Percorrer por autor "Freitas, Marisa"
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- 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.
- 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.
- A comprehensive review on xanthone derivatives as α-glucosidase inhibitorsPublication . Santos, Clementina M.M.; Freitas, Marisa; Fernandes, Eduardaα-Glucosidase plays an important role in carbohydrate metabolism and is therefore an attractive therapeutic target for the treatment of diabetes, obesity and other related complications. In the last two decades, considerable interest has been given to natural and synthetic xanthone derivatives in this field of research. Herein, a comprehensive review of the literature on xanthones as inhibitors of α-glucosidase activity, their mechanism of action, experimental procedures and structure-activity relationships have been reviewed for more than 280 analogs. With this overview we intend to motivate and challenge researchers (e.g. chemistry, biology, pharmaceutical and medicinal areas) for the design of novel xanthones as multipotent drugs and exploit the properties of this class of compounds in the management of diabetic complications.
- Design, synthesis and preliminar antioxidant evaluation of new hydroxy- chromone and xanthone derivativesPublication . Albuquerque, Hélio; Proença, Carina; Ribeiro, Daniela; Freitas, Marisa; Santos, Clementina M.M.; Fernandes, Eduarda; Silva, ArturChromone and xanthone derivativas are well-known for their outstanding antioxidant properties. ln an effort to develop new antioxidants with improved efficacy, here we cteveloped a new synthetic strategy to prepare hydroxylated chromones 3 and xanthones 4 with extended conjugated rr-systems. The synthetic strategy involved the aldolcondensation of 2-methylchromones 1 with cinnamaldehyde 2 to give chromones 3. Subsequent electrocyclization and oxidation of chromones 3 afforded xanthones 4 (Fig. 1 ). The scavenging activities of both derivativas 3 and 4 were addressed against both reactive oxygen species (ROS) and reactive nitrogen species (RNS). Ali tested compounds exhibited scavenger effects dependent on the concentration, with ICso values found in the micromolar range [1].
- Evaluation of in vitro anti-diabetic potential of 2, 3-diaryb(anthones through the inhibition of a-glucosidasePublication . Santos, Clementina M.M.; Freitas, Marisa; Araújo, Alberto N.; Silva, Artur; Fernandes, EduardaType 2 diabetes mellitus is a chronic metabolic disorder caused by abnormal carbohydrate metabolism with a consequent hyperglycemia status, resulting from inadequate insulin secretion, action, or both. One possible therapeutic approach to decrease postprandial hyperglycemia is to retard the absorption of glucose via inhibition of carbohydrate hydrolyzing enzymes, such as a-glucosidase [l]. This enzyme catalyzes the final step of the digestive process of starch and break down oligosaccharides to monosaccharides. The currently marketed u-glucosidase inhibitors are confined to glycosidic compounds, such as acarbose, miglitol and voglibose, with moderate affinity for the enzyme and with disturbing side effects. Thus, in the last two decades, considerable interest hás been given to the pursuit ofnovel drugs, structurally diverse, in which several xanthone derivatives are induded [1, 2]. Our goal was to study the inhibitory activity of a panei of hydroxylated 2, 3-diarykanthones XH1-XH9, against of a-glucosidase activity. The in vitro assay was performed by monitoring the hydrolysis of the substrate p-nitrophenyl glucopyranoside into the product p-nitrophenol at 405 nm. In addiüon, the study of the inhibiüon type was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plot [3]. The IC^ values obtained ranged from 9 to 27 ^iM, considerably lower than the positive control"acarbose (IC = 515 ± 19 |iM). For the active compounds, a noncompetitive type inhibition was recorded. More details concerning the structure-activity relationship will be presented and discussed in this communication.
- Inhibition of Leukotriene B4 production in human Neutrophils by 2-StyrylchromonesPublication . Gomes, Ana Sara; Fernandes, Eduarda; Freitas, Marisa; Silva, Artur; Santos, Clementina M.M.; Pinto, Diana; Cavaleiro, José; Lima, José Costa
- Inhibition of NF-kB activation and cytokines production in THP-1 monocytes by 2-styrylchromonesPublication . Gomes, Ana Sara; Capela, João Paulo; Ribeiro, Daniela; Freitas, Marisa; Silva, Artur; Pinto, Diana; Santos, Clementina M.M.; Cavaleiro, José; Lima, José L.F.C.; Fernandes, EduardaNuclear factor kappa B (NF-kB) is one of the most important transcription factors whose modulation triggers a cascade of signaling events, namely the expression of many cytokines, enzymes, chemokines, and adhesion molecules, some of which being potential key targets for intervention in the treatment of inflammatory conditions. The 2-styrylchromones (2-SC) designation represents a well-recognized group of natural and synthetic chromones, vinylogues of flavones (2-phenylchromones). Several 2-SC were recently tested for their anti-inflammatory potential, regarding the arachidonic acid metabolic cascade, showing some motivating results. In addition, several flavones with structural similarities to 2-SC have shown NF-kB inhibitory properties. Hence, the aim of the present work was to continue the investigation on the interference of 2-SC in inflammatory pathways. Herein we report their effects on lipopolysaccharide (LPS)-induced NF-kB activation and consequent production of proinflammatory cytokines/chemokine, using a human monocytic cell line (THP-1). From the twelve 2-SC tested, three of them were able to significantly inhibit the NF-kB activation and to reduce the production of the proinflammatory cytokines/chemokine. The compound 3',4',5-trihydroxy-2- styrylchromone stood up as the most active in both assays, being a promising candidate for an anti-inflammatory drug.
- Inhibition of pancreatic α-amylase activity by a group of hydroxyxanthonesPublication . Santos, Clementina M.M.; Proença, Carina; Freitas, Marisa; Araújo, Alberto N.; Silva, Artur; Fernandes, EduardaDiabetes mellitus is a non-infectious and non-transmissible life threatening disease. It is one of the fastest growing health challenges of the current century, in which the number of adults living with diabetes have more than tripled over the past 20 years. According to the International Diabetes Federation, 1 in 11 adults (20-79 years) have diabetes (463 million people) and 2 in 3 people with diabetes live in urban areas.1 This may be closely related to genetic and lifestyle factors such as physical inactivity, unhealthy diets, obesity, raised blood cholesterol and glucose, stress, etc.2 Diabetes mellitus is an endocrine disorder that occurs when pancreas does not produce enough insulin, when the body cannot use insulin efficiently or both situations, leading to chronic hyperglycemia. Thus, the control of postprandial blood glucose level via the inhibition of digestive enzymes, such as α-glucosidase and/or α-amylase, is a relevant strategy for the management of type 2 diabetes and its complications.3 During the last two decades, in the pursuit for novel antidiabetic drugs, a wide variety of natural and synthetic xanthone derivatives have been applied in the inhibition of α-glucosidase enzyme activity, however, the effects of this class of compounds on the activity of α-amylase enzyme is scarce.4 With this ratio in mind and as part of our on-going project, the aim of the present study is to investigate the effect of a series of hydroxyxanthones 1 on pancreatic α-amylase activity to find out the relevance of this group of compounds in controlling blood glucose levels for the treatment of disorders related with the carbohydrate uptake. Different concentrations of xanthones 1 were incubated with the enzyme and the hydrolysis of the substrate 2-chloro-p-nitrophenyl-α-D-maltotriose was monitored spectrophotometrically at 405 nm. Acarbose was used as the standard inhibitor. In addition, the study of the inhibition type was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plot.5 The results pointed out that the IC50 values obtained ranged from 23 to 90 μM, considerably higher than the values obtained for the positive control acarbose (IC50 = 0.62 ± 0.07 μM). For the active compounds, two of them revealed a competitive type of inhibition while for the remaining ones a noncompetitive type of inhibition was recorded. More details concerning the structureactivity relationship will be presented and discussed in this communication.