Indole-3-ethylsulfamoylphenylacrylamides: Potent histone deacetylase inhibitors with anti-inflammatory activity

Mehndiratta, Samir; Hsieh, Yu-Lin; Liu, Yi Min; Wang, Amber Weiching; Lee, Hsueh Yun; Liang, Lung Yu; Kumar, Sunil; Teng, Che-Ming; Yang, Congrong; Liou, Jing Ping

doi:10.1016/j.ejmech.2014.08.020

Cited by 43 publications

(27 citation statements)

References 27 publications

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“…Analyses of these small molecule HDAC inhibitors indicated the N -hydroxyacrylamide group plays an important role in the inhibition of HDAC activity [ 11 ]. We previously developed a series of indole-3-ethylsulfamoylphenylacrylamides compounds that were based on the core structure of PXD101 (Belinostat) and show apparent anti-inflammatory activity [ 12 ]. Among these compounds, we found that N-hydroxy-3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (MPT0G157) exhibited both inhibitory characteristics of HDAC and lipopolysaccharide (LPS)-induced NF-κB signals/cytokines release superior to PXD101 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…We previously developed a series of indole-3-ethylsulfamoylphenylacrylamides compounds that were based on the core structure of PXD101 (Belinostat) and show apparent anti-inflammatory activity [ 12 ]. Among these compounds, we found that N-hydroxy-3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (MPT0G157) exhibited both inhibitory characteristics of HDAC and lipopolysaccharide (LPS)-induced NF-κB signals/cytokines release superior to PXD101 [ 12 ]. However, the molecular action of MPG0G157 in the inhibition of cancer growth has not been clearly elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis

Huang

Mehndiratta

et al. 2015

Oncotarget

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Histone deacetylases (HDACs) display multifaceted functions by coordinating the interaction of signal pathways with chromatin structure remodeling and the activation of non-histone proteins; these epigenetic regulations play an important role during malignancy progression. HDAC inhibition shows promise as a new strategy for cancer therapy; three HDAC inhibitors have been approved. We previously reported that N-hydroxy-3-{4-[2-(2-methyl-1H-indol-3-yl)-ethylsulfamoyl]-phenyl}-acrylamide (MPT0G157), a novel indole-3-ethylsulfamoylphenylacrylamide compound, demonstrated potent HDAC inhibition and anti-inflammatory effects. In this study, we evaluated its anti-cancer activity in vitro and in vivo. MPT0G157 treatment significantly inhibited different tumor growth at submicromolar concentration and was particularly potent in human colorectal cancer (HCT116) cells. Apoptosis and inhibited HDACs activity induced by MPT0G157 was more potent than that by the marketed drugs PXD101 (Belinostat) and SAHA (Vorinostat). In an in vivo model, MPT0G157 markedly inhibited HCT116 xenograft tumor volume and reduced matrigel-induced angiogenesis. The anti-angiogenetic effect of MPT0G157 was found to increase the hyperacetylation of heat shock protein 90 (Hsp90) and promote hypoxia-inducible factor-1α (HIF-1α) degradation followed by down-regulation of vascular endothelial growth factor (VEGF) expression. Our results demonstrate that MPT0G157 has potential as a new drug candidate for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis

Huang

Mehndiratta

et al. 2015

Oncotarget

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“…[118,119] According to recent trendsi nr esearch in to selective HDAC inhibitors for certain isoforms, N-hydroxy-(4-oxime)cinnamamide derivatives exhibited selectivei nhibition of HDAC6 and HDAC8( 92-95,T able 14). [127] [121] Compounds 97 and 98 were more selective towards HDAC1 and 2.…”

Section: H Dac Inhibitorsmentioning

confidence: 97%

“…Compound 106 was proposed as an ew lead structure in the search for anti-inflammatory agents among N-hydroxycinnamamides. [127]…”

Section: H Dac Inhibitorsmentioning

confidence: 99%

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

et al. 2015

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The cinnamamide scaffold has been incorporated in to the structure of numerous organic compounds with therapeutic potential. The scaffold enables multiple interactions, such as hydrophobic, dipolar, and hydrogen bonding, with important molecular targets. Additionally, the scaffold has multiple substitution options providing the opportunity to optimize and modify the pharmacological activity of the derivatives. In particular, cinnamamide derivatives have exhibited therapeutic potential in animal models of both central and peripheral nervous system disorders. Some have undergone clinical trials and were introduced on to the pharmaceutical market. The diverse activities observed in the nervous system included anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative properties. Over the last decade, research has focused on the molecular mechanisms of action of these derivatives, and the data reported in the literature include targeting the γ-aminobutyric acid type A (GABAA ) receptors, N-methyl-D-aspartate (NMDA) receptors, transient receptor potential (TRP) cation channels, voltage-gated potassium channels, histone deacetylases (HDACs), prostanoid receptors, opioid receptors, and histamine H3 receptors. Here, the literature data from reports evaluating cinnamic acid amide derivatives for activity in target-based or phenotypic assays, both in vivo and in vitro, relevant to disorders of the central and peripheral nervous systems are analyzed and structure-activity relationships discussed.

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“…The presence of the carboxamide moiety at positions 2 and 3 has led to the activity of these compounds tend to inhibit various enzymes and proteins. Many studies have been done in this regard, and various properties such as anticancer [6], antimalarial [7], anti-inflammatory [8], anti-diabetic [9][10][11], antimicrobial [12], antitubercular [13], antibacterial [14] and cytotoxic [7] have been reported, for indole derivatives.…”

Section: Introductionmentioning

confidence: 99%

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

Chehardoli

Bahmani

2020

Mol Divers

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Indole derivatives have been the focus of many researchers in the study of pharmaceutical compounds for many years. Researchers have investigated the effect of carboxamide moiety at positions 2 and 3, giving unique inhibitory properties to these compounds. The presence of carboxamide moiety in indole derivatives causes hydrogen bonds with a variety of enzymes and proteins, which in many cases, inhibits their activity. In this review, synthetic strategies of indole 2 and 3-carboxamide derivatives, the type, and mode of interaction of these derivatives against HLGP, HIV-1, renin enzyme, and structure-activity studies of these compounds were investigated. It is hoped that indole scaffolds will be tested in the future for maximum activity in pharmacological compounds.

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Indole-3-ethylsulfamoylphenylacrylamides: Potent histone deacetylase inhibitors with anti-inflammatory activity

Cited by 43 publications

References 27 publications

Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis

Anticancer activity of MPT0G157, a derivative of indolylbenzenesulfonamide, inhibits tumor growth and angiogenesis

Cinnamamide Derivatives for Central and Peripheral Nervous System Disorders—A Review of Structure–Activity Relationships

Synthetic strategies, SAR studies, and computer modeling of indole 2 and 3-carboxamides as the strong enzyme inhibitors: a review

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