Browsing by Author "Santos, Clementina M.M."
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- 1,6-Conjugate Additions of Carbon Nucleophiles to 2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-onesPublication . Albuquerque, Hélio; Santos, Clementina M.M.; Balanay, Mannix P.; Cavaleiro, José; Silva, ArturKGaA, Weinheim The 1,6-conjugate addition of nitromethane to 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones was accomplished and led mainly to the corresponding β-(nitromethyl)chromones. (E)-5′-(Nitromethyl)-3′-styryl-[1,1′-biphenyl] -2-ol and 3′-aryl-2′-nitro-5′-(nitromethyl)spiro[chromane-2,1′-cyclohexan]-4-one derivatives were also isolated as minor products from tandem processes, which result from the addition of a second molecule of nitromethane. The nucleophile scope was investigated with malononitrile, acetylacetone, ethyl cyanoacetate, and diethyl malonate, which gave the expected 1,6-addition products; in the last case, it was also possible to isolate a minor product formed through a 1,8-/1,6-addition sequence. Computational calculations provided a rationale for the experimental reactivity of carbon nucleophiles with 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl] -4H-chromen-4-ones. The further functionalization of some adducts allowed the preparation of new nitrogen-containing heterocyclic compounds, such as new styrylpyrrolidines and new pyrazole and bis(pyrazole) derivatives.
- 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-(4-Arylbuta-1,3-dien- or 1-en-3-yn-1-yl)chromones as synthons for the synthesis of other nitrogen and oxygen heterocyclic compoundsPublication . Albuquerque, Hélio; Santos, Clementina M.M.; Silva, Artur; Cavaleiro, JoséIt is well known the great biological relevance of oxygen and nitrogen heterocycles. Herein, the reactivity of 2-(4-aryl-1,3-dien- and 1-en-3-yn-1-yl)chromones are explored in order to establish new synthetic routes towards the preparation of new heterocyclic compounds such as xanthones and triazoles. The reactive sites of the starting chromone derivatives (the double and triple bonds) allow them to be involved in reactions such as Diels-Alder and Huisgen cycloadditions. These reactions are used separately or subsequently in order to prepare new biologically active compounds emphasizing the synthetic potential of the referred chromone derivatives. Using these new synthetic routes we were able to develop new compounds, such xanthones bearing triazole moiety, which are expected to enclosure interesting biological properties.
- 2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in Diels-Alder reactions - experimental and computational studiesPublication . Albuquerque, Hélio; Santos, Clementina M.M.; Lima, Carlos F.R.A.C.; Santos, Luís M.N.B.F.; Cavaleiro, José; Silva, ArturThe synthesis and reactivity of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in Diels–Alder (DA) reactions with several electron-poor and electron-rich dienophiles under microwave irradiation was studied. The optimized reaction conditions were achieved with N-methylmaleimide as the dienophile and Sc(OTf )3 (OTf = triflate) as a Lewis acid under microwave-assisted and solvent-free conditions. The Lewis acid improved the reaction yields as it prevented the adducts obtained from undergoing a second DA reaction; thus, the formation of a bisadduct was avoided. The α, :γ,δ-diene of the starting chromones was the most reactive, and the computational results confirmed the experimental findings. Theoretical calculations also provided a rationale for the unexpected lack of reactivity shown by some dienophiles. The adducts prepared were dehydrogenated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); however, the aza adducts were sensitive to the highly energetic reaction conditions necessary for the aromatization.
- 2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in Diels–Alder reactions: experimental and computational studiesPublication . Albuquerque, Hélio; Santos, Clementina M.M.; Lima, Carlos F.R.A.C.; Santos, Luís M.N.B.F.; Cavaleiro, José; Silva, ArturThe synthesis and reactivity of 2-[(1 £,3£)-4-arylbuta-1 ,3-dien-l-yl]-4H-chromen-4-ones 1 as dienes in Diets-Alder (DA) reactions towards several electron-poor and electron-rich dienophiles under microwave irradiation was studied. The optimized reaction conditions were achieved by using N-methylmaleimide2 as dienophile and Sc(0Tf)3 as Lewis acid under microwave-assisted and solvent-free conditions. The Lewis acid improved the reaction yields since it prevented the adducts obtained to undergo a second DA reaction, thus avoiding formation of a bisadduct. The a,~:y ,o-diene of the starting chromones showed to be the most reactive and the computational results confirmed the experimental findings. Theoretical calculations also allowed explaining some unexpected lack of reactivity by some dienophiles. The adducts prepared were dehydrogenated by using DDQ, however, the aza-adducts showed to be sensitive to the high energetic reaction conditions necessary to perform the aromatization.
- 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 with potencial antioxidant activityPublication . Santos, Clementina M.M.; Silva, Artur; Cavaleiro, José
- 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.