1H-Imidazo[4,5-c]quinoline derivatives as novel potent TNF-α suppressors: synthesis and structure–activity relationship of 1-, 2-and 4-substituted 1H-imidazo[4,5-c]quinolines or 1H-imidazo[4,5-c]pyridines

Izumi, Tomoyuki; Sakaguchi, Jun; Takeshita, Mitsuhiro; Tawara, Harumi; Kato, Kenichi; Dose, Hitomi; Tsujino, Tomomi; Watanabe, Yoshinari; Kobayashi, Hideo

doi:10.1016/s0968-0896(03)00178-0

Cited by 30 publications

(10 citation statements)

References 16 publications

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“…In these experiments, conducted both on humans (in vitro) and on mice (in vivo), the authors clearly demonstrated that the active products exerted their inhibitory effect on anti-CD3/ antiCD28-induced lymphocytes. Moreover, the antiinflammatory property of a novel IH-imidazo[4,5-c]quinoline, was recently described (12). This product which displayed a structure closely related to that of imidazo[ 1,2-a]quinoxalines, also acted by suppressing TNF-a production.…”

Section: Discussionmentioning

confidence: 96%

“…Based on the resemblance between agonists and antagonists, two families of drugs characterized as agents capable of acting on TNF-a activity and/or production have been studied: the imidazoquinolines (11-12), of which imiquimod is the pioneer, and the imidazo[I,2-a]quinoxalines (13)(14). Because they are potent suppressors of TNF-a activity (12) and display an excellent anti-inflammatory activity in vivo (13), some compounds of these families have already been described as imiquimod antagonist.…”

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confidence: 99%

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Impairment of TNF-α Production and Action by Imidazo[1,2- α] Quinoxalines, as Derivative Family Which Displays Potential Anti-Inflammatory Properties

Morjaria

Deleuze‐Masquéfa

Lafont

et al. 2006

Int J Immunopathol Pharmacol

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In a previous study, we analysed the synthesis and properties of a series ofimidazo [I,2-a]quinoxalines designed in our laboratory as possible imiquimod analogues. We found that these imidazo[I,2-a]quinoxalines were in fact potent inhibitors of phosphodiesterase 4 enzymes (PDE4). PDE4 inhibition normally results in an increase in intracellular cAMP which, in PBMC, induces the suppression of TNF-a. mRNA transcription and thus cytokine synthesis. Such an effect is antagonistic to that of imiquimod. Furthermore, some TNF-a.-induced activity, such as cell apoptosis which is dependent on the intracellular cAMP levels might also be affected. Therefore, by counteracting the properties of TNF-a. and/or its production, the imidazo[I,2-a]quinoxalines could be considered as potential antiinflammatory drugs. The present study was performed to confirm or refute this hypothesis. For this, we characterized the effects of imidazo[I,2-a]quinoxalines both on TNF-a. activity and synthesis in regard to their ability to act as inhibitors ofPDE4 (IPDE4). We found that the imidazo[I,2-a]quinoxalines dosedependently prevented the TNF-a.-triggered death of L929 cells, with the 8-series (-NHCH3 in R4) being the most potent. Moreover, when the effect of the 8-series on TNF-a. production was investigated using y982 T cells, it was observed that these compounds impaired the TCR:CD3-triggered TNF-n production. Structure-activity analysis revealed that these properties of the drugs did not coincide with their IPDE4 properties. This prompted further exploration into other signalling mechanisms possibly involved in TNF-n action and production, notably the p38 MAPK and the PI3K pathway. We demonstrate here that the imidazo[I,2-a)quinoxalines targeted these pathways in a different way: they activated the p38 MAPK pathway whilst inhibiting the PI3K pathway. Such effects on cell signalling could account for the imidazo[I,2-a]quinoxalines effects on 1) action and 2) production ofTNF-a., which define these drugs as potential anti-inflammatory agents.Tumour Necrosis Factor a (TNF-a) is an important pro-inflammatory cytokine that exhibits a variety of effects depending upon cell type and cell signalling (1). Simulation by TNF-a. can cause the release of other inflammatory cytokines or mediate cell proliferation, differentiation and death (apoptosis or necrosis) through the activation of signalling cascades. Overproduction ofTNF-a can

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Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

Impairment of TNF-α Production and Action by Imidazo[1,2- α] Quinoxalines, as Derivative Family Which Displays Potential Anti-Inflammatory Properties

Morjaria

Deleuze‐Masquéfa

Lafont

et al. 2006

Int J Immunopathol Pharmacol

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“…Both ssRNA and dsRNA (TLR3 ligand) are immediately degraded by RNase in serum, which limits their usefulness as vaccine adjuvants. Imidazoquinolines, such as imiquimod and resiquimod, were originally discovered while investigating a variety of adenine analogues that stimulated IFN production ( FiguRe 5) and imiquimod has since been licensed for human use [85][86][87][88]. It was later revealed that imidazoquinolines are recognized by TLR7 and/or TLR8, and promote Ab production and upregulation of MHC class II molecules.…”

Section: Tlr5: Recombinant Flagellin Fusion Proteinsmentioning

confidence: 99%

Overview and Outlook of Toll-like Receptor ligand–antigen Conjugate Vaccines

Fujita

Taguchi

2012

Therapeutic Delivery

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The discovery of Toll-like receptors (TLRs) facilitated our understanding of the innate and adaptive immune systems, and has raised the potential to develop novel methods of vaccine and immunotherapy. For effective vaccination, antigens and adjuvants must be administered simultaneously via the same route. Many studies have demonstrated that TLR ligands covalently coupled to the antigens have several benefits over nonconjugated antigens. This review introduces the applications of TLR ligands as vaccine adjuvants, focusing on the development of vaccines composed of antigen and TLR ligand in single molecules (TLR ligand–antigen conjugates) using Pam3/2Cys, lipid A analogues, recombinant flagellin, imidazoquinoline analogues and unmethylated CpG motifs to activate immune systems through TLR2, TLR4, TLR5, TLR7/8 and TLR9, respectively.

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“…The first route, Scheme , began with the chlorination of 4-hydroxy-3-nitro-1 H -quinolin-2-one, 3 , employing a modification of the method of Gabriel, using phosphorus oxychloride in toluene, with triethylamine as a base, to provide 2,4-dichloro-3-nitroquinoline, 4 . Alternatively, the chlorination can be accomplished using phenylphosphonic dichloride . By careful control of the reaction temperature, the 4-chloro substituent was selectively displaced by a number of primary amines to give the corresponding nitroamines, as demonstrated by the reaction with isobutylamine to give 5 .…”

Section: Chemistrymentioning

confidence: 99%

“…Alternatively, the chlorination can be accomplished using phenylphosphonic dichloride. 9 By careful control of the reaction temperature, the 4-chloro substituent was selectively displaced by a number of primary amines to give the corresponding nitroamines, as demonstrated by the reaction with isobutylamine to give 5. Catalytic hydrogenation of 5 gave the corresponding diamine 6.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Structure−Activity-Relationships of 1H-Imidazo[4,5-c]quinolines That Induce Interferon Production

et al. 2005

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1H-Imidazo-[4,5-c]quinolines were prepared while investigating novel nucleoside analogues as potential antiviral agents. While these compounds showed no direct antiviral activity when tested in a number of cell culture systems, some demonstrated potent inhibition of virus lesion development in an intravaginal guinea pig herpes simplex virus-2 assay. We have determined that the in vivo antiviral activity can be attributed to the ability of these molecules to induce the production of cytokines, especially interferon (IFN), in this model. Subsequently, we found that the compounds also induce in vitro production of IFN in human peripheral blood mononuclear cells (hPBMCs). The in vitro results reported herein and the in vivo results reported previously led to the discovery of imiquimod, 26, which was developed as a topical agent and has been approved for the treatment of genital warts, actinic keratosis, and superficial basal cell carcinoma.

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1H-Imidazo[4,5-c]quinoline derivatives as novel potent TNF-α suppressors: synthesis and structure–activity relationship of 1-, 2-and 4-substituted 1H-imidazo[4,5-c]quinolines or 1H-imidazo[4,5-c]pyridines

Cited by 30 publications

References 16 publications

Impairment of TNF-α Production and Action by Imidazo[1,2- α] Quinoxalines, as Derivative Family Which Displays Potential Anti-Inflammatory Properties

Impairment of TNF-α Production and Action by Imidazo[1,2- α] Quinoxalines, as Derivative Family Which Displays Potential Anti-Inflammatory Properties

Overview and Outlook of Toll-like Receptor ligand–antigen Conjugate Vaccines

Synthesis and Structure−Activity-Relationships of 1H-Imidazo[4,5-c]quinolines That Induce Interferon Production

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