Boronate Ester Hydrogels for Biomedical Applications: Challenges and Opportunities.

Boronate ester (BE) hydrogels are increasingly used for biomedical applications. The dynamic nature of these molecular networks enables bond rearrangement, which is associated with viscoelasticity, injectability, printability, and self-healing, among other properties. BEs are also sensitive to pH, redox reactions, and the presence of sugars, which is useful for the design of stimuli-responsive materials.

Natural Products Targeting the Fungal Unfolded Protein Response as an Alternative Crop Protection Strategy.

Discovering new solutions for crop protection is a major challenge for the next decades as a result of the ecotoxicological impact of classical fungicides, the emergence of fungicide resistances, and the consequence of climate change on pathogen distribution. Previous work on fungal mutants deficient in the unfolded protein response (UPR) supported that targeting this pathway is a promising plant disease control strategy. In particular, we showed that the UPR is involved in fungal virulence by altering cell protection against host defense compounds, such as phytoalexins and phytoanticipins.

30th Annual GPA Medicinal Chemistry Conference.

The Group for the Promotion of Pharmaceutical Chemistry in Academia (GPA) held their 30th annual conference in August 2022 in Trinity College Dublin, Ireland. There were 9 keynote presentations, 10 early career researcher presentations and 41 poster presentations.

Role of Phenylpropanoids and Flavonoids in Plant Resistance to Pests and Diseases.

Phenylpropanoids and flavonoids are specialized metabolites frequently reported as involved in plant defense to biotic or abiotic stresses. Their biosynthetic accumulation may be constitutive and/or induced in response to external stimuli. They may participate in plant signaling driving plant defense responses, act as a physical or chemical barrier to prevent invasion, or as a direct toxic weapon against microbial or insect targets.

Characterization of NRPS and PKS genes involved in the biosynthesis of SMs in Alternaria dauci including the phytotoxic polyketide aldaulactone.

Alternaria dauci is a Dothideomycete fungus, causal agent of carrot leaf blight. As a member of the Alternaria genus, known to produce a lot of secondary metabolite toxins, A. dauci is also supposed to synthetize host specific and non-host specific toxins playing a crucial role in pathogenicity.

A vitamin E long-chain metabolite and the inspired drug candidate α-amplexichromanol relieve asthma features in an experimental model of allergen sensitization.

Benefits for vitamin E intake in diseases with inflammatory components have been described and related in part, to endogenously formed metabolites (long-chain metabolites, LCM). Here, we have evaluated the role of LCM in relieving asthma features. To this aim, the endogenous vitamin E metabolite α-13'-carboxychromanol (α-T-13'-COOH) that acts as potent 5-lipoxygenase inhibitor has been administered either intraperitoneally or by oral gavage to BALB/c mice sensitized by subcutaneous injection of ovalbumin (OVA).

Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3.

Naturally occurring substances are valuable resources for drug development. In this respect, chalcones are known to be antiproliferative agents against prostate cancer cell lines through various mechanisms or targets. Based on the literature and preliminary results, we aimed to study and optimise the efficiency of a series of chalcones to inhibit androgen-converting AKR1C3, known to promote prostate cancer.

29th Annual GP2A Medicinal Chemistry Conference.

The 29th Annual GPA (Group for the Promotion of Pharmaceutical chemistry in Academia) Conference was a virtual event this year due to the COVID-19 pandemic and spanned three days from Wednesday 25 to Friday 27 August 2021. The meeting brought together an international delegation of researchers with interests in medicinal chemistry and interfacing disciplines. Abstracts of keynote lectures given by the 10 invited speakers, along with those of the 8 young researcher talks and the 50 flash presentation posters, are included in this report.

Natural chalcones elicit formation of specialized pro-resolving mediators and related 15-lipoxygenase products in human macrophages.

Specialized pro-resolving mediators (SPMs) comprise lipid mediators (LMs) produced from polyunsaturated fatty acids (PUFAs) via stereoselective oxygenation particularly involving 12/15-lipoxygenases (LOXs). In contrast to pro-inflammatory LMs such as leukotrienes formed by 5-LOX and prostaglandins formed by cyclooxygenases, the SPMs have anti-inflammatory and inflammation-resolving properties. Although glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs) that block prostaglandin production are still prime therapeutics for inflammation-related diseases despite severe side effects, novel concepts focus on SPMs as immunoresolvents for anti-inflammatory pharmacotherapy.

Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E synthase-1.

Semisynthetic Vitamin E Derivatives as Potent Antibacterial Agents against Resistant Gram-Positive Pathogens.

New 5-substituted vitamin E derivatives were semisynthesized, and their antibacterial activity against human Gram-positive and Gram-negative pathogens was evaluated. Several vitamin E analogues were active against methicillin-resistant Staphylococcus aureus (MRSA) and/or methicillin-resistant Staphylococcus epidermidis (MRSE); structure-activity relationships (SARs) are discussed. As a result, it is shown that the presence of a carboxylic acid function at the C-5 position and/or at the end of the side chain is crucial for the antibacterial activity.

Structure-based design, semi-synthesis and anti-inflammatory activity of tocotrienolic amides as 5-lipoxygenase inhibitors.

Inflammation contributes to the development of various pathologies, e.g. asthma, cardiovascular diseases, some types of cancer, and metabolic disorders.

Novel Insights into the Mode of Action of Vasorelaxant Synthetic Polyoxygenated Chalcones.

Polyphenols consumption has been associated with a lower risk of cardiovascular diseases (CVDs) notably through nitric oxide (NO)- and estrogen receptor α (ERα)-dependent pathways. Among polyphenolic compounds, chalcones have been suggested to prevent endothelial dysfunction and hypertension. However, the involvement of both the NO and the ERα pathways for the beneficial vascular effects of chalcones has never been demonstrated.

Design, Synthesis, Pharmacological Evaluation and Vascular Effects of Delphinidin Analogues.

Background: Among polyphenolic compounds suggested to prevent cardiovascular diseases (CVDs) and to explain the "French paradox", the anthocyanidin delphinidin (Dp) has been reported to support at least partly the vascular beneficial effects of dietary polyphenolic compounds including those from fruits and related products as red wine. It has also been highlighted that Dp interacts directly with the active site of estrogen receptor α (ERα), leading to activation of endothelial NO synthase (eNOS) pathway thus contributing to the prevention of endothelial dysfunction in mice aorta. However, anthocyanidins have very low bioavailability and despite a well described in vitro efficacy, the very high hydrophilicity and physicochemical instability of Dp might explain the lack of in vivo reported effects.

Efficient Semi-Synthesis of Natural δ-( R)-Tocotrienols from a Renewable Vegetal Source.

Recent studies have highlighted the biological potential of tocotrienols, a vitamin E subfamily. The major natural sources of tocotrienols are complex mixtures requiring particularly challenging purification processes. The present study describes efficient semi-synthetic strategies toward relevant δ-( R)-tocotrienol derivatives, using as a starting material δ-( R)-garcinoic acid, the major vitamin E derivative isolated from Garcinia kola nuts, a renewable vegetal source.

Endogenous metabolites of vitamin E limit inflammation by targeting 5-lipoxygenase.

Systemic vitamin E metabolites have been proposed as signaling molecules, but their physiological role is unknown. Here we show, by library screening of potential human vitamin E metabolites, that long-chain ω-carboxylates are potent allosteric inhibitors of 5-lipoxygenase, a key enzyme in the biosynthesis of chemoattractant and vasoactive leukotrienes. 13-((2R)-6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)-2,6,10-trimethyltridecanoic acid (α-T-13'-COOH) can be synthesized from α-tocopherol in a human liver-on-chip, and is detected in human and mouse plasma at concentrations (8-49 nM) that inhibit 5-lipoxygenase in human leukocytes.

Aldaulactone - An Original Phytotoxic Secondary Metabolite Involved in the Aggressiveness of on Carrot.

Qualitative plant resistance mechanisms and pathogen virulence have been extensively studied since the formulation of the gene-for-gene hypothesis. The mechanisms involved in the quantitative traits of aggressiveness and plant partial resistance are less well-known. Nevertheless, they are prevalent in most plant-necrotrophic pathogen interactions, including the - interaction.

Pro-Angiogenic Effects of Low Dose Ethoxidine in a Murine Model of Ischemic Hindlimb: Correlation between Ethoxidine Levels and Increased Activation of the Nitric Oxide Pathway.

Ethoxidine, a benzo[c]phenanthridine derivative, has been identified as a potent inhibitor of topoisomerase I in cancer cell lines. Our group has reported paradoxical properties of ethoxidine in cellular processes leading to angiogenesis on endothelial cells. Because low concentration ethoxidine is able to favor angiogenesis, the present study aimed to investigate the ability of 10 M ethoxidine to modulate neovascularization in a model of mouse hindlimb ischemia.

"The 24th Conference" of the Groupement des Pharmacochimistes de l'Arc Atlantique (GP2A).

The GP2A European Conference is a two-day meeting focused on medicinal chemistry and the use of tools to explore all fields of drug discovery and drug design such as molecular modelling, bioorganic chemistry, MS studies, in vitro in vivo assays, and structure activity relationships. Abstracts of keynote lectures, plenary lectures, junior lectures, flash presentations, and posters presented during the meeting are collated in this report.

Semisynthetic and Natural Garcinoic Acid Isoforms as New mPGES-1 Inhibitors.

Over the last twenty years, tocotrienol analogues raised great interest because of their higher level and larger domain of biological activities when compared with tocopherols. Amongst the most promising therapeutic application, anti-inflammatory potency has been evaluated through the inhibition of various mediators of inflammation. Here, we worked on the isolation of two natural isoforms of garcinoic acid (i.

Ethoxyfagaronine, a synthetic analogue of fagaronine that inhibits vascular endothelial growth factor-1, as a new anti-angiogeneic agent.

Angiogenesis plays a pivotal role in tumorigenesis and also contributes to the pathogenesis of hematologic malignancies. A number of plant compounds have shown efficacy in preclinical and clinical studies and some of them possess an anti-angiogenic activity. Our present findings report anti-angiogenic activities of ethoxyfagaronine (etxfag), a synthetic derivative of fagaronine.

Partial resistance of carrot to Alternaria dauci correlates with in vitro cultured carrot cell resistance to fungal exudates.

Although different mechanisms have been proposed in the recent years, plant pathogen partial resistance is still poorly understood. Components of the chemical warfare, including the production of plant defense compounds and plant resistance to pathogen-produced toxins, are likely to play a role. Toxins are indeed recognized as important determinants of pathogenicity in necrotrophic fungi.

Hydroxamate, a key pharmacophore exhibiting a wide range of biological activities.

Naturally occurring hydroxamic acid derivatives are biosynthesized by microorganisms (siderophores) and plants (benzoxazinoids). Recent developments in drug discovery have highlighted the numerous biological and pharmacological properties that the hydroxamic acid function may possess, leading to therapeutic applications. These properties may be explained by its ability to chelate metals via the presence of two oxygen atoms.

ortho-Lithium/magnesium carboxylate-driven aromatic nucleophilic substitution reactions on unprotected naphthoic acids.

Substitution of an ortho-fluoro or methoxy group in 1- and 2-naphthoic acids furnishing substituted naphthoic acids occurs in good to excellent yields upon reaction with alkyl/vinyl/aryl organolithium and Grignard reagents, in the absence of a metal catalyst without the need to protect the carboxyl (CO(2)H) group. This novel nucleophilic aromatic substitution is presumed to proceed via a precoordination of the organometallic with the substrate, followed by an addition/elimination.

Free and immobilized matrix molecules: impairing ionization by quenching secondary ion formation in laser desorption MS.

Within the last 25 years, matrix-assisted laser desorption ionization (MALDI) has become a powerful analytical tool in mass spectrometry (MS). While the method has been successfully applied to characterize large organic molecules such as proteins, sugars and polymers, its utilization for small molecules (≤ 600 Da) is significantly impaired by the coformation of matrix ions. Reducing or eliminating matrix-related signals has been subject of many studies.