A comprehensive review on xanthone derivatives as α-glucosidase inhibitors

α-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.This work received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007265) and National Funds (FCT/MEC, Fundação para a Ciência e Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/QUI/50006/2013; FCT UID/QUI/00062/2013, and “Programa Operacional Competitividade e Internacionalização” (COMPETE) (POCI- 01-0145-FEDER-029241), and under the framework of QREN (NORTE-01-0145-FEDER-000024). Thanks are also due to Faculdade de Farmácia da Universidade do Porto and Instituto Politécnico de Bragança.info:eu-repo/semantics/publishedVersio

A patrimonialização da cidade-velha e o seu contributo para desenvolvimento local

Classificação JEL: O20, O30, Z32, Z10Esta Dissertação foi elaborada enquanto requisito parcial para a obtenção do grau de Mestre em Estudo de Desenvolvimento, Diversidades Locais e Desafios Mundiais. O objetivo desta dissertação, consiste na compreensão do contributo da nomeação da Cidade-Velha como património mundial da humanidade, e definir se a nomeação de 2009 contribuiu ou não, para o seu desenvolvimento local. Desta forma esta dissertação será delineada em três critérios fundamentais, Cidade-Velha enquanto património mundial da Humanidade, a análise do processo da patrimonialização e análise dos impactos dessa patrimonialização. O objetivo central desta pesquisa consiste em compreender quais os impactos junto da população e se, isso, levou ou não ao desenvolvimento local da comunidade, com destaque para o sector do turismo.This thesis has been prepared as a partial requirement for the degree of Master in Development study, Local Diversities and Global Challenges. The objective of this thesis consists in understanding the contribution of nomination of Cidade-Velha has world heritage site and define if this nomination (2009) has contribute for a local development. This dissertation will be delineated between three fundamental criteria: Cidade-Velha as World Heritage of Humanity, the analysis of the patrimonial process and analysis of impacts. The main objectives of this research is to understand the impacts on the population and if this change led or not the local development of community, with special attention to tourism secto

Electrochemical characterization of bioactive hydroxyxanthones by cyclic voltammetry

The present study reports the electrochemical behavior of several phenolic and catecholic-substituted 2,3-diarylxanthones on a glassy carbon electrode, challenged by cyclic voltammetry at different pH values (4.0, 7.4, and 11.0). Higher pH values required lower anodic and cathodic peak voltages. The oxidation of catecholic groups occurred at lower peak potentials in a reversible and pH dependent manner. Anodic peak potentials appeared at higher pH values and were attributed to the electrochemically irreversible oxidation of the phenolic groups. The number and position of hydroxyl substituents were the determinants for the electrochemical behavior and found to correlate with the scavenging activity for reactive oxygen (ROS) and nitrogen species (RNS). A xanthone with two catechol units presented the lowest anodic potential voltage (Epa = 0.15 V) and proved to be the most effective ROS and RNS scavenger.Faculdade de Farmácia da Universidade do Porto, Universidade de Aveiro, Fundação para a Ciência e a Tecnologia (Portugal) and FEDER for funding the Organic Chemistry Research Unit (project PEst-C/QUI/UI0062/2011) and also to the Portuguese National NMR Network (RNRMN)

Synthesis and in vitro α-glucosidase inhibitory activity of polyhydroxylated 2-styrylchromones

2-Styrylchromones (2-SC) are a small class of naturally-occurring oxygen-containing heterocycles. Although they are scarce in nature, a large number of 2-SC derivatives has been synthesized and their biological activ ity evaluated, namely as antiallergic, anti-inflammatory, antimicrobial, antioxidant and antitumor agents [l]. As far as we know, the antidiabetic activity of 2-SC is still unexplored. With this rational in mind, a series of 12 polyhydroxylated derivatives of 2-SC (1) were synthethized and used as inhibitors of the carbohydrate hydrolyzing enzyme a-glucosidase. This enzyme catalyzes the final step of the digestive process of starch and break down oligosaccharides to monosaccharides being one of the most currently used therapeutic approaches to decrease postprandial hyperglycemia and consequently to control type 2 diabetes mellitus [2]. The synthesis of polyhydroxylated 2-SC involves a multi-step strategy starting with the condensation of the appropriate 2'-hydroxyacetophenones with cinnamic acid derivatives, base-promoted Baker- Yenkataraman rearrangement of the esters formed, cyclodehydration and finnaly cleavage of the protecting groups to afford the desired polyhydroxylated 2-SC (3]. The in vitro assay to evaluate the inhibitory activity of the compounds under study and the positive control, acarbose, against a-glucosidase was performed by monitoring the hydrolysis of the substrate p-nitrophenyl glucopyranoside into the product p-nitrophenol at 405 nm. In addition, the study of the inhibition type was carried out through nonlinear regression Michaelis-Menton enzymatic kinetics and the corresponding Lineweaver-Burk plot [4].This work received financial support from the European Union (FEDER funds POCI/01 /0145/FEDER/007265) and National Funds (FCT/MEC, Fundayiio para a Ciencia e Tecnologia and Ministerio da Educação e Ciência) under the Partnership Agreement PT2020 UID/ AGR/00690/2013; UID/QUI/50006/2013; UID/QUI/00062/2019, and "Programa Operacional Competitividade e Intemacionalizayiio" (COMPETE) (POCI-01-0145-FEDER-029241), and under the framework of QREN (NORTE-01-0145-FEDER-000024).info:eu-repo/semantics/publishedVersio

Inhibition of the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase by hydroxylated xanthones

Xanthones are oxygen-containing heterocyclic compounds that exhibit a wide range of biological and pharmacological properties. Some natural and synthetic derivatives have been identified for their antidiabetic profile, mainly as α-glucosidase inhibitors. However, studies concerning the inhibition of both carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase are scarce. Thus, in order to identify some of these dual-target antidiabetic agents, a series of new synthetic xanthones were evaluated together with their commercial parents mangiferin (4), α-mangostin (5) and γ-mangostin (6). The results showed that xanthones exhibited a systematic stronger inhibition against α-glucosidase rather than for α-amylase. Derivatives 2c, 3a and 3b, bearing one catechol moiety, were the most active inhibitors of α-amylase, while xanthones 2c, 3b and 3c were the most active against α-glucosidase activity, with IC50 values lower than 10 μM. These findings suggest that the substitution pattern of the xanthone scaffold modulated the inhibitory activity of these compounds, and some structure–activity relationships could be established for both assays. In addition, the type of inhibition was also studied, and the results indicate a competitive type of inhibition for α-amylase activity by xanthones 2c, 3b, 3c and γ-mangostin (6). On the other hand, non-competitive inhibition mechanisms can be ascribed for all xanthones 1–6 against α-glucosidase. The present work can open a promising area of research based on the design of novel xanthone derivatives, based on natural ones, for targeting key enzymes involved in glucose metabolism and therefore in the management of type 2 diabetes mellitus.The work was supported by UIBD/00690/2020 and UIDB/50006/2020 with funding from FCT/MCTES through national funds, and by EXPL/MED-QUI/0815/2021, with funding from FCT. Carina Proença acknowledges funding from FCT and MCTES through national funds and COMPETE, grant number PTDC/MED-QUI/29243/2017 -POCI-01-0145-FEDER-029243. Marisa Freitas acknowledges her contract under the Scientific Employment Stimulus - Individual Call (CEEC Individual) 2020.04126.CEECIND/CP1596/CT0006.info:eu-repo/semantics/publishedVersio

Novel chromone and xanthone derivatives: synthesis and ROS/RNS scavenging activities

Chromones and xanthones are oxygen-containing heterocyclic compounds acknowledged by their antioxidant properties. In an effort to develop novel agents with improved activity, a series of compounds belonging to these chemical classes were prepared. Their syntheses involve the condensation of appropriate 2-methyl-4H-chromen-4-ones, obtained via Baker-Venkataraman rearrangement, with (E)-3-(3,4-dimethoxyphenyl)acrylaldehyde to provide the corresponding 2-[(1E,3E)-4-(3,4-dimethoxyphenyl)buta-1,3-dien-1-yl]-4H-chromen-4-ones. Subsequent electrocyclization and oxidation of these compounds led to the synthesis of 1-aryl-9H-xanthen-9-ones. After cleavage of the protecting groups, hydroxylated chromones and xanthones were assessed as scavenging agents against both reactive oxygen species (ROS) [superoxide radical (O2(•-)), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), singlet oxygen ((1)O2), and peroxyl radical (ROO(•))] and reactive nitrogen species (RNS) [nitric oxide ((•)NO) and peroxynitrite anion (ONOO(-))]. Generally, all the tested new hydroxylated chromones and xanthones exhibited scavenger effects dependent on the concentration, with IC50 values found in the micromolar range. Some of them were shown to have improved scavenging activity when compared with previously reported analogues, allowing the inference of preliminary conclusions on the structure-activity relationship

Design, synthesis and preliminar antioxidant evaluation of new hydroxy- chromone and xanthone derivatives

Chromone 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].Sincere thanks are expressed to Faculdade de Farmácia da Universidade do Porto, Universidade de Aveiro, Instituto Politécnico de Bragança, Fundação para a Ciência e a Tecnologia (FCT, Portugal), European Union, QREN, FEDER and COMPETE funding UCIBIOREQUIMTE (FCT UID/Multi/04378/2013) and OOPNA (FCT UID/QUI/00062/2013) Research Units and also to the Portuguesa National NMR Network (RNRMN).info:eu-repo/semantics/publishedVersio

2,3-Diarylxanthones as strong scavengers of reactive oxygen and nitrogen species: a structure–activity relationship study

Xanthones 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

Anti-inflammatory potential of 2-styrylchromones regarding their interference with arachidonic acid metabolic pathways

Cyclooxygenases (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.The authors acknowledge FCT and FEDER financial support for the project POCI/QUI/59284/2004 and the Organic Chemistry Research Unit (no. 62; Univ. Aveiro). Ana Gomes acknowledges FCT and FSE her PhD grant (SFRH/BD/23299/2005)

2-Styrylchromones: novel strong scavengers of reactive oxygen and nitrogen species

http://apps.isiknowledge.com/full_record.do?product=UA&search_mode=GeneralSearch&qid=1&SID=S2NjaL1GBbk143plPl1&page=1&doc=1&colname=WOS2-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