Discovery of novel heteroaryl-substituted chalcones as inhibitors of TNF-α-induced VCAM-1 expression

Meng, Charles Q.; Zheng, Xiaoxiang; Ni, Liming; Ye, Zhihong; Simpson, Jacob E.; Worsencroft, Kimberly J.; Hotema, Martha; Weingarten, M. David; Skudlarek, Jason W.; Gilmore, Joshua M.; Hoong, Lee K.; Hill, Russell R.; Marino, Elaine M.; Suen, Ki‐Ling; Kunsch, Charles; Wasserman, Martin A.; Sikorski, James A.

doi:10.1016/j.bmcl.2004.01.021

Cited by 25 publications

(8 citation statements)

References 20 publications

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“…Among flavonols (KAEM, QUER, and MYRI) and flavones (FLVO, CHRY, APGN, LUTE, BILE, and BIL), only KAEM, CHRY, APGN and LUTE were inhibitors of TNF-α-mediated ICAM-1 expression [40]. Flavones LUTE and APGN inhibited TNF-α-induced upregulation of THP-1 adhesion and VCAM-1 expression [40]: while heteroaryl-substituted chalcones inhibited only VCAM-1 expression [41]. TNF-α-stimulated E-selectin expression was inhibited by fisetin, LUTE, APGN, KAEM, QUER, ERIO, GNTE and butein among the 37 flavonoids tested [42].…”

Section: Flavonesmentioning

confidence: 96%

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α

Kumazawa¹,

Kawaguchi²,

Takimoto

2006

CPD

143

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Flavonoids have beneficial activities which modulate oxidative stress, allergy, tumor growth and viral infection, and which stimulate apoptosis of tumor cells. In addition to these activities, dietary flavonoids are able to regulate acute and chronic inflammatory responses. Here we describe new aspects of regulatory mechanisms by which flavonoids suppress production of tumor necrosis factor-alpha (TNF-alpha) by macrophages, microglial cells and mast cells stimulated with lipopolysaccharide (LPS) and others via toll-like receptors (TLRs), and TNF-alpha-mediated acute and chronic inflammatory responses. Treatment with flavonoids such as luteolin, apigenin, quercetin, genistein, (-)-epigallocatechin gallate, and anthocyanidin resulted in significant downregulation of LPS-elicited TNF-alpha and nitric oxide (NO) production and diminished lethal shock. In chronic diseases, pathogenesis of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis which is triggered by TNF-alpha, was improved by the oral administration of flavonoids after the onset of CIA. Here, we discuss that inhibitory effects of flavonoids on acute and chronic inflammation are due to regulation of signaling pathways, including the nuclear factor kappaB (NF-kappaB) activation and mitogen-activated protein (MAP) kinase family phosphorylation. FcetaRI expression by NF-kappaB activation was also reduced by flavonoids; while accumulation of lipid rafts, which is the critical step for signaling, was blocked by flavonoids. The intake of dietary flavonoids reduces acute and chronic inflammation due to blocking receptor accumulation and signaling cascades, and would assist individuals at high-risk from life-style related diseases.

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Section: Flavonesmentioning

confidence: 96%

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α

Kumazawa¹,

Kawaguchi²,

Takimoto

2006

CPD

143

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“…Chalcones have several biological activities (Calliste et al, 2001), including anti-cancer and anti-oxidant activity (Anto et al, 1995;De Vincenzo et al, 2000), antimitotic activity (Edwards et al, 1990), inhibition of the release of chemical mediators (Ko et al, 2003), inhibiting TNF-alphainduced VCAM-1 expression (Meng et al, 2004), antiangiogenisis (Nam et al, 2003), and anti-inflammatory activity (Rojas et al, 2002;Won et al, 2005). The molecular cytotoxic mechanisms of the anticancer hydroxychalcones are of interest (Sabzevari et al, 2004), and work for developing potent anti-inflammatory chalcones has continued.…”

Section: Introductionmentioning

confidence: 98%

Structure activity relationship studies of anti-inflammatory TMMC derivatives: 4-Dimethylamino group on the B ring responsible for lowering the potency

Jin

et al. 2008

Arch. Pharm. Res.

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We previously synthesized 2',4',6'-tris(methoxymethoxy)chalcone (TMMC) derivatives with various substituents on the A ring that showed potent anti-inflammatory effects by inhibiting NO production in RAW 264.7 cells. The 2'-hydroxy group on the A ring could elevate the electrophilicity of Michael addition of GSH and electron donating groups on the A ring could stabilize the GSH adduct by decreasing the acidity of the alpha-hydrogen. Using this interpretation, we tested various substituents on the B ring and established a proper balance between biological activity and the position of the electron donating or electron withdrawing groups on the B ring. In this case, the 2'-hydroxy group was excluded because it could cause the formation of GSSG through a phenoxy radical and can confuse the interpretation of the biological results. Chalcone derivatives without 2'-hydroxy are likely to deplete cellular GSH levels by a Michael addition process. Strong electron donating groups on the B ring, such as 4-dimethylamino group, gave the weakest inhibition of NO production. A 4-dimethyamino group on the B ring could decrease the stability of the GSH adduct by weakening the C-S bond strength through movement of an electron pair on nitrogen via an aromatic ring.

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“…Chalcones and flavonoids generally exhibit versatile biological activity, in particular antituberculous [6]. The ability of chalcones to inhibit leukocyte aggregation is completely lost upon hydrogenation of the double bond [7]. Taking into account the above stated, it seemed to be important to examine condensations of new acetophenone derivatives, specifically of those containing a carbamate moiety, with various carbonyl compounds.…”

mentioning

confidence: 98%

Some condensations of methyl 4-acetylphenylcarbamate

et al. 2010

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Discovery of novel heteroaryl-substituted chalcones as inhibitors of TNF-α-induced VCAM-1 expression

Cited by 25 publications

References 20 publications

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α

Structure activity relationship studies of anti-inflammatory TMMC derivatives: 4-Dimethylamino group on the B ring responsible for lowering the potency

Some condensations of methyl 4-acetylphenylcarbamate

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Discovery of novel heteroaryl-substituted chalcones as inhibitors of TNF-α-induced VCAM-1 expression

Cited by 25 publications

References 20 publications

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor &#945;

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor &#945;

Structure activity relationship studies of anti-inflammatory TMMC derivatives: 4-Dimethylamino group on the B ring responsible for lowering the potency

Some condensations of methyl 4-acetylphenylcarbamate

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Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α

Immunomodulating Effects of Flavonoids on Acute and Chronic Inflammatory Responses Caused by Tumor Necrosis Factor α