TA-270 [4-Hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], an Anti-Asthmatic Agent, Inhibits Leukotriene Production Induced by IgE Receptor Stimulation in RBL-2H3 Cells

Abstract

A novel quinolinone derivative, TA-270 [4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone], has been shown to inhibit antigen-induced asthmatic responses including the early-phase bronchoconstriction in actively sensitized guinea pigs. Here we characterized the action mechanisms of TA-270 in cellular level in vitro. In RBL-2H3 mast cells sensitized with dinitrophenol (DNP)-specific IgE, the antigen exhibited several mast cell functions, including hexosaminidase release as a marker of degranulation, production of tumor necrosis factor-␣, and production of immunologically detective leukotrienes. These antigeninduced actions were associated with the activation of several early signaling events, including inositol phosphate production reflecting phospholipase C activation and extracellular signal-regulated kinase activation. When the cells were treated with TA-270, the antigen-induced leukotriene production was almost completely suppressed, but other antigen-induced actions listed above were hardly affected. This drug also failed to affect the antigen-induced phospholipase A 2 activation as evaluated by the total release of arachidonic acid and its metabolites from the cells prelabeled with radioactive arachidonic acid. However, TA-270 clearly changed the arachidonic acid metabolic pathway. It suppressed the accumulation of 5-lipoxygenase products, including leukotrienes, but hardly affected the accumulation of cyclooxygenase products. The inhibitory action of TA-270 on leukotriene production was also observed in human neutrophils and eosinophils. We conclude that TA-270 inhibits 5-lipoxygenase activity and, thereby, suppresses the antigen-induced leukotriene production.

Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol via a Darzens Condensation/Friedel–Crafts Alkylation Strategy

“…The transformation of cyclopenin and cyclopenol into viridicatin and viridicatol through a decarboxylation/rearrangement process was realized by the White and Smith groups (Scheme 1b). 15 The rearrangement of benzo- [6,7]-1,4-diazepino [5,4-b]oxazole derivatives was reported by Tachikawa (Scheme 1c). 16 The condensation process of diazomethane (Scheme 1d) 17 and its derivatives (Scheme 1e) 18 with isatins was realized by the groups of Undheim, Pellicciari, and Gois.…”

“…5 Desaubry and co-workers synthesized 3-O-methylviridicatin analogues with improved anti-TNF-α properties. 6 Furthermore, compounds containing the 3-hydroxyquinolin-2-one skeleton have also been intensively studied as pharmaceutical agents such as the antiallergy agent TA-270, 7 selective inhibitors of HIV-1 reverse transcriptase, 8 potent D-amino acid oxidase (DAAO) 9 and mitogen-activated protein (MAP) kinase 10 inhibitors, [ 3 H]glycine binding to rat cortical membranes inhibitors, 11 and maxi-K channel openers with antibacterial activities. 12 However, the synthesis of 3-hydroxy-4-quinolin-2-ones has remained largely unexplored: only a few synthetic strategies have been developed for the construction of the skeleton.…”

Design and Synthesis of Novel Quinolinone-3-aminoamides and Their α-Lipoic Acid Adducts as Antioxidant and Anti-inflammatory Agents

“…Studies of the action mechanisms of TA 270 in cellular level in vitro revealed that it specifically suppresses the antigeninduced leukotriene production, probably by inhibiting 5-lipoxygenase in inflammatory cells. 19 A naturally occurring quinolinone alkaloid has been recently isolated from the aleurone layer of Oryza satiVa cv Hengjinmi. This compound exhibited moderate antioxidant activity in a DPPH free radical scavenging assay.…”

“…This compound was designed as an antioxidant, and further studies showed that it is as well a potent inhibitor of immediate- and late-airway responses, pulmonary inflammatory cell accumulation and, airway hyper-responsiveness, therefore, it may be of therapeutic use for the treatment of bronchial asthma. Studies of the action mechanisms of TA 270 in cellular level in vitro revealed that it specifically suppresses the antigen-induced leukotriene production, probably by inhibiting 5-lipoxygenase in inflammatory cells …”

Synthesis of 2,4-Diarylquinolines: Nickel-Catalysed Ligand-Free Cross-Couplings of 4-Chloro-2-Arylquinolines with Arylmagnesium Halides in 2-Methyltetrahydrofuran

“…Compounds containing the quinoline scaffold in the structural framework are expected to have wide-spectrum biological activity. Among their various applications, [1][2][3] functionalised quinolines are in widespread use as a result of their antimalarial, [4][5][6] anti-inflammatory, 7,8 anti-asthmatic, 9,10 antibacterial 11,12 and anti-hypersensitive activities. 13,14 Transition metal-catalysed cross-coupling has proved to be efficient in forming new C-C bonds.…”