Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition

Peduto, Antonella; Krauth, Verena; Collarile, Selene; Dehm, Fiederike; Ambruosi, Marika; Belardo, Carmela; Guida, Francesca; Massa, António; Esposito, Veronica; Maione, Sabatino; Rosa, Mario De; Werz, Oliver; Filosa, Rosanna

doi:10.1016/j.ejmech.2015.11.048

Cited by 23 publications

(7 citation statements)

References 24 publications

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“…To confirm the implication of 5-LO in the pathogenesis of cancer, researchers have used several medications such as 5-LO inhibitors (zileuton, ZYflo, ABT-761), FLAP inhibitors (MK-886) or other related drugs (zafirlukast and montelukast) in inhibiting cell proliferation and inducing cell death in vitro and in vivo [11]. Our group has synthesized and characterized several agents such as quinone-based derivatives with anti-cancer and anti-inflammatory properties [12,13,14,15,16,17,18,19,20,21,22,23]. These studies on the development of quinone-based compounds with antitumor activity have led to investigate the natural compound embelin and its analogues known as inhibitors of 5-LO and able to suppress proliferation of GBM cells [24].…”

Section: Introductionmentioning

confidence: 99%

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

Zappavigna

Cossu

Abate

et al. 2019

IJMS

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5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated by MTT assay. The effects of the compound on apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array, Real Time qPCR, confocal microscopy analysis and the western blotting technique. Our results showed that EA-100C Red had a higher anti-proliferative effect on LN229 as compared to U87MG cells. The compound induced a significant increase of apoptosis and autophagy and up-regulated pro-apoptotic genes (Bcl3, BNIP3L, and NFKBIA) in both GBM cell lines. In this light, we studied the effects of EA-100C red on the expression of CHOP and XBP1, that are implicated in ER-stress-mediated cell death. In summary, our findings revealed that EA-100C red induced ER stress-mediated apoptosis associated to autophagy in GBM cells through CHOP and Beclin1 up-regulation and activation of caspases 3, 9, JNK and NF-kappaB pathway. On these bases, EA-100C red could represent a promising compound for anti-cancer treatment.

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Section: Introductionmentioning

confidence: 99%

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

Zappavigna

Cossu

Abate

et al. 2019

IJMS

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“…Several benzoquinones have been found effective in treating some forms of cancer [ 17 ]; in details, it has been shown that these compounds act on cells by regulating numerous mechanisms, such as apoptosis, cell cycle [ 30 ], interacting with human-telomeric G-quadruplex DNA [ 31 ] or producing reactive oxygen species (ROS) [ 32 ]. Our group has been interested for a long time in synthesis and biological evaluation of anti-inflammatory and anti-cancer agents including quinone-based compounds [ 20 – 23 ]. Within the context of our investigations on quinone derivatives and on their possible therapeutic use, we recently studied the natural compound embelin and the synthetic derivative RF-Id [ 15 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells

Zappavigna

Scuotto

Cossu

et al. 2016

J Exp Clin Cancer Res

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BackgroundEmbelin is a potent dual inhibitor of 5-lipoxigenase (5-LOX) and microsomal prostaglandin E2 synthase (mPGES)-1 that suppresses proliferation of human glioma cells and induces apoptosis by inhibiting XIAP and NF-κB signaling pathway. Synthetic structural modification yielded the derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id), an embelin constrained analogue, with improved efficiency against 5-LOX in human neutrophils and anti-inflammatory activity in vivo. Taking into account that lipoxygenase (LOX) metabolites, from arachidonic acid and linoleic acid, have been implicated in tumor progression, here, we determined whether RF-Id was able to hinder glioblastoma (GBM) cancer cell growth and the related mechanisms.MethodsU87MG and LN229 cells were plated in 96-wells and treated with increasing concentrations of RF-Id. Cell viability was evaluated by MTT assay. The effects of the compounds on cell cycle, apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array and evaluating caspase cascade and NFκB pathway by western blotting technique.ResultsHere, we found that RF-Id induced a stronger inhibition of GBM cell growth than treatment with embelin. Flow cytometry analysis showed that RF-Id induced about 30 % apoptosis and a slight increase of autophagy after 72 h on U87-MG cells. Moreover, the compound induced an increase in the percentage of cells in G2 and S phase that was paralleled by an increase of p21 and p27 expression but no significant changes of the mitochondrial membrane potential; array analysis showed a significant upregulation of CASP8 and a downregulation of IAP family and NFκB genes in cells treated with RF-Id. RF-Id induced a significant cleavage of caspases 8, 9, 3 and 7, blocked c-IAP2/XIAP interaction by inducing XIAP degradation and inhibited NFκB pathway.Conclusions RF-Id induced a caspase-dependent apoptosis in GBM cells by inhibiting IAP family proteins and NFκB pathway and represents a promising lead compound for designing a new class of anti-cancer drugs with multiple targets.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0440-x) contains supplementary material, which is available to authorized users.

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“…Compound 9 was afforded by annexation of benzene and indole, which showed a satisfactory IC 50 value of 0.2 μM. 41 In a carrageenan-induced mouse paw edema experiment, this compound performed well in reducing the inflammatory reactions. Systematical modifications at the meta-, orthoor ortho/para-position of 2-phenylthiomethyl moiety in its structure indicated that 2,6-dichloro and 3,5-dichloro derivatives exhibited higher potency in inhibiting 5-LOX activity than 2,3-dichloro and 3,4-dichloro derivatives.…”

Section: Inhibitors Obtained By the Modification Of Previously Known mentioning

confidence: 97%

Recent development of lipoxygenase inhibitors as anti-inflammatory agents

2018

Med. Chem. Commun.

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Inflammation is favorable in most cases, because it is a kind of body defensive response to external stimuli; sometimes, inflammation is also harmful, such as attacks on the body's own tissues. It could be that inflammation is a unified process of injury and resistance to injury. Inflammation brings extreme pain to patients, showing symptoms of rubor, swelling, fever, pain and dysfunction. As the specific mechanism is not clear yet, the current anti-inflammatory agents are given priority for relieving suffering of patients. Thus it is emergent to find new anti-inflammatory agents with rapid effect. Lipoxygenase (LOX) is a kind of rate-limiting enzyme in the process of arachidonic acid metabolism into leukotriene (LT) which mediates the occurrence of inflammation. The inhibition of LOX can reduce LT, thereby producing an anti-inflammatory effect. In this review, the LOX inhibitors reported in recent years are summarized, and, in particular, their activities, structure-activity relationships and molecular docking studies are emphasized, which will provide new ideas to design novel LOX inhibitors.

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Exploring the role of chloro and methyl substitutions in 2-phenylthiomethyl-benzoindole derivatives for 5-LOX enzyme inhibition

Cited by 23 publications

References 24 publications

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

The 1,4 benzoquinone-featured 5-lipoxygenase inhibitor RF-Id induces apoptotic death through downregulation of IAPs in human glioblastoma cells

Recent development of lipoxygenase inhibitors as anti-inflammatory agents

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