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

Abstract

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

EAPB0203, a member of the imidazoquinoxaline family, inhibits growth and induces caspase-dependent apoptosis in T-cell lymphomas and HTLV-I–associated adult T-cell leukemia/lymphoma

“…We found that, contrary to imiquimod, these imidazo[1,2-a]quinoxalines inhibit both the production and the effects of tumor necrosis factor-␣; hence, these imiquimod antagonists can be considered as potential anti-inflammatory drugs. 11 Among these new products, EAPB0203 exhibits an important cytotoxic activity in vitro and is 50 times more potent than imiquimod against a human melanoma cell line (G.M. et al, unpublished data, 2007).…”

“…26 We recently showed that these imidazo[1,2-a]quinoxalines activate the p38 MAPK pathway and inhibit the PI3K pathway. 11 The effective concentrations of imidazo[1,2-a]quinoxalines in …”

Expression and Secretion of CXCL8 (IL-8), Release of Tryptase and Transcription of Histidine Decarboxylase mRNA by Anti-IgE-Activated Human Umbilical Cord Blood-Derived Cultured Mast Cells

“…TNF ␣ and IL-1 ␤ , resulting in local inflammation [17][18][19][20] . Directional migration of mast cells is presumably based on the existence of locally produced chemotactic factors such as chemokines which play a critical role in selective recruitment and activation of several inflammatory cell types [21][22][23][24][25][26] . IL-8 or CXCL8 is a chemokine with a defining CXC amino acid motif that was initially characterized for its leukocyte chemotactic activity [27][28][29] .…”

Metabolism and Pharmacokinetics of EAPB0203 and EAPB0503, Two Imidazoquinoxaline Compounds Previously Shown to Have Antitumoral Activity on Melanoma and T-Lymphomas

“…Some data on the mechanism of action of these two compounds have been published (Morjaria et al, 2006;Moarbess et al, 2008b). However, the specific cellular targets of these two compounds remain to be identified.…”

“…We have shown that imidazo[1,2-a]quinoxaline derivatives inhibit cyclic nucleotide phosphodiesterase enzymes 4, resulting in an increased intracellular cAMP level and, consequently, cAMP response element-binding protein phosphorylation (Deleuze-Masquéfa et al, 2004), and that these compounds activate the p38 mitogen-activated protein kinase pathway and inhibit the phosphatidylinositol 3-kinase pathway (Morjaria et al, 2006). The mechanism of action of EAPB0203 has been studied in T-cell lymphomas and HTLV-Iassociated adult T-cell leukemia/lymphoma (Moarbess et al, 2008b).…”