Antipsoriatic Anthrones with Modulated Redox Properties. 4. Synthesis and Biological Activity of Novel 9,10-Dihydro-1,8-dihydroxy-9-oxo-2- anthracenecarboxylic and -hydroxamic Acids

Müller, Klaus; Prinz, Helge

doi:10.1021/jm9701785

Cited by 35 publications

(19 citation statements)

References 52 publications

(122 reference statements)

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“…In psoriasis, NGF can have a pleiotropic role in the pathogenesis by regulating nerve growth, neuropeptides, angiogenesis, cell trafficking, and the function of T cells and mast cells, as recently reviewed (Raychaudhuri and Raychaudhuri, 2009). The HaCaT cell line has been widely used for the in vitro testing of antipsoriatic compounds (Muller and Prinz, 1997;Geilen et al, 1997). Therefore, in this study, we detail the mechanisms of neurotrophin-mediated induction of VEGF in HaCaT cell lines.…”

Section: Discussionmentioning

confidence: 99%

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Zhang¹,

Y²

2014

Genet. Mol. Res.

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ABSTRACT. Decades of research have provided the data to confirm the hypothesis that there is bidirectional communication between the central nervous system and the immune system in psoriasis pathogenesis, but the contribution of the cutaneous neural system remains underexplored. In this study, we evaluated the molecular mechanisms by which nerve growth factor (NGF) regulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) production. The mRNA and protein levels of VEGF secretion from HaCaT cells by NGF were increased in a concentration-dependent manner. In addition, the NGFinduced increase in VEGF is accompanied by an increase in HIF-1α, but not HIF-2α or HIF-1β. However, this increase is abrogated by pretreatment with a mammalian target of rapamycin (mTOR) inhibitor rapamycin. Pharmacologic inhibitors of the Trk tyrosine kinase, PI-3 kinase, and mTOR pathways prevent NGF-stimulated increases in HIF-1α and VEGF. Mutation of the siRNA-mediated silencing of HIF-1α expression blocks NGF-induced increases in VEGF transcription. Our 9325 NGF and VEGF in HaCaT keratinocytes©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (4): 9324-9335 (2014) study indicates that NGF regulates the expression of VEGF through the PI3K/mTOR signaling pathway in human HaCaT keratinocytes.

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Section: Discussionmentioning

confidence: 99%

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Zhang¹,

Y²

2014

Genet. Mol. Res.

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“…HaCaTs are immortalized cell lines derived from keratinocytes in normal adult skin and the excessive proliferation of these keratinocytes results in psoriatic lesions (7). Therefore, HaCaT cells have been widely used as an in vitro model for the study of anti-psoriasis agents (8,9). …”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits proliferation of human keratinocytes through a mechanism associated with activation of the MAPK signaling pathway

Zhong

et al. 2013

Experimental and Therapeutic Medicine

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In the present study, the effects of metformin on the proliferation of human immortalized keratinocytes (HaCaTs) and the underlying mechanisms were investigated. HaCaT cells in the logarithmic growth phase were treated with 50 mM metformin for 24, 48 and 72 h. Cell morphology after 24 h of treatment was observed under a microscope. Cell proliferation was detected using a colorimetric cell proliferation and cytotoxicity assay kit. Western blot analyses were performed to detect the protein phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-related kinase 1/2 (ERK1/2). Metformin treatment resulted in morphological changes of the HaCaT cells. The survival rates of HaCaT cells treated with metformin were 36.18, 12.70 and 10.12% at 24, 48 and 72 h, respectively. As the treatment time extended, the survival rates of HaCaT cells decreased. Western blot analysis results showed that the mean level of phosphorylated (p)-AMPK in the HaCaT cells without metformin treatment was 2.856±0.323. However, the mean p-AMPK level following metformin treatment for 24 h increased to 5.198±0.625, indicating a significant difference between these two groups (P<0.05). The mean absorbance ratio of p-ERK1/2 was 7.550±1.087 for the untreated cells, but the levels in cells following metformin treatment for 24 h increased to 10.430±1.217, indicating a significant difference between the two groups (P<0.05). In conclusion, metformin treatment upregulated the levels of p-AMPK and p-ERK1/2 in HaCaT cells, and significantly inhibited HaCaT cell proliferation in vitro by a mechanism associated with activation of the mitogen-activated protein kinase signaling pathway.

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“…[4] The parent anthrone, namely 9A C H T U N G T R E N N U N G (10H)-anthracenone, has been classically used as a reagent for the analytical determination of sugars and many of its derivatives have interesting biological properties: antimicrobial, laxative, antipsoriatic or as telomerase inhibitors. [5] Recently, it has been found that some anthrone derivatives may display potent and selective antitumour activity. [6] Anthrone has been used as the diene component in Diels-Alder cycloadditions with a variety of dienophiles.…”

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Bifunctional Thiourea‐Catalyzed Asymmetric Addition of Anthrones to Maleimides

et al. 2010

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For the first time, the addition of anthrones to maleimides catalyzed by bifunctional thiourea catalysts is reported. The thiourea moiety is able to activate the maleimide and the tertiary amine deprotonates the anthrone, furnishing the final DielsAlder or Michael adducts in excellent yields and enantioselectivities.Keywords: anthrones; Diels-Alder cycloaddition; enantioselective; maleimides; Michael addition; organocatalysis Anthrones are important compounds in natural products and in medicinal chemistry.[1] They are isolated, either in the free form or as O-or C-glycosides, from a wide variety of natural sources (plants, shrubs), such as rhubarb, Cassia, and "Cµscara sagrada" bark, among others.[2] From the chemical standpoint, anthrones and their enol tautomers, the 9-anthrols, play a central role in the chemistry of anthracenes, because by oxidation of the central ring they afford 9,10-anthraquinones, extremely valuable compounds as pigments or anticancer agents.[3] On the other hand, the reduction of anthrones provides anthracenes, useful in the preparation of dyestuffs and of optoelectronic materials.[4]The parent anthrone, namely 9A C H T U N G T R E N N U N G (10H)-anthracenone, has been classically used as a reagent for the analytical determination of sugars and many of its derivatives have interesting biological properties: antimicrobial, laxative, antipsoriatic or as telomerase inhibitors.[5] Recently, it has been found that some anthrone derivatives may display potent and selective antitumour activity. [6] Anthrone has been used as the diene component in Diels-Alder cycloadditions with a variety of dienophiles. [7,8] Kinetic studies performed by Koerner and Rickborn [8] on the reaction between anthrone and Nmethylmaleimide showed that a substantial acceleration took place in basic solvents such as DMF, pyridine or triethylamine, or upon the addition of a small quantity of triethylamine to a chloroform or THF solution of the reactants.[8] These results were interpreted by a catalytic oxyanion acceleration of the process, probably via the anthrone enolate (Scheme 1).Building upon these results, Riant and Kagan investigated the effect of chiral bases in the same reaction, [9] finding that quinidine and prolinol were the most enantioselective catalysts (up to 61% ee was achieved with a 10 mol% loading of quinidine in chloroform at À50 8C). Later on, Yamamoto and coworkers [10] described the asymmetric cycloaddition of anthrone and maleimides catalyzed by C 2 -chiral 2,5-bis(hydroxymethyl)pyrrolidines, obtaining good enantioselectivities in some instances (up to 87% ee). The enantioselective Diels-Alder cycloaddition of substituted anthrones with maleimides catalyzed by chiral bicyclic guanidines, which takes place with excellent yields and enantioselectivities (85-99% ee) when run in dichloromethane solution at À20 8C, was reported in 2006 by Tan and co-workers.[11] This reaction showed, however, a very strong temperature dependence, and the enantiomeric purity of the Diels-Alder adduct was much...

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Antipsoriatic Anthrones with Modulated Redox Properties. 4. Synthesis and Biological Activity of Novel 9,10-Dihydro-1,8-dihydroxy-9-oxo-2- anthracenecarboxylic and -hydroxamic Acids

Cited by 35 publications

References 52 publications

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Metformin inhibits proliferation of human keratinocytes through a mechanism associated with activation of the MAPK signaling pathway

Bifunctional Thiourea‐Catalyzed Asymmetric Addition of Anthrones to Maleimides

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