Anti-inflammatory and Anti-allergic Activities of Hydroxylamine and Related Compounds.

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as analgesic or antipyretic agents for the clinical treatment of inflammatory diseases such as arthritis, lumbago and rheumatism. These NSAIDs (e.g., ibuprofen, aspirin, and indomethacin) exhibit an inhibitory action on the cyclooxygenase (COX) that catalyzes the biosynthesis of prostaglandins and thromboxane from arachidonic acid. There are two isoforms of the membrane-bound COXs, COX-1 expressed constitutively, and COX-2 induced by stimuli of cytokines, mitogens or hormones. The constitutive COX-1 has also been reported to be induced by the stimulus of an angiogenic cytokine vascular endothelial growth factor (VEGF) 1) or by shear stress in vascular endothelial cells. 2)Recently, several COX-2 selective inhibitors such as meloxicam 3) and celecoxib 4) have been developed as NSAIDs because these substances show little gastropathy, a typical side effect of NSAIDs.We have previously reported the synthesis of a number of novel oximes and their derivatives, with several compounds showing anti-inflammatory activities in carrageenan-induced rat foot-pad swelling assay and histamine-induced rat vascular permeability assay. 5,6) We also reported the COX-1 inhibitory effect of the 4Ј-piperidinoacetophenone oxime (POx), 4Ј-morpholinoacetophenone oxime (M-Ox) and their Oacetyl derivatives (P-Ox-Ac or M-Ox-Ac). 6)The metabolic products of arachidonic acid catalyzed by 5-lipoxygenase (LOX) are leukotrienes (LTs) which function as important mediators in many types of inflammation reaction including allergy, asthma, and arthritis. For instance, LTC 4 and LTD 4 , well-known components of the slow-reacting substance of anaphylaxis (SRS-A), induce severe bronchoconstriction and increase vascular permeability, and LTB 4 causes leukocyte chemotaxis.7-10) Therefore, the development of dual inhibitors of COX and 5-LOX should be promising for the treatment of several inflammatory and allergy symptoms. Many investigations have shown that the enzymes catalyzing the arachidonic acid cascade (COX, 5-LOX, and/or 12-LOX) were inhibited by various hydroxamic acids and their derivatives. [11][12][13][14] Kramer et al. have reported a dual inhibitory action to COX and 5-LOX by hydroxylamine analogs of 2, 6 di-tert-butylphenols. 15)The purpose of the present study is to search more effective anti-inflammatory or anti-allergic drugs such as COX-2 selective and/or 5-LOX inhibitors. Hydroxylamine derivatives, which are substances reduced from anti-inflammatory oximes, are potential candidates for both anti-inflammatory and anti-allergic agents. Thus, anti-inflammatory oximes (POx and M-Ox) were reduced to the corresponding hydroxylamines; (1-hydroxylamino-1-(4Ј-piperidinophenyl) ethane, P-HA, and 1-hydroxylamino-1-(4Ј-morpholinophenyl) ethane, M-HA). 16,17) We also prepared N,O-diacetyl hydroxylamine derivatives, i.e., 1-(N,O-diacetyl hydroxylamino)-1-(4Ј-piperidinophenyl) ethane (P-HA-Ac) and 1-(N,O-diacetyl hydroxylamino)-1-(4Ј-morpholinophenyl) ethane (M-HA-Ac), as O-acetyl oximes ...

2-Methoxycinnamaldehyde Reduces IL-1.BETA.-Induced Prostaglandin Production in Rat Cerebral Endothelial Cells

“…COX-2, the inducible form of the enzyme, can undergo rapid induction in response to many factors such as bacterial lipopolysaccharides, growth factors, cytokines and phorbol esters. 22,23) Therefore, in this paper, effect of 2-methoxycinnamaldehyde and 2-methoxycinnamic acid on COX activity, COX protein and COX mRNA expression in CECs with IL-1b inducement were also measured. For each of the primer sets, non-specific amplification was not visualized after electrophoresis and ethidium bromide staining of agarose gels.…”

Screening and evaluation of antioxidant activity of some amido-carbonyl oxime derivatives and their radical scavenging activities

“…Also, they have been used as anti-skinning agents in paint, blocking agents in the polymer industry and chelators in variable industrial applications. Some oxime derivatives clinical used as anti-inflammatory and anti-allergic agents [5][6][7].…”

“…Recent studies showed the oximes have powerful antioxidants [8][9][10][11] antiepileptic drug [12], anti-inflammatory [13][14][15], antimicrobial [16,17], oxidative effect [18], antihyperglycemic agent [19] and hepatoprotective [20] activities.…”

Anti-inflammatory Activity of N-Naphthoyl D-Alanine in vivo

“…The reasons for expecting such anti-inflammatory activity are as follows; 1) the stereochemistry at the chiral center (C3) was the same as that of D-alanine 2) the planarity between C4-C5 in naproxen might be replaced with the double bond nature of the amide function (N4-C5) 3) the zigzag structure in naproxen could be mimicked as the zigzag structure drawn in bold lines in Fig. 1 4) the planarity between C5-C6 in R-1 might be obtained by the π electron donation from the aromatic ring to the amide carbonyl function 5) R-1 had a naphthalene ring that might settle on the planar domain of the binding site of the COXs advocated by Gund et al 8 First, anti-inflammatory activities against four compounds, 9 R-1, S-1, 2, and R-3, were evaluated by carrageenan-induced mouse foot-pad swelling assay 10,11 at a dose of 150 mg/kg and statistical analyses were performed by Dunnett's method. Obtained data on the percentage inhibition and judgments on significant differences from the control group are summarized in Table 1.…”

“…We evaluated six compounds (R-4 -R-9) 9 for anti-inflammatory activities by carrageenan-induced mouse foot-pad swelling assay 10,11 with a usual dose of 150 mg/kg. The percentage inhibition, determinations of S or NS, and log P values 12 of aromatic ring moiety are listed in Table 2.…”