K
• 年卷期：v.56,no.17(September 12, 2013)
• ISSN：1520-4804

文摘

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 渭M); 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-伪 inducing properties, confirming its high selectivity for human TLR8.