Show simple item record

dc.contributor.authorKokatla, Hari Prasad
dc.contributor.authorSil, Diptesh
dc.contributor.authorMalladi, Subbalakshmi S.
dc.contributor.authorBalakrishna, Rajalakshmi
dc.contributor.authorHermanson, Alec R.
dc.contributor.authorFox, Lauren M.
dc.contributor.authorWang, Xinkun
dc.contributor.authorDixit, Anshuman
dc.contributor.authorDavid, Sunil A.
dc.identifier.citationKokatla, 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.
dc.description.abstractToll-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.en_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis 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
dc.subjectTLR8 agonistsen_US
dc.subjectVaccine adjuvantsen_US
dc.subjectInnate immunityen_US
dc.subjectSonogashira couplingen_US
dc.titleExquisite Selectivity For Human Toll-like Receptor 8 in Substituted Furo[2,3-c]quinolinesen_US
kusw.kuauthorKokatla, Hari Prasad
kusw.kuauthorSil, Diptesh
kusw.kuauthorMalladi, Subbalakshmi
kusw.kuauthorBalakrishna, Rajalakshmi
kusw.kuauthorHermanson, Alec R.
kusw.kuauthorFox, Lauren M.
kusw.kuauthorDixit, Anshuman
kusw.kuauthorDavid, Sunil A.
kusw.kudepartmentMedicinal Chemistryen_US
kusw.oanotesPer SHERPA/RoMEO 4/6/2017: Author's Pre-print: grey tick subject to Restrictions below, author can archive pre-print (ie pre-refereeing) Restrictions:

Must obtain written permission from Editor Must not violate ACS ethical Guidelines

Author's Post-print: grey tick subject to Restrictions below, author can archive post-print (ie final draft post-refereeing) Restrictions:

If mandated by funding agency or employer/ institution If mandated to deposit before 12 months, must obtain waiver from Institution/Funding agency or use AuthorChoice 12 months embargo

Publisher's Version/PDF: cross author cannot archive publisher's version/PDF General Conditions:

On author's personal website, pre-print servers, institutional website, institutional repositories or subject repositories Non-Commercial Must be accompanied by set statement (see policy) Must link to publisher version Publisher's version/PDF cannot be used
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US

Files in this item


This item appears in the following Collection(s)

Show simple item record