Potent adjuvantic activity of a CCR1-agonistic bis-quinoline

Ukani, Rehman; Lewis, Tyler C.; Day, Timothy P.; Wu, Wenyan; Malladi, Subbalakshmi S.; Warshakoon, Hemamali J.; David, Sunil A.

doi:10.1016/j.bmcl.2011.11.014

Cited by 15 publications

(31 citation statements)

References 27 publications

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“…Although entirely bereft of any proinflammatory activity, the bis- quinoline compound 41 was found to be a potent adjuvant which appears to be related to its functional agonism at CCR1. 54 Given some similarities in activity profiles between the furo[2,3- c ]pyridines and 41 , we decided to evaluate and compare the adjuvantic activity of 37b alongside the reference compounds, 40 and 41 . Rabbits were immunized using bovine α-lactalbumin as a model subunit antigen.…”

Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships in Human Toll-like Receptor 8-Active 2,3-Diamino-furo[2,3-c]pyridines

et al. 2012

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In our ongoing search toward identifying novel and synthetically simpler candidate vaccine adjuvants, we hypothesized that the imidazo[1,2-a]pyrazines, readily accessible via the Groebke-Blackburn-Bienaymé multicomponent reaction, would possess sufficient structural similarity with TLR7/8-agonistic imidazoquinolines. With pyridoxal as the aldehyde component, furo[2,3- c]pyridines, rather than the expected imidazo[1,2-a]pyridines were obtained, which were characterized by NMR spectroscopy and crystallography. Several analogues were found to activate TLR8-dependent NF-κB signaling. In a focused library of furo[2,3-c]pyridines, a distinct SAR was observed with varying substituents at C2. In human PBMCs, none of the furo[2,3-c]pyridines showed any proinflammatory cytokine induction, but upregulated several chemokine ligand genes. In immunization studies in rabbits, the most active compound showed prominent adjuvantic effects. The complete lack of proinflammatory cytokine induction coupled with strong adjuvantic activity of the novel furo[2,3-c]pyridines render this hitherto unknown chemotype an attractive class of compounds which are expected to be devoid of local or systemic reactogenicity.

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Section: Resultsmentioning

confidence: 99%

Structure–Activity Relationships in Human Toll-like Receptor 8-Active 2,3-Diamino-furo[2,3-c]pyridines

et al. 2012

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“…From this perspective, we have explored in detail structure–activity relationships (SARs) of several immunostimulatory chemotypes. 11 − 18 …”

Section: Introductionmentioning

confidence: 99%

Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure–Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds

et al. 2014

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Toll-like receptor (TLR) 7 and 8 agonists are potential vaccine adjuvants, since they directly activate APCs and enhance Th1-driven immune responses. Previous SAR investigations in several scaffolds of small molecule TLR7/8 activators pointed to the strict dependence of the selectivity for TLR7 vis-à-vis TLR8 on the electronic configurations of the heterocyclic systems, which we sought to examine quantitatively with the goal of developing “heuristics” to define structural requisites governing activity at TLR7 and/or TLR8. We undertook a scaffold-hopping approach, entailing the syntheses and biological evaluations of 13 different chemotypes. Crystal structures of TLR8 in complex with the two most active compounds confirmed important binding interactions playing a key role in ligand occupancy and biological activity. Density functional theory based quantum chemical calculations on these compounds followed by linear discriminant analyses permitted the classification of inactive, TLR8-active, and TLR7/8 dual-active compounds, confirming the critical role of partial charges in determining biological activity.

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“…The chemotypes that we have explored thus far include agonists of TLR2, 19–21 TLR7, 22–26 TLR8, 27,28 NOD1, 29 as well as C-C chemokine receptor type 1. 30 …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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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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Potent adjuvantic activity of a CCR1-agonistic bis-quinoline

Cited by 15 publications

References 27 publications

Structure–Activity Relationships in Human Toll-like Receptor 8-Active 2,3-Diamino-furo[2,3-c]pyridines

Structure–Activity Relationships in Human Toll-like Receptor 8-Active 2,3-Diamino-furo[2,3-c]pyridines

Determinants of Activity at Human Toll-like Receptors 7 and 8: Quantitative Structure–Activity Relationship (QSAR) of Diverse Heterocyclic Scaffolds

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

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