Inhibiting glucose reabsorption by sodium glucose co-transporter proteins (SGLTs) in the kidneys is a relatively new strategy for treating type 2 diabetes. Selective inhibition of SGLT2 over SGLT1 is ...critical for minimizing adverse side effects associated with SGLT1 inhibition. A library of C-glucosyl dihydrochalcones and their dihydrochalcone and chalcone precursors was synthesized and tested as SGLT1/SGLT2 inhibitors using a cell-based fluorescence assay of glucose uptake. The most potent inhibitors of SGLT2 (IC50 = 9–23 nM) were considerably weaker inhibitors of SGLT1 (IC50 = 10–19 μM). They showed no effect on the sodium independent GLUT family of glucose transporters, and the most potent ones were not acutely toxic to cultured cells. The interaction of a C-glucosyl dihydrochalcone with a POPC membrane was modeled computationally, providing evidence that it is not a pan-assay interference compound. These results point toward the discovery of structures that are potent and highly selective inhibitors of SGLT2.
•Limonium algarvense flowers and green tea had similar antioxidant properties.•L. algarvense had higher iron chelating potential than green tea.•L. algarvense had higher anti-inflammatory potential ...than green tea.•L. algarvense infusion had higher amounts of salicylic, gallic and coumaric acids.•L. algarvense samples were not toxic.
This work reports the in vitro antioxidant and anti-inflammatory activities and toxicity of infusions and decoctions of Limonium algarvense flowers, and green tea. The total contents in different phenolic groups and the quantification of individual phenolics by HPLC are also reported. L. algarvense and green tea had similar antioxidant properties, except for hydroxyl radical-scavenging activity, higher on green tea, and iron chelating potential, higher on L. algarvense. The later species also had the uppermost anti-inflammatory potential. Green tea decoction had the highest content of phenolic groups, but the infusion of L. algarvense had higher amounts of salicylic, gallic and coumaric acids. L. algarvense was not toxic, whereas green tea was toxic for S17 cells. Under our experimental conditions, infusions and decoctions of L. algarvense flowers had similar or higher antioxidant and anti-inflammatory properties than green tea, and thus, may be useful for alleviating symptoms associated with oxidative and inflammatory-related diseases.
The escalating antimicrobial resistance crisis urges the development of new antibacterial treatments with innovative mechanisms of action, particularly against the critical priority ...carbapenem-resistant Acinetobacter baumannii (CRAB), Pseudomonas aeruginosa (CRPA) and Enterobacteriaceae (CRE). Membrane-disrupting dodecyl deoxyglycosides have been reported for their interesting phosphatidylethanolamine-associated bactericidal activity against Gram-positive strains; however, their inability to penetrate the Gram-negative outer membrane (OM) renders them useless against the most challenging pathogens. Aiming to repurpose alkyl deoxyglycosides against Gram-negative bacteria, this study investigates the antimicrobial effects of five reference compounds with different deoxygenation patterns or anomeric configurations in combination with polymyxins as adjuvants for enhanced OM permeability. The generation of the lead 4,6-dideoxy scaffold was optimized through a simultaneous dideoxygenation step and applied to the synthesis of a novel alkyl 4,6-dideoxy C-glycoside 5, herein reported for the first time. When combined with subtherapeutic colistin concentrations, most glycosides demonstrated potent antimicrobial activity against several multidrug-resistant clinical isolates of CRAB, CRE and CRPA exhibiting distinct carbapenem resistance mechanisms, together with acceptable cytotoxicity against human HEK-293T and Caco-2 cells. The novel 4,6-dideoxy C-glycoside 5 emerged as the most promising prototype structure for further development (MIC 3.1 μg/mL when combined with colistin 0.5 μg/mL against CRPA or 0.25 μg/mL against several CRE and CRAB strains), highlighting the potential of C-glycosylation for an improved bioactive profile. This study is the first to show the potential of IM-targeting carbohydrate-based compounds for the treatment of infections caused by MDR Gram-negative pathogens of clinical importance.
The concept of Pan-Assay Interference Compounds (PAINS) is regarded as a threat to the recognition of the broad bioactivity of natural products. Based on the established relationship between altered ...membrane dipole potential and transmembrane protein conformation and function, we investigate here polyphenols' ability to induce changes in cell membrane dipole potential. Ultimately, we are interested in finding a tool to prevent polyphenol PAINS-type behavior and produce compounds less prone to untargeted and promiscuous interactions with the cell membrane. Di-8-ANEPPS fluorescence ratiometric measurements suggest that planar lipophilic polyphenols-phloretin, genistein and resveratrol-act by decreasing membrane dipole potential, especially in cholesterol-rich domains such as lipid rafts, which play a role in important cellular processes. These results provide a mechanism for their labelling as PAINS through their ability to disrupt cell membrane homeostasis. Aiming to explore the role of C-glucosylation in PAINS membrane-interfering behavior, we disclose herein the first synthesis of 4-glucosylresveratrol, starting from 5-hydroxymethylbenzene-1,3-diol, via C-glucosylation, oxidation and Horner-Wadsworth-Emmons olefination, and resynthesize phloretin and genistein C-glucosides. We show that C-glucosylation generates compounds which are no longer able to modify membrane dipole potential. Therefore, it can be devised as a strategy to generate bioactive natural product derivatives that no longer act as membrane dipole potential modifiers. Our results offer a new technology towards rescuing bioactive polyphenols from their PAINS danger label through C-C ligation of sugars.
Marine organisms are an important source of natural products with unique and diverse chemical structures that may hold the key for the development of novel drugs. Docosahexaenoic acid (DHA) is an ...omega-3 fatty acid marine natural product playing a crucial regulatory role in the resolution of inflammation and acting as a precursor for the biosynthesis of the anti-inflammatory specialized pro-resolving mediators (SPMs) resolvins, protectins, and maresins. These metabolites exert many beneficial actions including neuroprotection, anti-hypertension, or anti-tumorigenesis. As dysregulation of SPMs is associated with diseases of prolonged inflammation, the disclosure of their bioactivities may be correlated with anti-inflammatory and pro-resolving capabilities, offering new targets for drug design. The availability of these SPMs from natural resources is very low, but the evaluation of their pharmacological properties requires their access in larger amounts, as achieved by synthetic routes. In this report, the first review of the total organic syntheses carried out for resolvins, protectins, and maresins is presented. Recently, it was proposed that DHA-derived pro-resolving mediators play a key role in the treatment of COVID-19. In this work we also review the current evidence on the structures, biosynthesis, and functional and new-found roles of these novel lipid mediators of disease resolution.
Winter savory Satureja montana is a medicinal herb used in traditional gastronomy for seasoning meats and salads. This study reports a comparison between conventional (hydrodistillation, HD, and ...Soxhlet extraction, SE) and alternative (supercritical fluid extraction, SFE) extraction methods to assess the best option to obtain bioactive compounds. Two different types of extracts were tested, the volatile (SFE-90 bar, second separator vs HD) and the nonvolatile fractions (SFE-250 bar, first and second separator vs SE). The inhibitory activity over acetyl- and butyrylcholinesterase by S. montana extracts was assessed as a potential indicator for the control of Alzheimer’s disease. The supercritical nonvolatile fractions, which showed the highest content of (+)-catechin, chlorogenic, vanillic, and protocatechuic acids, also inhibited selectively and significantly butyrylcholinesterase, whereas the nonvolatile conventional extract did not affect this enzyme. Microbial susceptibility tests revealed the great potential of S. montana volatile supercritical fluid extract for the growth control and inactivation of Bacillus subtilis and Bacillus cereus, showing some activity against Botrytis spp. and Pyricularia oryzae. Although some studies were carried out on S. montana, the phytochemical analysis together with the biological properties, namely, the anticholinesterase and antimicrobial activities of the plant nonvolatile and volatile supercritical fluid extracts, are described herein for the first time.
Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a ...challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.
Alzheimer’s disease (AD) is a complex and progressive disease, which affects millions of people around the world. Despite the many efforts over the years to find efficient therapeutics, there is no ...cure yet. Nonetheless, many compounds have been proven to decrease Alzheimer’s symptoms. After a short overview of the hypotheses considered in AD drug development and the drugs approved for AD treatment, which lead to symptom release, we focus on the valorization of natural marine sources that decrease AD symptoms, particularly on docosahexaenoic acid (DHA), an important component in membrane phospholipids and the most abundant n−3 polyunsaturated fatty acids (PUFA) found in gray matter of the brain and in retina and on the DHA-containing phospholipids (DHA-PLs) present in marine sources, namely fish, krill, mollusks and in fisheries and aquaculture by-products. DHA-PLs’ bioactivities are presented, namely their properties in anti-neurodegeneration, neuroinflammation, as anticancer agents, as well as their benefits to obesity and visual problems. Fisheries and aquaculture by-products are also highlighted as they have a high content of DHA and DHA-rich phospholipids, can be extracted by green methodologies and should be considered in a circular economy for a healthy sustainable future.
Nucleosides have gained significant attention since the discovery of the structure of DNA. Nucleoside analogues may be synthesized through multiple synthetic pathways, however the N-glycosylation of ...a nucleobase is the most common method. Amongst the different classical N-glycosylation methodologies, the Vorbrüggen glycosylation is the most popular method. This review focuses on the synthesis and therapeutic applications of several FDA approved nucleoside analogues as antiviral and anticancer agents. Moreover, this review also focuses on the potential of these compounds as new antibacterial and anti-Alzheimer's disease agents, offering an overview of the most recent research in these fields.
Display omitted
•Overview of widely employed N-glycosylation methodologies and refinements.•Synthetic methodologies towards therapeutically relevant nucleoside analogues.•Nucleoside analogues with antiviral, antitumor, antibacterial, and anti-AD properties.
PDF
