François Noël - Academia.edu (original) (raw)
Papers by François Noël
Antiviral Research, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Journal of the Brazilian Chemical Society, 2020
Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhi... more Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhibitors aiming the discovery of new hits with activity in cognitive disorders. 1,4-Disubstituted α-hydroxy-1,2,3-triazoles were obtained as racemates in moderate to good yields by the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction (click chemistry) as the key step between propargyl alcohols and aryl azides, previously prepared from anilines or boronic acids. Benzo[c]chromene-triazoles were planned to be obtained by palladium-catalyzed C−H activation using [bis(trifluoroacetoxy)iodobenzene] (PhI(TFA) 2) of some α-hydroxy-1,2,3-triazoles, since benzo[c]chromenes are also privileged groups with several biological activities, including to the central nervous system. Unexpectedly, 9H-fluorenes-1,2,3-triazoles, instead of benzo[c]chromenetriazoles, were obtained by Friedel-Crafts alkylation reaction. The two series of compounds were tested for inhibition of the glycine transporter (rat GlyT1 isoform) but only the α-hydroxy-1,2,3-triazole 9b was active (half maximal inhibitory concentration (IC 50) = 8.0 µM).
Life Sciences, 1997
Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human f... more Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human flatworm Schistosoma mansoni. As an action on ATPases responsible for calcium homeostasis arises as a possible explanation for the molecular mechanism of this effect, we tested here the effect of praziquantel on different preparations from male adult worms that were previously characterized for their content in (Nd+K+)-ATPase and (Ca'+-Mg'+)ATPase activities from different origins. Concentrations as high as 100 ?M praziquantel did not inhibit (Na++K+)-ATPase from tegument and carcass nor (Ca2'-Mg ')ATPase from heterogeneous (P,) and microsomal (P4) fractions. As 100 pM praziquantel was also without effect on calcium permeability of microsomal vesicles actively loaded with 45Ca2+, the present results discard three hypotheses recently raised for the mechanism of praziquantel-induced contraction of S. mansoni.
Bioorganic & Medicinal Chemistry, 2015
Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recent... more Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with c-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24 h treatment. No change in the Na,K-ATPase a1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with c-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.
Revista Virtual de Química, 2010
This work describes the discovery of new N-phenylpiperazine prototypes belonging to pyrazole seri... more This work describes the discovery of new N-phenylpiperazine prototypes belonging to pyrazole series, i.e. LASSBio-579 (10a), or to 1,2,3-triazole series, represented by LASSBio-581 (10c), which were designed from the structural simplification of the atypical antipsychotic drug clozapine (8). The evaluation of the affinity and intrinsic activity profiles of LASSBio-579 and LASSBio-581 indicate its ability to bind dopamine receptors from D 2-like family, acting as pre-synaptic agonists. Additionally, the investigation of the antipsychotic properties of these two prototypes in behavioral models has confirmed its effectiveness, which is also dependent on the modulation of serotoninergic receptors 5-HT 2A and 5-HT 1A. The pronounced antipsychotic effect evidenced for these N-phenylpiperazine derivatives through in vivo pharmacological assays confirmed their importance as new neuroactive drug-candidate prototypes for the treatment of schizophrenia.
PLoS ONE, 2011
Background and Aims: Schistosomiasis is an intravascular parasitic disease associated with inflam... more Background and Aims: Schistosomiasis is an intravascular parasitic disease associated with inflammation. Endothelial cells control leukocyte transmigration and vascular permeability being modulated by pro-inflammatory mediators. Recent data have shown that endothelial cells primed in vivo in the course of a disease keep the information in culture. Herein, we evaluated the impact of schistosomiasis on endothelial cell-regulated events in vivo and in vitro. Methodology and Principal Findings: The experimental groups consisted of Schistosoma mansoni-infected and agematched control mice. In vivo infection caused a marked influx of leukocytes and an increased protein leakage in the peritoneal cavity, characterizing an inflamed vascular and cellular profile. In vitro leukocyte-mesenteric endothelial cell adhesion was higher in cultured cells from infected mice as compared to controls, either in the basal condition or after treatment with the pro-inflammatory cytokine tumor necrosis factor (TNF). Nitric oxide (NO) donation reduced leukocyte adhesion to endothelial cells from control and infected groups; however, in the later group the effect was more pronounced, probably due to a reduced NO production. Inhibition of control endothelial NO synthase (eNOS) increased leukocyte adhesion to a level similar to the one observed in the infected group. Besides, the adhesion of control leukocytes to endothelial cells from infected animals is similar to the result of infected animals, confirming that schistosomiasis alters endothelial cells function. Furthermore, NO production as well as the expression of eNOS were reduced in cultured endothelial cells from infected animals. On the other hand, the expression of its repressor protein, namely caveolin-1, was similar in both control and infected groups. Conclusion/Significance: Schistosomiasis increases vascular permeability and endothelial cell-leukocyte interaction in vivo and in vitro. These effects are partially explained by a reduced eNOS expression. In addition, our data show that the disease primes endothelial cells in vivo, which keep the acquired phenotype in culture.
Planta medica, Jan 23, 2015
Diene valepotriates obtained from Valeriana glechomifolia present antidepressant-like activity, m... more Diene valepotriates obtained from Valeriana glechomifolia present antidepressant-like activity, mediated by dopaminergic and noradrenergic neurotransmissions. Also, previous studies have shown inhibitory activity of diene valepotriates towards Na(+)/K(+)-ATPase from the rat brain in vitro. Nevertheless, in vivo studies regarding the action of diene valepotriates on this enzyme are still lacking. Considering that Na(+)/K(+)-ATPase cerebral activity is involved in depressive disorders, the aim of this study was to investigate the effects of acute (5 mg/kg, p. o.) and repeated (5 mg/kg, p. o., once a day for three days) diene valepotriate administration on Na(+)/K(+)-ATPase activity in the cortex and hippocampus of mice submitted or not submitted to the forced swimming test. In addition, the protein expression of Na(+)/K(+)-ATPase α1, α2, and α3 isoforms in the cortex of mice repeatedly treated with diene valepotriates (and submitted or not submitted to the forced swimming test) was in...
Vascular Pharmacology, 2007
Schistosomiasis, an intravascular parasitic disease caused by Schistosoma mansoni, is related to ... more Schistosomiasis, an intravascular parasitic disease caused by Schistosoma mansoni, is related to alterations of murine vascular reactivity in the mesenteric bed, characterized by an impairment of the l-arginine/NO pathway and an increased potency of 5-hydroxytryptamine. The current study was performed to test the hypothesis that a similar alteration of reactivity also occurs in the aorta and to identify the mechanism behind such an increase. We found that aorta from mice infected with male S. mansoni exhibited an enhanced contraction in response to noradrenaline and 100 mM KCl. The inhibition of nitric oxide synthase increased aortic maximal contraction in response to noradrenaline in both groups, but the effect was less pronounced in infected mice than in control mice. Endothelium-dependent relaxation induced by acetylcholine was also smaller in infected mice compared to control mice, while endothelial-independent relaxation induced by sodium nitroprusside and forskolin was similar in both groups. The inhibition of voltage-dependent L-type Ca(2+) channels reduced the maximal contraction in response to noradrenaline more effectively in infected than in control mice. Conversely the inhibition of K(ATP) channels had a smaller effect in the infected group. As a conclusion, our data indicate that schistosomiasis also alters murine vascular reactivity outside the mesenteric bed, due to a partial impairment of NO signaling, a reduced contribution of K(ATP) channels and an increased Ca(2+) influx through L-type Ca(2+) channels.
The FASEB Journal, 2004
Alzheimer's disease (AD) and several other neurological disorders have been linked to the overact... more Alzheimer's disease (AD) and several other neurological disorders have been linked to the overactivation of glutamatergic transmission and excitotoxicity as a common pathway of neuronal injury. The betaamyloid peptide (Abeta) is centrally related to the pathogenesis of AD, and previous reports have demonstrated that the blockade of glutamate receptors prevents Abeta-induced neuronal death. We show that taurine, a beta-amino acid found at high concentrations in the brain, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate receptor agonists. The protective effect of taurine is not mediated by interaction with glutamate receptors, as demonstrated by binding studies using radiolabeled glutamate receptor ligands. The neuroprotective action of taurine is blocked by picrotoxin, an antagonist of GABA(A) receptors. GABA and the GABA(A) receptor agonists phenobarbital and melatonin also protect neurons against Abeta-induced neurotoxicity. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmacological manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults. GABAergic transmission may represent a promising target for the treatment of AD and other neurological disorders in which excitotoxicity plays a relevant role.
Phytochemistry, 2010
The flavone glycosides, named scutellarein-7-O-b-D-apiofuranoside and apigenin-7-O-b-D-apiofurano... more The flavone glycosides, named scutellarein-7-O-b-D-apiofuranoside and apigenin-7-O-b-D-apiofuranosyl-(1 ? 2)-b-D-apiofuranoside, and the flavone celtidifoline (5,6,4 0 ,5 0-tetrahydroxy-7,3 0-dimethoxyflavone), along with other 11 known compounds, were isolated from leaves of the ethyl acetate extract of Lantana trifolia L. using step gradient High Speed Countercurrent Chromatography (HSCCC) and High Performance Liquid Chromatography (HPLC), respectively. Their structures were elucidated by spectroscopic methods, including 2D NMR and mass spectrometry (ESI-MS) techniques. The ethanolic and ethyl acetate extracts produced an intense sedative effect in mice, one hour after oral administration of 1 mg/kg. This effect was neither due to a benzodiazepine-like effect of the three flavone derivatives neither of the phenylpropanoids, betonyoside F and verbascoside, that were tested for their affinity for the [ 3 H] flunitrazepam binding sites.
Nucleic Acids Research, 2008
The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime ... more The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime target for development of HCV replication inhibitors. Here, we report the identification of a new class of HCV NS5B inhibitors belonging to the coumestan family of phytoestrogens. Based on the in vitro NS5B RNA-dependent RNA polymerase (RdRp) inhibition in the low micromolar range by wedelolactone, a naturally occurring coumestan, we evaluated the anti-NS5B activity of four synthetic coumestan analogues bearing different patterns of substitutions in their A and D rings, and observed a good structure-activity correlation. Kinetic characterization of coumestans revealed a noncompetitive mode of inhibition with respect to nucleoside triphosphate (rNTP) substrate and a mixed mode of inhibition towards the nucleic acid template, with a major competitive component. The modified order of addition experiments with coumestans and nucleic acid substrates affected the potencies of the coumestan inhibitors. Coumestan interference at the step of NS5B-RNA binary complex formation was confirmed by cross-linking experiments. Molecular docking of coumestans within the allosteric site of NS5B yielded significant correlation between their calculated binding energies and IC 50 values. Coumestans thus add to the diversifying pool of anti-NS5B agents and provide a novel scaffold for structural refinement and development of potent NS5B inhibitors.
Memórias do Instituto Oswaldo Cruz, 1998
Journal of Pharmacological and Toxicological Methods, 2002
Introduction: The sarcoplasmic reticulum present in eukaryotic cells contains Ca 2 + pumps (SERCA... more Introduction: The sarcoplasmic reticulum present in eukaryotic cells contains Ca 2 + pumps (SERCA type) that accumulate Ca 2 + from the cytosol and Ca 2 + channels, such as ryanodine receptors and inositol 1,4,5-trisphosphate receptors, that release Ca 2 + from the lumen of this organelle. The use of a preparation rich in sarcoplasmic reticulum vesicles and poorly contaminated with plasmalemmal vesicles would be a prerequisite for studies of Ca 2 + efflux through ryanodine and inositol 1,4,5-trisphosphate receptors, so the present work was aimed to characterize the distribution profiles of various markers of sarcoplasmic reticulum and plasma membrane among fractions obtained from rat vas deferens. Methods: Oxalate-dependent Ca 2 + uptake, thapsigargin-sensitive (Ca 2 +-Mg 2 +) ATPase activity and binding of [ 3 H]ryanodine and [ 3 H]inositol 1,4,5-trisphosphate were measured in the nuclear, mitochondrial, and microsomal fractions obtained by differential centrifugation of rat vas deferens homogenate. Results: The recovery of the thapsigargin-resistant (Ca 2 +-Mg 2 +) ATPase activity, supposed to label the plasma membrane, was the same among nuclear, mitochondrial, and microsomal fractions, whereas the recovery of the thapsigargin-sensitive (Ca 2 +-Mg 2 +) activity, oxalate-dependent Ca 2 + uptake, and [ 3 H]inositol 1,4,5-trisphosphate binding, used as sarcoplasmic reticulum markers, was higher in nuclear fraction than in the others. The recovery profiles of the four sarcoplasmic reticulum markers, including [ 3 H]ryanodine binding, were statistically the same among the different subcellular fractions. Caffeine, an agonist of ryanodine receptors, induced the release of 17% of Ca 2 + taken up by the vesicles present in the nuclear fraction but had no effect in microsomes. Discussion: Although this nuclear fraction is less purified in sarcoplasmic reticulum markers than the microsomal fraction, it is more suitable for studying Ca 2 + release through ryanodine receptors, primarily because it is less contaminated with vesicles from the plasma membrane which are able to take up Ca 2 + but are insensitive to caffeine.
Journal of Molecular and Cellular Cardiology, 1985
European Journal of Pharmacology, 2009
Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a ne... more Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a neglected disease for which there is an urgent need for searching new drug candidates. According to TDR/WHO, existing leads with proven schistosomicidal activity, like meclonazepam, might be the objects of further exploration. Here, we decided to investigate if the benzodiazepine binding sites that we recently characterized in adult Schistosoma mansoni could represent the molecular target of meclonazepam for its effect on worm motility and morphological appearance. The EC 50 of meclonazepam for its contracturant effect is 10-20 times lower than its IC 50 for binding to the worm benzodiazepine binding sites. On the contrary, benzodiazepines like flunitrazepam and diazepam have affinities at least 50 times higher than meclonazepam for these binding sites but did not induce contraction of the worms. We also confirmed the existence of a great similarity between the appearance, kinetics, Emax and external calcium dependency of the contractile effect of praziquantel and meclonazepam. Based on computer-aided molecular modeling calculations, we verified that a certain structural similarity exists between the active enantiomers of both drugs. We further proposed the hypothesis of common pharmacophoric elements including amide and imine subunits and the asymmetric carbons of S-(+)-meclozepam and R-(−)-praziquantel. As a whole, the present data indicate that the contracturant effect of meclonazepam is not a result of its binding to the worm benzodiazepine binding sites but that it shares some basic transduction pathway with praziquantel, even if not through identical molecular targets or binding sites.
European Journal of Pharmacology, 2004
European Journal of Pharmacology, 2007
Changes in myocardial expression of Na + /K +-ATPase α-subunit isoforms have been demonstrated in... more Changes in myocardial expression of Na + /K +-ATPase α-subunit isoforms have been demonstrated in different models of cardiac hypertrophy and hypertension. Here we studied the expression of these isozymes in stroke-prone spontaneously hypertensive rats (SHRSP) and the influence of high salt diet and treatment with the dihydropyridine lacidipine. Adult SHRSP were offered either 1% NaCl or water as drinking solution for 6 weeks. Salt-loaded SHRSP were treated or not with 1 mg/kg/day lacidipine. Compared to Wistar Kyoto (WKY) rats, non-salt-loaded SHRSP presented significant hypertension and cardiac hypertrophy. Salt intake markedly enhanced cardiac hypertrophy, an effect blunted by lacidipine. [ 3 H]Ouabain binding assays on total particulate fractions from heart ventricles revealed the existence of two high-affinity sites with K d ∼ 25 and ∼ 200 nM, ascribed to the α 3 and α 2 isoforms, respectively. B max of α 3 was unexpectedly high (40% of total high-affinity binding) in ventricles from WKY rats but very low in all groups of SHRSP. On the other hand, B max of α 2 was similar in WKY and non-salt-loaded SHRSP; however, salt loading of SHRSP resulted in a B max reduction of 20% (P b 0.05), an effect blocked by lacidipine. These effects were largely confirmed by immunoblotting analysis, which, in addition, demonstrated that the density of the ubiquitous α 1 isoform was comparable among the experimental groups. In conclusion, WKY rats showed a high myocardial expression of the Na + /K +-ATPase α 3 subunit, which was not found in SHRSP; the level of the α 2 isoform was similar in untreated SHRSP and WKY; salt-loading of SHRSP promoted reduction of the α 2 isoform, and this effect was completely hampered by lacidipine.
Biochemical Pharmacology, 1984
Cardiac glycoside binding to microsomes prepared from rat heart ventricles and enriched in (Na+ +... more Cardiac glycoside binding to microsomes prepared from rat heart ventricles and enriched in (Na+ + K+)-ATPase was measured by a rapid filtration technique. The relation between ouabain binding to microsomes and (Na+ + K+)-ATPase activity has also been examined. Data were statistically analysed by means of two different non linear regression methods. The experimental results were fitted the most closely by a model describing that ouabain specific binding occurred at two classes of independent sites. High affinity sites were characterized by a dissociation constant of 0.21 +/- 0.01 microM and a low capacity (9.4 +/- 1.4 pmoles/enzymatic unit). Low affinity sites were characterized by a dissociation constant equal to 13 +/- 3 microM and a capacity equal to 87 +/- 15 pmoles/enzymatic unit. Similar results were obtained with the more lipophilic glycoside digoxin. It was also observed that dihydroouabain, a ouabain derivative with a saturated lactone ring, competes with 3H-ouabain for the binding to the two classes of sites. Binding to these two classes of sites appeared to be associated with a corresponding inhibition of (Na+ + K+)-ATPase activity.
Annals of the New York Academy of Sciences, 1997
... How to Cite. QUINTAS, LEM, LOPEZ, LB, SOUCCAR, C. and NOËL, F. (1997), Na + /K + -ATPase Dens... more ... How to Cite. QUINTAS, LEM, LOPEZ, LB, SOUCCAR, C. and NOËL, F. (1997), Na + /K + -ATPase Density Is Sexually Dimorphic in the Adult Rat Kidney. Annals of the New York Academy of Sciences, 834: 552554. doi: 10.1111/j.1749-6632.1997.tb52316.x. Author Information. 1 ...
Life Sciences, 2011
Cardiac glycosides have been extensively used in the treatment of congestive heart failure for mo... more Cardiac glycosides have been extensively used in the treatment of congestive heart failure for more than 200 years. Recently, cardenolides and bufadienolides were isolated from mammalian tissue and are considered as a new class of steroidal hormones. The aim of the present work was to characterize the interaction between the most clinical used cardiac glycoside digoxin and the cardiac glycosides known to exist endogenously, i.e., ouabain, marinobufagin and telocinobufagin, on human kidney Na + /K +-ATPase. Main methods: Inhibition of Na + /K +-ATPase activity from crude membrane preparations of human kidney was performed using increasing concentrations of the drugs alone or mixtures of ouabain:digoxin, telocinobufagin:digoxin and marinobufagin:digoxin in a fixed ratio 1:4, 2:3 and 3:2, respectively. The colorimetric method of Fiske and Subbarow was used to measure the inorganic phosphate released. Key findings: Analyses of inhibition curves showed that the experimental curves for all combinations were superimposed on the theoretical additive curves indicating that an additive effect occurs among distinct cardenolides and bufadienolides combinations on the human α1β1 Na + /K +-ATPase protomer. Significance: Considering the extensive use of digoxin in the treatment of heart failure and the recent findings that endogenous cardiac glycosides may have altered levels in many diseases, including heart failure, the demonstration of additive effect between cardiac glycosides can help in the understanding of recent clinical observations, including that lower than usual doses of cardiac glycosides are necessary for decreasing mortality in these patients.
Antiviral Research, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Journal of the Brazilian Chemical Society, 2020
Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhi... more Two series of new compounds containing 1,2,3-triazole moiety were designed as putative GlyT1 inhibitors aiming the discovery of new hits with activity in cognitive disorders. 1,4-Disubstituted α-hydroxy-1,2,3-triazoles were obtained as racemates in moderate to good yields by the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction (click chemistry) as the key step between propargyl alcohols and aryl azides, previously prepared from anilines or boronic acids. Benzo[c]chromene-triazoles were planned to be obtained by palladium-catalyzed C−H activation using [bis(trifluoroacetoxy)iodobenzene] (PhI(TFA) 2) of some α-hydroxy-1,2,3-triazoles, since benzo[c]chromenes are also privileged groups with several biological activities, including to the central nervous system. Unexpectedly, 9H-fluorenes-1,2,3-triazoles, instead of benzo[c]chromenetriazoles, were obtained by Friedel-Crafts alkylation reaction. The two series of compounds were tested for inhibition of the glycine transporter (rat GlyT1 isoform) but only the α-hydroxy-1,2,3-triazole 9b was active (half maximal inhibitory concentration (IC 50) = 8.0 µM).
Life Sciences, 1997
Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human f... more Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human flatworm Schistosoma mansoni. As an action on ATPases responsible for calcium homeostasis arises as a possible explanation for the molecular mechanism of this effect, we tested here the effect of praziquantel on different preparations from male adult worms that were previously characterized for their content in (Nd+K+)-ATPase and (Ca'+-Mg'+)ATPase activities from different origins. Concentrations as high as 100 ?M praziquantel did not inhibit (Na++K+)-ATPase from tegument and carcass nor (Ca2'-Mg ')ATPase from heterogeneous (P,) and microsomal (P4) fractions. As 100 pM praziquantel was also without effect on calcium permeability of microsomal vesicles actively loaded with 45Ca2+, the present results discard three hypotheses recently raised for the mechanism of praziquantel-induced contraction of S. mansoni.
Bioorganic & Medicinal Chemistry, 2015
Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recent... more Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with c-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24 h treatment. No change in the Na,K-ATPase a1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with c-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.
Revista Virtual de Química, 2010
This work describes the discovery of new N-phenylpiperazine prototypes belonging to pyrazole seri... more This work describes the discovery of new N-phenylpiperazine prototypes belonging to pyrazole series, i.e. LASSBio-579 (10a), or to 1,2,3-triazole series, represented by LASSBio-581 (10c), which were designed from the structural simplification of the atypical antipsychotic drug clozapine (8). The evaluation of the affinity and intrinsic activity profiles of LASSBio-579 and LASSBio-581 indicate its ability to bind dopamine receptors from D 2-like family, acting as pre-synaptic agonists. Additionally, the investigation of the antipsychotic properties of these two prototypes in behavioral models has confirmed its effectiveness, which is also dependent on the modulation of serotoninergic receptors 5-HT 2A and 5-HT 1A. The pronounced antipsychotic effect evidenced for these N-phenylpiperazine derivatives through in vivo pharmacological assays confirmed their importance as new neuroactive drug-candidate prototypes for the treatment of schizophrenia.
PLoS ONE, 2011
Background and Aims: Schistosomiasis is an intravascular parasitic disease associated with inflam... more Background and Aims: Schistosomiasis is an intravascular parasitic disease associated with inflammation. Endothelial cells control leukocyte transmigration and vascular permeability being modulated by pro-inflammatory mediators. Recent data have shown that endothelial cells primed in vivo in the course of a disease keep the information in culture. Herein, we evaluated the impact of schistosomiasis on endothelial cell-regulated events in vivo and in vitro. Methodology and Principal Findings: The experimental groups consisted of Schistosoma mansoni-infected and agematched control mice. In vivo infection caused a marked influx of leukocytes and an increased protein leakage in the peritoneal cavity, characterizing an inflamed vascular and cellular profile. In vitro leukocyte-mesenteric endothelial cell adhesion was higher in cultured cells from infected mice as compared to controls, either in the basal condition or after treatment with the pro-inflammatory cytokine tumor necrosis factor (TNF). Nitric oxide (NO) donation reduced leukocyte adhesion to endothelial cells from control and infected groups; however, in the later group the effect was more pronounced, probably due to a reduced NO production. Inhibition of control endothelial NO synthase (eNOS) increased leukocyte adhesion to a level similar to the one observed in the infected group. Besides, the adhesion of control leukocytes to endothelial cells from infected animals is similar to the result of infected animals, confirming that schistosomiasis alters endothelial cells function. Furthermore, NO production as well as the expression of eNOS were reduced in cultured endothelial cells from infected animals. On the other hand, the expression of its repressor protein, namely caveolin-1, was similar in both control and infected groups. Conclusion/Significance: Schistosomiasis increases vascular permeability and endothelial cell-leukocyte interaction in vivo and in vitro. These effects are partially explained by a reduced eNOS expression. In addition, our data show that the disease primes endothelial cells in vivo, which keep the acquired phenotype in culture.
Planta medica, Jan 23, 2015
Diene valepotriates obtained from Valeriana glechomifolia present antidepressant-like activity, m... more Diene valepotriates obtained from Valeriana glechomifolia present antidepressant-like activity, mediated by dopaminergic and noradrenergic neurotransmissions. Also, previous studies have shown inhibitory activity of diene valepotriates towards Na(+)/K(+)-ATPase from the rat brain in vitro. Nevertheless, in vivo studies regarding the action of diene valepotriates on this enzyme are still lacking. Considering that Na(+)/K(+)-ATPase cerebral activity is involved in depressive disorders, the aim of this study was to investigate the effects of acute (5 mg/kg, p. o.) and repeated (5 mg/kg, p. o., once a day for three days) diene valepotriate administration on Na(+)/K(+)-ATPase activity in the cortex and hippocampus of mice submitted or not submitted to the forced swimming test. In addition, the protein expression of Na(+)/K(+)-ATPase α1, α2, and α3 isoforms in the cortex of mice repeatedly treated with diene valepotriates (and submitted or not submitted to the forced swimming test) was in...
Vascular Pharmacology, 2007
Schistosomiasis, an intravascular parasitic disease caused by Schistosoma mansoni, is related to ... more Schistosomiasis, an intravascular parasitic disease caused by Schistosoma mansoni, is related to alterations of murine vascular reactivity in the mesenteric bed, characterized by an impairment of the l-arginine/NO pathway and an increased potency of 5-hydroxytryptamine. The current study was performed to test the hypothesis that a similar alteration of reactivity also occurs in the aorta and to identify the mechanism behind such an increase. We found that aorta from mice infected with male S. mansoni exhibited an enhanced contraction in response to noradrenaline and 100 mM KCl. The inhibition of nitric oxide synthase increased aortic maximal contraction in response to noradrenaline in both groups, but the effect was less pronounced in infected mice than in control mice. Endothelium-dependent relaxation induced by acetylcholine was also smaller in infected mice compared to control mice, while endothelial-independent relaxation induced by sodium nitroprusside and forskolin was similar in both groups. The inhibition of voltage-dependent L-type Ca(2+) channels reduced the maximal contraction in response to noradrenaline more effectively in infected than in control mice. Conversely the inhibition of K(ATP) channels had a smaller effect in the infected group. As a conclusion, our data indicate that schistosomiasis also alters murine vascular reactivity outside the mesenteric bed, due to a partial impairment of NO signaling, a reduced contribution of K(ATP) channels and an increased Ca(2+) influx through L-type Ca(2+) channels.
The FASEB Journal, 2004
Alzheimer's disease (AD) and several other neurological disorders have been linked to the overact... more Alzheimer's disease (AD) and several other neurological disorders have been linked to the overactivation of glutamatergic transmission and excitotoxicity as a common pathway of neuronal injury. The betaamyloid peptide (Abeta) is centrally related to the pathogenesis of AD, and previous reports have demonstrated that the blockade of glutamate receptors prevents Abeta-induced neuronal death. We show that taurine, a beta-amino acid found at high concentrations in the brain, protects chick retinal neurons in culture against the neurotoxicity of Abeta and glutamate receptor agonists. The protective effect of taurine is not mediated by interaction with glutamate receptors, as demonstrated by binding studies using radiolabeled glutamate receptor ligands. The neuroprotective action of taurine is blocked by picrotoxin, an antagonist of GABA(A) receptors. GABA and the GABA(A) receptor agonists phenobarbital and melatonin also protect neurons against Abeta-induced neurotoxicity. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmacological manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults. GABAergic transmission may represent a promising target for the treatment of AD and other neurological disorders in which excitotoxicity plays a relevant role.
Phytochemistry, 2010
The flavone glycosides, named scutellarein-7-O-b-D-apiofuranoside and apigenin-7-O-b-D-apiofurano... more The flavone glycosides, named scutellarein-7-O-b-D-apiofuranoside and apigenin-7-O-b-D-apiofuranosyl-(1 ? 2)-b-D-apiofuranoside, and the flavone celtidifoline (5,6,4 0 ,5 0-tetrahydroxy-7,3 0-dimethoxyflavone), along with other 11 known compounds, were isolated from leaves of the ethyl acetate extract of Lantana trifolia L. using step gradient High Speed Countercurrent Chromatography (HSCCC) and High Performance Liquid Chromatography (HPLC), respectively. Their structures were elucidated by spectroscopic methods, including 2D NMR and mass spectrometry (ESI-MS) techniques. The ethanolic and ethyl acetate extracts produced an intense sedative effect in mice, one hour after oral administration of 1 mg/kg. This effect was neither due to a benzodiazepine-like effect of the three flavone derivatives neither of the phenylpropanoids, betonyoside F and verbascoside, that were tested for their affinity for the [ 3 H] flunitrazepam binding sites.
Nucleic Acids Research, 2008
The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime ... more The hepatitis C virus (HCV) NS5B is essential for viral RNA replication and is therefore a prime target for development of HCV replication inhibitors. Here, we report the identification of a new class of HCV NS5B inhibitors belonging to the coumestan family of phytoestrogens. Based on the in vitro NS5B RNA-dependent RNA polymerase (RdRp) inhibition in the low micromolar range by wedelolactone, a naturally occurring coumestan, we evaluated the anti-NS5B activity of four synthetic coumestan analogues bearing different patterns of substitutions in their A and D rings, and observed a good structure-activity correlation. Kinetic characterization of coumestans revealed a noncompetitive mode of inhibition with respect to nucleoside triphosphate (rNTP) substrate and a mixed mode of inhibition towards the nucleic acid template, with a major competitive component. The modified order of addition experiments with coumestans and nucleic acid substrates affected the potencies of the coumestan inhibitors. Coumestan interference at the step of NS5B-RNA binary complex formation was confirmed by cross-linking experiments. Molecular docking of coumestans within the allosteric site of NS5B yielded significant correlation between their calculated binding energies and IC 50 values. Coumestans thus add to the diversifying pool of anti-NS5B agents and provide a novel scaffold for structural refinement and development of potent NS5B inhibitors.
Memórias do Instituto Oswaldo Cruz, 1998
Journal of Pharmacological and Toxicological Methods, 2002
Introduction: The sarcoplasmic reticulum present in eukaryotic cells contains Ca 2 + pumps (SERCA... more Introduction: The sarcoplasmic reticulum present in eukaryotic cells contains Ca 2 + pumps (SERCA type) that accumulate Ca 2 + from the cytosol and Ca 2 + channels, such as ryanodine receptors and inositol 1,4,5-trisphosphate receptors, that release Ca 2 + from the lumen of this organelle. The use of a preparation rich in sarcoplasmic reticulum vesicles and poorly contaminated with plasmalemmal vesicles would be a prerequisite for studies of Ca 2 + efflux through ryanodine and inositol 1,4,5-trisphosphate receptors, so the present work was aimed to characterize the distribution profiles of various markers of sarcoplasmic reticulum and plasma membrane among fractions obtained from rat vas deferens. Methods: Oxalate-dependent Ca 2 + uptake, thapsigargin-sensitive (Ca 2 +-Mg 2 +) ATPase activity and binding of [ 3 H]ryanodine and [ 3 H]inositol 1,4,5-trisphosphate were measured in the nuclear, mitochondrial, and microsomal fractions obtained by differential centrifugation of rat vas deferens homogenate. Results: The recovery of the thapsigargin-resistant (Ca 2 +-Mg 2 +) ATPase activity, supposed to label the plasma membrane, was the same among nuclear, mitochondrial, and microsomal fractions, whereas the recovery of the thapsigargin-sensitive (Ca 2 +-Mg 2 +) activity, oxalate-dependent Ca 2 + uptake, and [ 3 H]inositol 1,4,5-trisphosphate binding, used as sarcoplasmic reticulum markers, was higher in nuclear fraction than in the others. The recovery profiles of the four sarcoplasmic reticulum markers, including [ 3 H]ryanodine binding, were statistically the same among the different subcellular fractions. Caffeine, an agonist of ryanodine receptors, induced the release of 17% of Ca 2 + taken up by the vesicles present in the nuclear fraction but had no effect in microsomes. Discussion: Although this nuclear fraction is less purified in sarcoplasmic reticulum markers than the microsomal fraction, it is more suitable for studying Ca 2 + release through ryanodine receptors, primarily because it is less contaminated with vesicles from the plasma membrane which are able to take up Ca 2 + but are insensitive to caffeine.
Journal of Molecular and Cellular Cardiology, 1985
European Journal of Pharmacology, 2009
Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a ne... more Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a neglected disease for which there is an urgent need for searching new drug candidates. According to TDR/WHO, existing leads with proven schistosomicidal activity, like meclonazepam, might be the objects of further exploration. Here, we decided to investigate if the benzodiazepine binding sites that we recently characterized in adult Schistosoma mansoni could represent the molecular target of meclonazepam for its effect on worm motility and morphological appearance. The EC 50 of meclonazepam for its contracturant effect is 10-20 times lower than its IC 50 for binding to the worm benzodiazepine binding sites. On the contrary, benzodiazepines like flunitrazepam and diazepam have affinities at least 50 times higher than meclonazepam for these binding sites but did not induce contraction of the worms. We also confirmed the existence of a great similarity between the appearance, kinetics, Emax and external calcium dependency of the contractile effect of praziquantel and meclonazepam. Based on computer-aided molecular modeling calculations, we verified that a certain structural similarity exists between the active enantiomers of both drugs. We further proposed the hypothesis of common pharmacophoric elements including amide and imine subunits and the asymmetric carbons of S-(+)-meclozepam and R-(−)-praziquantel. As a whole, the present data indicate that the contracturant effect of meclonazepam is not a result of its binding to the worm benzodiazepine binding sites but that it shares some basic transduction pathway with praziquantel, even if not through identical molecular targets or binding sites.
European Journal of Pharmacology, 2004
European Journal of Pharmacology, 2007
Changes in myocardial expression of Na + /K +-ATPase α-subunit isoforms have been demonstrated in... more Changes in myocardial expression of Na + /K +-ATPase α-subunit isoforms have been demonstrated in different models of cardiac hypertrophy and hypertension. Here we studied the expression of these isozymes in stroke-prone spontaneously hypertensive rats (SHRSP) and the influence of high salt diet and treatment with the dihydropyridine lacidipine. Adult SHRSP were offered either 1% NaCl or water as drinking solution for 6 weeks. Salt-loaded SHRSP were treated or not with 1 mg/kg/day lacidipine. Compared to Wistar Kyoto (WKY) rats, non-salt-loaded SHRSP presented significant hypertension and cardiac hypertrophy. Salt intake markedly enhanced cardiac hypertrophy, an effect blunted by lacidipine. [ 3 H]Ouabain binding assays on total particulate fractions from heart ventricles revealed the existence of two high-affinity sites with K d ∼ 25 and ∼ 200 nM, ascribed to the α 3 and α 2 isoforms, respectively. B max of α 3 was unexpectedly high (40% of total high-affinity binding) in ventricles from WKY rats but very low in all groups of SHRSP. On the other hand, B max of α 2 was similar in WKY and non-salt-loaded SHRSP; however, salt loading of SHRSP resulted in a B max reduction of 20% (P b 0.05), an effect blocked by lacidipine. These effects were largely confirmed by immunoblotting analysis, which, in addition, demonstrated that the density of the ubiquitous α 1 isoform was comparable among the experimental groups. In conclusion, WKY rats showed a high myocardial expression of the Na + /K +-ATPase α 3 subunit, which was not found in SHRSP; the level of the α 2 isoform was similar in untreated SHRSP and WKY; salt-loading of SHRSP promoted reduction of the α 2 isoform, and this effect was completely hampered by lacidipine.
Biochemical Pharmacology, 1984
Cardiac glycoside binding to microsomes prepared from rat heart ventricles and enriched in (Na+ +... more Cardiac glycoside binding to microsomes prepared from rat heart ventricles and enriched in (Na+ + K+)-ATPase was measured by a rapid filtration technique. The relation between ouabain binding to microsomes and (Na+ + K+)-ATPase activity has also been examined. Data were statistically analysed by means of two different non linear regression methods. The experimental results were fitted the most closely by a model describing that ouabain specific binding occurred at two classes of independent sites. High affinity sites were characterized by a dissociation constant of 0.21 +/- 0.01 microM and a low capacity (9.4 +/- 1.4 pmoles/enzymatic unit). Low affinity sites were characterized by a dissociation constant equal to 13 +/- 3 microM and a capacity equal to 87 +/- 15 pmoles/enzymatic unit. Similar results were obtained with the more lipophilic glycoside digoxin. It was also observed that dihydroouabain, a ouabain derivative with a saturated lactone ring, competes with 3H-ouabain for the binding to the two classes of sites. Binding to these two classes of sites appeared to be associated with a corresponding inhibition of (Na+ + K+)-ATPase activity.
Annals of the New York Academy of Sciences, 1997
... How to Cite. QUINTAS, LEM, LOPEZ, LB, SOUCCAR, C. and NOËL, F. (1997), Na + /K + -ATPase Dens... more ... How to Cite. QUINTAS, LEM, LOPEZ, LB, SOUCCAR, C. and NOËL, F. (1997), Na + /K + -ATPase Density Is Sexually Dimorphic in the Adult Rat Kidney. Annals of the New York Academy of Sciences, 834: 552554. doi: 10.1111/j.1749-6632.1997.tb52316.x. Author Information. 1 ...
Life Sciences, 2011
Cardiac glycosides have been extensively used in the treatment of congestive heart failure for mo... more Cardiac glycosides have been extensively used in the treatment of congestive heart failure for more than 200 years. Recently, cardenolides and bufadienolides were isolated from mammalian tissue and are considered as a new class of steroidal hormones. The aim of the present work was to characterize the interaction between the most clinical used cardiac glycoside digoxin and the cardiac glycosides known to exist endogenously, i.e., ouabain, marinobufagin and telocinobufagin, on human kidney Na + /K +-ATPase. Main methods: Inhibition of Na + /K +-ATPase activity from crude membrane preparations of human kidney was performed using increasing concentrations of the drugs alone or mixtures of ouabain:digoxin, telocinobufagin:digoxin and marinobufagin:digoxin in a fixed ratio 1:4, 2:3 and 3:2, respectively. The colorimetric method of Fiske and Subbarow was used to measure the inorganic phosphate released. Key findings: Analyses of inhibition curves showed that the experimental curves for all combinations were superimposed on the theoretical additive curves indicating that an additive effect occurs among distinct cardenolides and bufadienolides combinations on the human α1β1 Na + /K +-ATPase protomer. Significance: Considering the extensive use of digoxin in the treatment of heart failure and the recent findings that endogenous cardiac glycosides may have altered levels in many diseases, including heart failure, the demonstration of additive effect between cardiac glycosides can help in the understanding of recent clinical observations, including that lower than usual doses of cardiac glycosides are necessary for decreasing mortality in these patients.