Synthesis and In Vitro Protein Tyrosine Kinase Inhibitory Activity of Furan-2-yl(phenyl)methanone Derivatives

Zheng, Fu‐Chun; Ban, Shu Rong; Feng, Xiu E; Zhao, Cheng; Lin, Wenhan; Li, Qing Shan

doi:10.3390/molecules16064897

Cited by 12 publications

(9 citation statements)

References 18 publications

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“…In support of these growing interests, we expanded upon the continuing structural optimization and mechanistic investigation on halophenols for finding a candidate compound. As a fact, we have reported the plentiful synthesis of a series of diphenylketone, diphenylmethane and phenyl furan-2-yl ketone halophenols, and their protective activity against H 2 O 2 induced injury in human umbilical vein endothelial cells (HUVECs) [ 11 , 13 ]. Moreover, we indeed found a “hit” compound, 5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanoe ( LM49 ) ( Figure 1 ) possessing an EC 50 value of 0.4 μM with the strong vascular endothelium protective ability [ 11 ], as evidenced being attributed to its anti-apoptotic, antioxidant, and anti-inflammatory abilities by further mechanical study [ 1 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking

et al. 2017

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We previously reported 5,2’-dibromo-2,4’,5’-trihydroxydiphenylmethanoe (LM49), a bromophenol analogue that shows strong protection from oxidative stress injury owing to its superior anti-inflammatory, antioxidant, and anti-apoptotic properties. A series of novel nitrogen-containing heterocycle bromophenols were herein synthesized by introducing substituted piperidine, piperazine, and imidazole to modify 2-position of the lead compound LM49. By further evaluating their cytoprotective activity against H2O2 induced injury in EA.hy926 cells, 14 target bromophenols showed moderate-to-potent activity with EC50 values in the range of 0.9–6.3 μM, which were stronger than that of quercetin (EC50: 18.0 μM), a positive reference compound. Of these, the most potent compound 22b is a piperazine bromophenol with an EC50 value of 0.9 μM equivalent to the LM49. Molecular docking studies were subsequently performed to deduce the affinity and binding mode of derived halophenols toward the Keap1 Kelch domain, the docking results exhibited that the small molecule 22b is well accommodated by the bound region of Keap1-Kelch and Nrf2 through stable hydrogen bonds and hydrophobic interaction, which contributed to the enhancement of affinity and stability between the ligand and receptor. The above facts suggest that 22b is a promising pharmacological candidate for further cardiovascular drug development. Moreover, the targeting Keap1-Nrf2 protein-protein interaction may be an emerging strategy for halophenols to selectively and effectively activate Nrf2 triggering downstream protective genes defending against injury.

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Section: Introductionmentioning

confidence: 99%

Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking

et al. 2017

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“…Halophenols, isolated from halobios such as various marine algae, ascidians and sponges exhibit a wide spectrum of bioactivities including protein tyrosine phosphatase (PTP1B) inhibitory [10], antioxidative [11,12], antithrombotic [13], antimicrobial [14,15], anti-inflammatory [16], enzyme inhibitory [17], cytotoxic [18], appetite suppressant [19], and PTK inhibitory activities [20]. Recently, we synthesized a variety of halophenols including 2,4′,5′-trihydroxyl-5,2′-dibromo diphenylmethanone (TDD, Figure 1), which has strong antioxidative and cytoprotective activities [21,22,23]. However, the detailed mechanisms underscoring its actions are unclear.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of 2,4′,5′-Trihydroxyl-5,2′-dibromo diphenylmethanone, a New Halophenol, against Hydrogen Peroxide-Induced EA.hy926 Cells Injury

Feng

et al. 2015

Molecules

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Vascular endothelial cells produce reactive oxygen species (ROS) during the process of energy metabolism in aerobic respiration. A growing body of evidence indicates that excessive ROS is implicated in the pathogenesis of cardiovascular diseases including atherosclerosis. The newly synthesized halophenol, 2,4′,5′-trihydroxyl-5,2′-dibromo diphenylmethanone (TDD), exhibits antioxidative and cytoprotective activities in vitro. In this study, the protective effect of TDD against hydrogen peroxide (H2O2)-induced oxidative injury of EA.hy926 cells was investigated. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide (MTT) assay, while the effect of TDD on the transcription profile of EA.hy926 cells subjected to H2O2-induced oxidative injury was evaluated by microarray analysis. Several signaling pathways, including apoptosis, were significantly associated with TDD. Flow cytometric analysis was used to evaluate anti-apoptotic effect of TDD. Subsequently, RT-PCR and Western blot were used to detect the expressions of the apoptosis-associated protein, Bcl-2 and Bax. Meanwhile the expression of cleaved caspase-3, an executioner of apoptosis, was also detected by Western blot. The results showed that pretreatment of EA.hy926 cells with TDD prevented the decrease of cell viability induced by H2O2, and attenuated H2O2-induced elevation of Bax and cleaved OPEN ACCESSMolecules 2015, 20 14255 caspase-3 while increased Bcl-2 expressions. In summary, TDD inhibited H2O2-induced oxidative injury of EA.hy926 cells through negative regulation of apoptosis. These findings suggest that TDD is a potential candidate for therapeutic intervention in oxidative stress-associated cardiovascular diseases.

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“…[ 47 ], where naturally occurring flavonoids have shown their complete retardation (using 100 μM quercetin) and suppression of growth (using apigenin and myricetin). In addition, not only natural (bromo)phenols, but also their synthetic analogs have also shown identical or even better in vitro protein tyrosine kinase inhibitory activity (μM) [ 63 ]. Thus, this could indicate pathway in searching for new chemical entities that could be further developed as therapeutic/chemopreventive agents for prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequently, while tebrophen eliminates PC3 cells and inhibits other studied cell line growth, it is suggested as a starting lead molecule for the design of more soluble derivatives with specific anticancer activity. For that purpose testing on several different prostate cell lines and detailed mechanistic study including tyrosine kinases [ 63 ] have to be performed.…”

Section: Discussionmentioning

confidence: 99%

Tebrophen — An Old Polyphenol Drug with Anticancer Potential †

et al. 2012

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In vitro high-throughput screening was carried out in order to detect new activities for old drugs and to select compounds for the drug development process comprising new indications. Tebrophen, a known antiviral drug, was found to inhibit activities on inflammation and cancer related targets. In primary screening this semisynthetic halogenated polyphenol was identified to inhibit the activities of kinases ZAP-70 and Lck (IC 50 0.34 µM and 16 µM, respectively), as well as hydrolase DPPIV (at 80 µM 41% inhibition). Next, it showed no cytotoxic effects on standard cell lines within 24 h. However, tebrophen slowed propagation of breast cancer (MDA-MB-231), osteosarcoma (U2OS) and cervical carcinoma (HeLa), through at least 35 population doublings in a dose-dependent manner. It completely stopped the division of the prostate cancer (PC3) cell line at 50 µM concentration and the cells entered massive cell death in less than 20 days. On the other hand, tebrophen did not influence the growth of normal fibroblasts. According to the measured oxidative burst and estimated in silico parameters its direct antioxidative ability is limited. The obtained results indicate that tebrophen can be considered a promising lead molecule for generating more soluble derivatives with specific anticancer efficacy.

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Synthesis and In Vitro Protein Tyrosine Kinase Inhibitory Activity of Furan-2-yl(phenyl)methanone Derivatives

Cited by 12 publications

References 18 publications

Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking

Synthesis of Novel Nitrogen-Containing Heterocycle Bromophenols and Their Interaction with Keap1 Protein by Molecular Docking

Protective Effect of 2,4′,5′-Trihydroxyl-5,2′-dibromo diphenylmethanone, a New Halophenol, against Hydrogen Peroxide-Induced EA.hy926 Cells Injury

Tebrophen — An Old Polyphenol Drug with Anticancer Potential †

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