Biology-oriented development of novel lipophilic antioxidants with neuroprotective activity

Silva, Tiago; Bravo, Joana; Summavielle, Teresa; Remião, Fernando; Pérez, Concepción; Gil, Carmen; Martı́nez, Ana; Borges, Fernanda

doi:10.1039/c4ra15164j

Cited by 20 publications

(26 citation statements)

References 91 publications

(222 reference statements)

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“…We had previously reported that short‐chain alkyl esters of caffeic acid significantly inhibited hydrogen peroxide‐induced neuronal PC12 cell death, but ferulate esters could not reduce oxidative stress‐induced cell damage . Lipophilicity is an important physicochemical property of phenolic compounds, and several lines of evidence have shown that esterification of phenolic compounds can increase the lipophilicity and therefore their pharmacological activity …”

Section: Discussionmentioning

confidence: 99%

“…In continuation of our interest in the synthesis and evaluation of the biological activities of HCAs, we have synthesized 30 HCA derivatives consisting of short‐ and long‐chain alkyl esters of p ‐coumaric acid, ferulic acid, sinapic acid, and caffeic acid and have tested their ability to promote cell survival and induction of differentiation in neuronal cells. We further performed a molecular docking simulation study in order to find out the binding potential of active derivatives with PI3K as a putative molecular target.…”

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confidence: 99%

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Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

et al. 2016

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The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 μm. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 μm led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

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Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

et al. 2016

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“…Preclinical investigations have revealed that using a combination of phenolic acids with traditional chemoradiotherapy or other polyphenols may be potentially efficient in reducing the spread of cancer [ 1 ]. In recent years, the cinnamic acid and its derivatives such as coumaric, caffeic, and ferulic acids have attracted considerable attention not only due to their pharmaceutical [ 2 ] and biological [ 3 ] activities but also to their technological and industrial applications [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Monitoring of the Surface Charge Density Changes of Human Glioblastoma Cell Membranes upon Cinnamic and Ferulic Acids Treatment

Naumowicz

Kusaczuk

Zając

et al. 2020

IJMS

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Cinnamic acid (CA) and ferulic acid (FA) are naturally occurring phenolic acids claimed to exert beneficial effects against disorders related to oxidative stress, including cancer. One such malignancy that still remains a therapeutic challenge mainly due to its heterogeneity and inaccessibility to therapeutic agents is Glioblastoma multiforme (GBM). Here, the influence of CA and FA on the surface charge density of human GBM cell line LN-229 was studied using the electrophoretic light scattering technique. Also, the cytotoxicity of both phenolic acids was determined by metabolic activity-assessing tetrazolium test (MTT) analysis after exposure to CA and FA for 24 h and 48 h. Results showed that both compounds reduced cell viability of LN-229 cells, with more pronounced effect evoked by CA as reflected in IC50 values. Further analyses demonstrated that, after treatment with both phenolic acids, the negative charge of membranes decreased at high pH values and the positive charge of the membranes increased at low pH values compared to the data obtained for untreated cells. Afterward, a four-equilibrium model was applied to estimate the total surface concentrations of both acidic and basic functional groups and their association constants with solution ions in order to calculate theoretical values of membrane surface charge densities. Then, the theoretical data were compared to the experimental data in order to verify the mathematical model. As such, our results indicate that application of electrochemical methods to determine specific drug–membrane interactions might be crucial for predicting their pharmacological activity and bioavailability.

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“… 56 – 59 The aim of this review, however, is to extensively address the alterations of signaling pathways involved in the neurotrophic action of polyphenols that lead to neuronal survival, growth, proliferation, and differentiation. The other aspects of neuroprotective activity of these compounds, which are mainly ascribed to the antioxidant action and mitigation of oxidative stress, have been reviewed elsewhere 5 , 7 , 8 , 60 – 62 and are only briefly mentioned here. It should also be mentioned that in in vitro studies, which are the main focus of this report, supraphysiological doses of polyphenols may have been used and, therefore, caution should be exerted in extrapolation of these data to in vivo conditions.…”

Section: Introductionmentioning

confidence: 99%

“…6-OHDA is a compound used to induce a Parkinson-like pathology in vitro and in vivo. It has been reported that baicalein 174 and also ferulic acid and caffeic acid derivatives, both belonging to hydroxycinnamic acid family ( Figure 1 ), 60 protect neuronal SH-SY5Y cells against 6-OHDA.…”

Section: Introductionmentioning

confidence: 99%

Modulation of neurotrophic signaling pathways by polyphenols

Moosavi¹,

Hosseini²,

Saso³

et al. 2015

DDDT

111

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Polyphenols are an important class of phytochemicals, and several lines of evidence have demonstrated their beneficial effects in the context of a number of pathologies including neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. In this report, we review the studies on the effects of polyphenols on neuronal survival, growth, proliferation and differentiation, and the signaling pathways involved in these neurotrophic actions. Several polyphenols including flavonoids such as baicalein, daidzein, luteolin, and nobiletin as well as nonflavonoid polyphenols such as auraptene, carnosic acid, curcuminoids, and hydroxycinnamic acid derivatives including caffeic acid phentyl ester enhance neuronal survival and promote neurite outgrowth in vitro, a hallmark of neuronal differentiation. Assessment of underlying mechanisms, especially in PC12 neuronal-like cells, reveals that direct agonistic effect on tropomyosin receptor kinase (Trk) receptors, the main receptors of neurotrophic factors including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) explains the action of few polyphenols such as 7,8-dihydroxyflavone. However, several other polyphenolic compounds activate extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/Akt pathways. Increased expression of neurotrophic factors in vitro and in vivo is the mechanism of neurotrophic action of flavonoids such as scutellarin, daidzein, genistein, and fisetin, while compounds like apigenin and ferulic acid increase cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Finally, the antioxidant activity of polyphenols reflected in the activation of Nrf2 pathway and the consequent upregulation of detoxification enzymes such as heme oxygenase-1 as well as the contribution of these effects to the neurotrophic activity have also been discussed. In conclusion, a better understanding of the neurotrophic effects of polyphenols and the concomitant modulations of signaling pathways is useful for designing more effective agents for management of neurodegenerative diseases.

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Biology-oriented development of novel lipophilic antioxidants with neuroprotective activity

Abstract: Discovery of hydroxycinnamic acid derivatives with enhanced in lipophilicity, blood brain barrier permeability and neuroprotective potential.

Cited by 20 publications

References 91 publications

Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

Monitoring of the Surface Charge Density Changes of Human Glioblastoma Cell Membranes upon Cinnamic and Ferulic Acids Treatment

Modulation of neurotrophic signaling pathways by polyphenols

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Biology-oriented development of novel lipophilic antioxidants with neuroprotective activity

Abstract: Discovery of hydroxycinnamic acid derivatives with enhanced in lipophilicity, blood brain barrier permeability and neuroprotective potential.

Cited by 20 publications

References 91 publications

Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

Monitoring of the Surface Charge Density Changes of Human Glioblastoma Cell Membranes upon Cinnamic and Ferulic Acids Treatment

Modulation of neurotrophic signaling pathways by&nbsp;polyphenols

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Modulation of neurotrophic signaling pathways by polyphenols