Novel benzoxazole derivatives DCPAB and HPAB attenuate Th1 cell-mediated inflammation through T-bet suppression

Abstract

Interferon-γ (IFN-γ), a critical inflammatory cytokine, is primarily produced by T helper 1 (Th1) cells and accelerates the pathogenesis of inflammatory colitis. Pharmacological suppression of IFN-γ production attenuates dysregulated inflammatory responses and may be beneficial for treating inflammatory disease. In this study, we aimed to discover potent anti-inflammatory compounds that suppress IFN-γ production and found that the novel benzoxazole derivatives, 2-((3,4-dichlorophenyl) amino) benzo[d]xazol-5-ol (DCPAB) and 2-((3,4-hydroxyphenyl) amino) benzo[d]xazol-5-ol (HPAB), suppressed IFN-γ production by T cells. Treatment of CD4+ T cells with DCPAB and HPAB selectively inhibited Th1 cell development, and DCPAB more potently suppressed IFN-γ than HPAB did. Interestingly, DCPAB and HPAB significantly suppressed the expression of T-box containing protein expressed in T cells (T-bet) that activates IFN-γ gene transcription. DCPAB additionally suppressed transcriptional activity of T-bet on IFN-γ gene promoter, whereas HPAB had no effect on T-bet activity. IFN-γ suppressive activity of DCPAB and HPAB was impaired in the absence of T-bet but was retrieved by the restoration of T-bet in T-bet-deficient T cells. Furthermore, DCPAB and HPAB attenuated inflammatory colitis development that was induced by CD4+ T cells in vivo. We suggest that the novel benzoxazole derivatives, DCPAB and HPAB, may have therapeutic effects on inflammatory colitis.

UV-Induced Photochemistry of 1,3-Benzoxazole, 2-Isocyanophenol, and 2-Cyanophenol Isolated in Low-Temperature Ar Matrixes

“…It is likely that the 4 → 1 photoisomerization proceeds through a two-step mechanism, involving an initial [1,5] H-atom shift from the hydroxyl group to the isocyano group, originating the nitrile ylide derivative 6, followed by cyclization of this intermediate to form 1. The energy profile for the conversion of nitrile ylide 6 to benzoxazole 1 is presented in Figure 3.…”

“…1,3-Benzoxazole 1 (also known as benzo­[ d ]­oxazole or benzoxazole) consists of an oxazole ring fused to a benzene ring (Scheme ). It is the nucleus of numerous compounds with important biological, pharmacological, and photophysical properties. − Its isomeric 1,2-benzisoxazole 2 (also known as benzo­[ d ]­isoxazole or benzisoxazole) has an isoxazole ring fused to a benzene ring (Scheme ). They differ by the relative position of the oxygen and nitrogen atoms: in oxazole, the two heteroatoms are separated by a carbon atom, while in isoxazole, they are bound directly.…”

Suppression of IFN-g Production in Murine Splenocytes by Histamine Receptor Antagonists

“…agonist [20], was found to suppress IFN-γ production in activated human peripheral blood mononuclear cells through suppression of expression of T-bet, which is the master transcription factor of Th1 differentiation [21]. A recent study reported that some benzoxazole derivatives could suppress IFN-γ production in murine CD4 + T cells in a similar manner to clozapine [22].…”

Suppression of IFN-γ Production in Murine Splenocytes by Histamine Receptor Antagonists

“…Interestingly, clozapine, which can function as an H 4 agonist [19], was found to suppress IFN-γ production in activated human peripheral blood mononuclear cells through suppression of expression of T-bet, which is the master transcription factor of Th1 differentiation [20]. A recent study reported that some benzoxazole derivatives can suppress IFN-γ production in murine CD4 + T cells in a similar manner to clozapine [21]. Accumulating evidence suggests that T-bet is involved in IFN-γ production both in CD4 + and CD8 + T cells, although T-bet-independent IFN-γ production was reported in CD8 + T cells [22,23,24].…”