Engaging Isatins in Multicomponent Reactions (MCRs) – Easy Access to Structural Diversity

Multicomponent reactions (MCRs) are a valuable tool in diversity-oriented synthesis. Its application to privileged structures is gaining relevance in the fields of organic and medicinal chemistry. Isatin, due to its unique reactivity, can undergo different MCRs, affording multiple interesting scaffolds, namely oxindole-derivatives (including spirooxindoles, bis-oxindoles and 3,3-disubstituted oxindoles) and even, under certain conditions, ring-opening reactions occur that leads to other heterocyclic compounds. Over the past few years, new methodologies have been described for the application of this important and easily available starting material in MCRs. In this review, we explore these novelties, displaying them according to the structure of the final products obtained

Avaliação e Caraterização da Ação Inibitória de Iminociclitóis na Atividade α-Glucosidase de Enterócitos de Mamífero

A diabetes, em particular a diabetes mellitus tipo 2, constitui um distúrbio metabólico que se carateriza por glicemias aumentadas resultantes de diminuição da libertação e/ou ação da insulina. Os inibidores das α-glucosidases surgem como agentes de elevado interesse terapêutico uma vez que podem contribuir para a diminuição da absorção intestinal de glicose e, consequentemente, para um desagravamento da hiperglicemia. Alguns compostos da família iminociclitol são inibidores das α- glucosidases [1] e têm vindo a ser sintetizados diversos compostos novos que podem ser promissores e cuja ação sobre a atividade α-glucosidase de mamífero ainda não foi estudada. Neste trabalho procurou-se estudar a ação de alguns novos compostos da família iminociclitol (figura 1) na atividade α-glucosidase de enterócitos de mamífero, tendo-se também avaliado o grau de toxidade. O efeito dos pares dos enantiómeros foi também estudado

Anti-proliferative effects of compounds derived from glucopyranuronamide

Chemotherapy is a major cancer treatment option. The synthesis of new compounds with better anti-proliferative properties and higher specificity is a current challenge in drug discovery today. Our goal with this work was to develop compounds derived from D-glucuronic acid and to evaluate their anti-proliferative properties. We have synthetized a library of hydroxyamide derivatives of D-glucuronic acid using amines and aminoalcohols. The synthesis of these compounds were based on the work of El-Nezhawy's group, who have designed some novel D-glucuronic acid acetylated and deacetylated derivatives, which showed interesting results with breast cancer cell lines. Anti-proliferative activity of the newly synthesized compounds was examined against human breast adenocarcinoma (MCF-7) and human colon carcinoma (MDST8) cell lines. Cell growth and viability was analysed by the Cell Counting Kit-8 method. The chemotherapeutic agent 5-fluoroacil was used as a positive control, allowing one to estimate the maximal anti-proliferative action expected in both carcinoma cell lines. All the compounds were studied in the 10-9-10-5M range. The compound N-(ethanol)-α/β D-glucopyranuronamide presented the best anti-proliferative potential with an IC50 (concentration of the compound causing 50% decrease in net cell growth) of 1.4x10-7M in MCF-7 cells. The 1-pheny-l-2-hydroxy-ethane-2-yl and the 1-propanol derivatives evoked weak anti-proliferative effects in MCF-7, with slight growth inhibition of 37% and 35%, respectively, for the highest concentration used (10-5M). On the contrary, the MDST-8 cell growth was not affected by these compounds. On the contrary, the 1-hydroxy-2-isopropyl-ethane-2-yl and 3-phenyl-1-hydroxy-propane-2-yl derivatives, exhibited weak anti-proliferative effects (22% and 40%, respectively) at 10-5M, in the MDST8 cell line, without affecting MCF-7 cell growth. None of the compounds exihibited toxic effects, at least up to 72h exposure, in the concentration range studied. These results show that the ethyl substituent was the most effective N-substituent for glucopyranuronamide for anti-proliferative actions in MCF-7 cell line, whilst in the case of the MDST8 cells, 3-phenyl-1-hydroxy-propane-2-yl was the most effective N-substituent. Moreover, all the glucopyranonamide compounds studied presented selective anti-proliferative effects for the different carcinoma cell lines used

Assessment of Dimethoate in Olive Oil Samples Using a Dual Responsive Molecularly Imprinting-Based Approach

A new generation of advanced materials developed by molecular imprinting technology showing a stimuli-responsive functionality are emerging. The switchable ability to control the uptake/release of the target analyte by action of external stimulus combined with a remarkable selectivity and specificity, makes these functional materials very attractive for sample preparation purposes. In this work, the usefulness of a sample preparation tool for the selective enrichment/pre-concentration of dimethoate from olive oil spiked samples based on “tailor-made” dual responsive magnetic and photonic molecularly imprinted polymers as sorbents is explored. To achieve this goal, a smart molecularly imprinted polymer (MIP) possessing magnetic and photonic responsiveness was successfully synthesized, and its physico-chemical and morphological characterization was assessed. Further, the trace analysis of dimethoate in spiked olive oil samples was validated and successfully implemented using smart-MIPs as sorbents in the sample preparation step, with high recoveries (83.5 0.3%) and low detection limit (0.03 g mL 1)

Novel hydroxyamides and amides containing D-glucopyranose or D-fructose units: biological assays in MCF-7 and MDST8 cell lines

A novel library of 15 compounds, hydroxyamides and amides containing a β-d-glucopyranose (d-Gluc) or a β-d-fructose (d-Fruc) units was designed and synthesized for antiproliferative assays in breast (MCF-7) and colon (MDST8) cancer cell lines. Twelve of them were hydroxyamides and were successfully synthesized from β-d-glucuronic acid (d-GluA). Six of these hydroxyamides which were acetylated hydroxy-β-d-glucopyranuronamide 2a–2f (1st Family) and the other six were their respective isomers, that is, hydroxy-β-d-fructuronamide 3a–3f (2nd Family), obtained by acid–base catalyzed isomerization. These compounds have the general structure, d-Glucsingle bondCdouble bond; length as m-dashONHsingle bondCHRsingle bond(CH2)nsingle bondOH and d-Frucsingle bondCdouble bond; length as m-dashONHsingle bondCHRsingle bond(CH2)nsingle bondOH, where R = an aromatic, alkyl or a hydrogen substituent, with n = 0 or 1. Eight of these contained a chiral aminoalcohol group. Three compounds were amides containing a d-glucopyranose unit (3rd Family). SAR studies were conducted with these compounds. Antiproliferative studies showed that compound 4a, the bromo-amide containing the β-d-glucopyranose ring, potently inhibits the proliferation of the MDST8 cells. Five compounds (2e, 2f, 3d, 3e, and 3f) were shown to potently selectively inhibit the proliferation of the MCF-7 cells. Compound 4b was the only one showing inhibition in both cell lines. In general, the more active compounds were the amides and hydroxyamides containing the β-d-fructose moiety, and containing an alkyl group or hydrogen. Half-inhibitory concentrations (IC50) of between 0.01 and 10 μM, were observed

3-Hydroxypyrrolidine and (3,4)-dihydroxypyrrolidine derivatives: inhibition of rat intestinal α-glucosidase

Thirteen pyrrolidine-based iminosugar derivatives have been synthesized and evaluated for inhibition of α-glucosidase from rat intestine. The compounds studied were the non-hydroxy, mono-hydroxy and dihydroxypyrrolidines. All the compounds were N-benzylated apart from one. Four of the compounds had a carbonyl group in the 2,5-position of the pyrrolidine ring. The most promising iminosugar was the trans-3,4-dihydroxypyrrolidine 5 giving an IC50 of 2.97 ± 0.046 and a KI of 1.18 mM. Kinetic studies showed that the inhibition was of the mixed type, but predominantly competitive for all the compounds tested. Toxicological assay results showed that the compounds have low toxicity. Docking studies showed that all the compounds occupy the same region as the DNJ inhibitor on the enzyme binding site with the most active compounds establishing similar interactions with key residues. Our studies suggest that a rotation of ∼90° of some compounds inside the binding pocket is responsible for the complete loss of inhibitory activity. Despite the fact that activity was found only in the mM range, these compounds have served as simple molecular tools for probing the structural features of the enzyme, so that inhibition can be improved in further studies

N-1,2,3-triazole-isatin derivatives for cholinesterase and β-amyloid aggregation inhibition: A comprehensive bioassay study

Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and β-amyloid (Aβ) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acet- ylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 μM. In some cases, these mo- lecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, mole- cular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Aβ anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite out- growth experiments led to the conclusion that these compounds are only weakly neurotoxic

ARIA 2016 : Care pathways implementing emerging technologies for predictive medicine in rhinitis and asthma across the life cycle

The Allergic Rhinitis and its Impact on Asthma (ARIA) initiative commenced during a World Health Organization workshop in 1999. The initial goals were (1) to propose a new allergic rhinitis classification, (2) to promote the concept of multi-morbidity in asthma and rhinitis and (3) to develop guidelines with all stakeholders that could be used globally for all countries and populations. ARIA-disseminated and implemented in over 70 countries globally-is now focusing on the implementation of emerging technologies for individualized and predictive medicine. MASK [MACVIA (Contre les Maladies Chroniques pour un Vieillissement Actif)-ARIA Sentinel NetworK] uses mobile technology to develop care pathways for the management of rhinitis and asthma by a multi-disciplinary group and by patients themselves. An app (Android and iOS) is available in 20 countries and 15 languages. It uses a visual analogue scale to assess symptom control and work productivity as well as a clinical decision support system. It is associated with an inter-operable tablet for physicians and other health care professionals. The scaling up strategy uses the recommendations of the European Innovation Partnership on Active and Healthy Ageing. The aim of the novel ARIA approach is to provide an active and healthy life to rhinitis sufferers, whatever their age, sex or socio-economic status, in order to reduce health and social inequalities incurred by the disease.Peer reviewe

ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe