Percorrer por autor "Fernandes, Eduarda"
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- 2,3-Diarylxanthones as potential inhibitors of Arachidonic acid metabolic pathwaysPublication . Santos, Clementina M.M.; Ribeiro, Daniela; Silva, Artur; Fernandes, EduardaIn response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting anti-inflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B4 (LTB4) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E2 (PGE2) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB4 production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC50 ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE2 production presented IC50 values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE2 catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs.
- 2,3-Diarylxanthones as strong scavengers of reactive oxygen and nitrogen species: a structure–activity relationship studyPublication . Santos, Clementina M.M.; Freitas, Marisa; Ribeiro, Daniela; Gomes, Ana Sara; Silva, Artur; Cavaleiro, José; Fernandes, EduardaXanthones are a class of oxygen-containing heterocyclic compounds widely distributed in nature. The natural derivatives can present different substitutions in the xanthone core that include hydroxyl, methoxyl, prenyl and glycosyl groups. The inclusion of aryl groups has only been reported for a few synthetic derivatives, the 2,3-diaryl moiety being recently introduced by our group. Xanthones are endowed with a broad spectrum of biological activities, many of them related to their antioxidant ability, including the scavenging of reactive oxygen species (ROS) and reactive nitrogen species (RNS), as well as metal chelating effects. Considering the interesting and promising antioxidant activities present in compounds derived from the xanthone core, the main goal of this work was to evaluate the scavenging activity of the new 2,3-diarylxanthones for ROS, including superoxide radical (O2 ), hydrogen peroxide (H2O2), singlet oxygen (1O2), peroxyl radical (ROO ) and hypochlorous acid (HOCl), and RNS, including nitric oxide ( NO) and peroxynitrite anion (ONOO ). The obtained results revealed that the tested 2,3-diarylxanthones are endowed with outstanding ROS and RNS scavenging properties, considering the nanomolar to micromolar range of the IC50 values found. The xanthones with two catechol rings were the most potent scavengers of all tested ROS and RNS. In conclusion, the new 2,3-diarylxanthones are promising molecules to be used for their potential antioxidant properties.
- 2-Styrylchromones as inhibitors of α-amylase and α-glucosidase enzymes for the management of type 2 diabetes mellitusPublication . Santos, Clementina M.M.; Proença, Carina; Freitas, Marisa; Araújo, Alberto N.; Silva, Artur; Fernandes, Eduardaalpha-amylase and alpha-glucosidase are key enzymes implicated in carbohydrate digestion and their inhibition has been suggested as a powerful approach for regulating blood glucose levels. The present work describes for the first time their inhibition by a group of twelve hydroxylated 2-styrylchromones (2-SC). Our findings revealed that 2-SC display strong systematic inhibition of alpha-glucosidase rather than alpha-amylase activity. The number and position of the hydroxy groups in the chromone moiety further modulate the inhibitory profile of the studied compounds, and the derivatives bearing one catechol unit are efficient inhibitors of both enzymes. Enzyme kinetic studies indicate that all active compounds act as competitive inhibitors of alpha-amylase while most of them behave as non-competitive inhibitors of alpha-glucosidase. The results are promising and pave the way to further deciphering the potential of this class of compounds as a suitable alternative for the management of type 2 diabetes and its complications.
- 2-Styrylchromones as novel inhibitors of xanthine oxidase. A structure-activity studyPublication . Fernandes, Eduarda; Carvalho, Félix; Silva, Artur; Santos, Clementina M.M.; Pinto, Diana; Cavaleiro, José; Bastos, Maria de LourdesThe purpose of this study was the evaluation of the xanthine oxidase (XO) inhibition produced by some synthetic 2-styrylchromones. Ten polyhydroxylated derivatives with several substitution patterns were synthesised, and these and a positive control, allopurinol, were tested for their effects on XO activity by measuring the formation of uric acid from xanthine. The synthesised 2-styrylchromones inhibited xanthine oxidase in a concentration-dependent and non-competitive manner. Some IC50 values found were as low as 0.55mM, which, by comparison with the IC50 found for allopurinol (5.43 mM), indicates promising new inhibitors. Those 2-styrylchromones found to be potent XO inhibitors should be further evaluated as potential agents for the treatment of pathologies related to the enzyme’s activity, as is the case of gout, ischaemia/ reperfusion damage, hypertension, hepatitis and cancer.
- 2-Styrylchromones: novel strong scavengers of reactive oxygen and nitrogen speciesPublication . Gomes, Ana Sara; Fernandes, Eduarda; Silva, Artur; Pinto, Diana; Santos, Clementina M.M.; Cavaleiro, José; Lima, José Costa2-Styrylchromones are a small group of naturally occurring chromones, vinylogues of flavones (2-phenylchromones). Natural and synthetic 2-styrylchromones have been tested in different biological systems, showing activities with potential therapeutic applications. In particular, the potential and hitherto understudied antioxidant behavior of these compounds has been raised as a matter of interest. Thus the present work consisted in the study of the in vitro scavenging activities for reactive oxygen species (ROS) and reactive nitrogen species (RNS) of various 2-styrylchromone derivatives and structurally similar flavonoids. Some of the studied 2-styrylchromones proved to be extremely efficient scavengers of the different ROS and RNS, showing, in some cases, IC50s under 1 lM. The hydroxylation pattern of 2-styrylchromones, especially in the B-ring but also in the A ring, modulates the activity of these compounds, the catecholic derivatives being the most effective scavengers. The styryl pattern also contributes to their observed outstanding antioxidant activity. In conclusion, the scavenging activities for ROS/RNS of 2-styrylchromone derivatives, here shown for the first time, provide novel and most promising compounds to be applied as antioxidants.
- Analysis of the antidiabetic potential of natural xanthones through the inhibition of α-amylase and α-glucosidase activitiesPublication . Santos, Clementina M.M.; Proença, Carina; Freitas, Marisa; Araújo, Alberto N.; Silva, Artur; Fernandes, EduardaDiabetes mellitus (DM) is a complex endocrine disorder associated with a state of hyperglycemia caused by the deficiency in the secretion of insulin and/or in the action of this pancreatic hormone. Thus, the control of postprandial blood glucose level via the inhibition of carbohydrate-hydrolyzing enzymes, such as α‐amylase and α‐glucosidase, is a consistent strategy for the management of type 2 DM and its related complications.1,2 In the past two decades, diversely functionalized xanthones, an important class of oxygen-containing heterocyclic compounds, have been recognized by scientific community for their interesting antidiabetic profile, exemplified by the number of studies developed in this area.3 Recent advances have been noticed in the inhibition of α-glucosidase activity by natural xanthones. However, the effects of this class of compounds on the activity of α-amylase enzyme is still scarce.1-3 As part of our on-going project, the main goal of the present study is to evaluate the inhibitory effects of a group of natural xanthones [mangiferin (1), α-mangostin (2) and γ-mangostin (3)] against both α‐amylase and α‐glucosidase enzymatic activity, using a spectrophotometric screening methodology.4,5 Acarbose was used as standard inhibitor for both assays. In addition, the study of the inhibition type for the two enzymes was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plots. The results showed that the studied xanthones exhibited a stronger inhibition against α-glucosidase when compared to α-amylase activity. Mangiferin (1) was not active against any enzyme, α-mangostin (2) was only able to inhibit the action of α-glucosidase, while γ-mangostin (3) inhibited both enzymes, being more active against α-glucosidase activity. In addition, the type of inhibition mechanism was also studied, and the results indicate a competitive type of inhibition for γ-mangostin (3) against α-amylase activity while the action of α-mangostin (2) and γ-mangostin (3) against α-glucosidase activity is through a non-competitive inhibition mechanism. The present work can open a promising area of research based on the design of novel xanthone derivatives for targeting key enzymes involved in glucose metabolism and therefore in the management of type 2 DM.
- Analysis of the antidiabetic potential of natural xanthones through the inhibition of α-amylase and α-glucosidase activitiesPublication . Santos, Clementina M.M.; Proença, Carina; Freitas, Marisa; Araújo, Alberto N.; Silva, Artur; Fernandes, EduardaDiabetes mellitus (DM) is a complex endocrine disorder associated with a state of hyperglycemia caused by the deficiency in the secretion of insulin and/or in the action of this pancreatic hormone. Thus, the control of postprandial blood glucose level via the inhibition of carbohydrate-hydrolyzing enzymes, such as α‐amylase and α‐glucosidase, is a consistent strategy for the management of type 2 DM and its related complications.1,2 In the past two decades, diversely functionalized xanthones, an important class of oxygen-containing heterocyclic compounds, have been recognized by scientific community for their interesting antidiabetic profile, exemplified by the number of studies developed in this area.3 Recent advances have been noticed in the inhibition of α-glucosidase activity by natural xanthones. However, the effects of this class of compounds on the activity of α-amylase enzyme is still scarce.1-3 As part of our on-going project, the main goal of the present study is to evaluate the inhibitory effects of a group of natural xanthones [mangiferin (1), α-mangostin (2) and γ-mangostin (3)] against both α‐amylase and α‐glucosidase enzymatic activity, using a spectrophotometric screening methodology.4,5 Acarbose was used as standard inhibitor for both assays. In addition, the study of the inhibition type for the two enzymes was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plots. The results showed that the studied xanthones exhibited a stronger inhibition against α-glucosidase when compared to α-amylase activity. Mangiferin (1) was not active against any enzyme, α-mangostin (2) was only able to inhibit the action of α-glucosidase, while γ-mangostin (3) inhibited both enzymes, being more active against α-glucosidase activity. In addition, the type of inhibition mechanism was also studied, and the results indicate a competitive type of inhibition for γ-mangostin (3) against α-amylase activity while the action of α-mangostin (2) and γ-mangostin (3) against α-glucosidase activity is through a non-competitive inhibition mechanism. The present work can open a promising area of research based on the design of novel xanthone derivatives for targeting key enzymes involved in glucose metabolism and therefore in the management of type 2 DM.
- Anti-inflammatory potencial of 2-Styrylchromones regarding their interference with arachidonic acid metabolic pathwaysPublication . Gomes, Ana Sara; Fernandes, Eduarda; Silva, Artur; Santos, Clementina M.M.; Pinto, Diana; Cavaleiro, José; Lima, José Costa
- Anti-inflammatory potential of 2-styrylchromones regarding their interference with arachidonic acid metabolic pathwaysPublication . Gomes, Ana Sara; Fernandes, Eduarda; Silva, Artur; Pinto, Diana; Santos, Clementina M.M.; Cavaleiro, José; Lima, José CostaCyclooxygenases (COXs) are the key enzymes in the biosynthesis of prostanoids. COX-1 is a constitutive enzyme while the expression of COX-2 is highly stimulated in the event of inflammatory processes, leading to the production of large amounts of prostaglandins (PGs), in particular PGE2 and PGI2, which are pro-inflammatory mediators. Lipoxygenases (LOXs) are enzymes that produce hydroxy acids and leukotrienes (LTs). 5-LOX metabolizes arachidonic acid to yield, among other products, LTB4, a potent chemoattractantmediator of inflammation. The aim of the present work was to evaluate the anti-inflammatory potential of 2-styrylchromones (2-SC), a chemical family of oxygen heterocyclic compounds, vinylogues of flavones (2-phenylchromones), by studying their COX-1 and COX-2 inhibitory capacity as well as their effects on the LTB4 production by stimulated human polymorphonuclear leukocytes (PMNL). Some of the tested 2-SC were able to inhibit both COX-1 activity and LTB4 production which makes them dual inhibitors of the COX and 5-LOX pathways. The most effective compounds in this study were those having structural moieties with proved antioxidant activity (30,40-catechol and 40-phenol substituted B-rings). This type of compounds may exhibit anti-inflammatory activity with a wider spectrum than that of classical non-steroidal anti-inflammatory drugs (NSAIDs) by inhibiting 5-LOX product-mediated inflammatory reactions, towards which NSAIDs are ineffective.
- Arylxanthones with anti-inflammator potential in cellular systemsPublication . Santos, Clementina M.M.; Ribeiro, Daniela; Silva, Artur; Fernandes, EduardaXanthones are a family of naturally-occurring oxygenated heterocyclic compounds. A wide range of natural and synthetic analogues are known to possess diverse biological activities including antifungal, antimalarial, antioxidant and antitumor, among others [1]. There are only a few publications related to arylxanthones [2], most of them focused on arylxanthones synthetic strategies and their biomedical potential, mainly highlighting them as effective scavengers of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [3,4]. As far as we know, the anti-inflammatory potential of xanthones bearing an aryl group has not been studied so far. With this idea in mind, our purpose was to evaluate the putative anti-inflammatory effects of several arylxanthones bearing hydroxyl groups in certain positions of their main core, namely through their ability to inhibit 5-lipoxygenase (5-LOX) and cyclooxygenase 1 (COX-1) and 2 (COX-2), both enzymes involved in the arachidonic acid metabolism [5,6]. Preliminary results showed that some of the studied arylxanthones were able to prevent leukotriene B4 production in human neutrophils, the xanthone with a catechol group at position 2 being the most active one. The inhibition of prostaglandin E2 production was assessed in human whole blood and the majority of the tested compounds were able to inhibit COX-1 while being completely ineffective in COX-2.