Preparation and Preclinical Characterization of a Simple Ester for Dual Exogenous Supply of Lactate and Beta-hydroxybutyrate.

Elevation of the plasma levels of ()-lactate (Lac) and/or ()-beta-hydroxybutyrate (BHB) occurs naturally in response to strenuous exercise and prolonged fasting, respectively, resulting in millimolar concentrations of these two metabolites. It is increasingly appreciated that Lac and BHB have wide-ranging beneficial physiological effects, suggesting that novel nutritional solutions, compatible with high-level and/or sustained consumption, which allow direct control of plasma levels of Lac and BHB, are of strong interest. In this study, we present a molecular hybrid between ()-lactate and the BHB-precursor ()-1,3-butanediol in the form of a simple ester referred to as .

Enantioselective Synthesis of α-Quaternary Isochromanes by Oxidative Aminocatalysis and Gold Catalysis.

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α-branched aldehydes and propargylic alcohols are transformed into α-quaternary ethers with excellent optical purities (>90 % ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter.

The Biological Activities of Polyether Ionophore Antibiotic Routiennocin is Independent of Absolute Stereochemistry.

Carboxylic polyether ionophores (CPIs) are among the most prevalent agricultural antibiotics (notably in the US) and these compounds have been in use for decades. The potential to reposition CPIs beyond veterinary use, e. g.

Characterization of the Bacteria-derived Hypoxia-selective Cytotoxin BE-43547.

Background/aim: Hypoxia-activated pro-drugs, such as TH-302, may kill hypoxic treatment-resistant tumor cells, but have failed in clinical trials. This may be related to variable levels of drug-activating reductases. Compounds such as bacteria-derived BE-43547, which target hypoxic cells independently of reductases, may be beneficial.

NRF2 activators inhibit influenza A virus replication by interfering with nucleo-cytoplasmic export of viral RNPs in an NRF2-independent manner.

In addition to antioxidative and anti-inflammatory properties, activators of the cytoprotective nuclear factor erythroid-2-like-2 (NRF2) signaling pathway have antiviral effects, but the underlying antiviral mechanisms are incompletely understood. We evaluated the ability of the NRF2 activators 4-octyl itaconate (4OI), bardoxolone methyl (BARD), sulforaphane (SFN), and the inhibitor of exportin-1 (XPO1)-mediated nuclear export selinexor (SEL) to interfere with influenza virus A/Puerto Rico/8/1934 (H1N1) infection of human cells. All compounds reduced viral titers in supernatants from A549 cells and vascular endothelial cells in the order of efficacy SEL>4OI>BARD = SFN, which correlated with their ability to prevent nucleo-cytoplasmic export of viral nucleoprotein and the host cell protein p53.

Polyether Ionophore Antibiotics Target Drug-Resistant Clinical Isolates, Persister Cells, and Biofilms.

Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture (e.g.

oxSTEF Reagents Are Tunable and Versatile Electrophiles for Selective Disulfide-Rebridging of Native Proteins.

Site-selective disulfide rebridging has emerged as a powerful strategy to modulate the structural and functional properties of proteins. Here, we introduce a novel class of electrophilic reagents, designated oxSTEF, that demonstrate excellent efficiency in disulfide rebridging via double thiol exchange. The oxSTEF reagents are prepared using an efficient synthetic sequence which may be diverted to obtain a range of derivatives allowing for tuning of reactivity or steric bulk.

α-Lactam Electrophiles for Covalent Chemical Biology.

Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3-membered N-heterocyclic compounds-such as aziridines, azirines, and oxaziridines-possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, however, their utility within the field remains unexplored.

PSL Chemical Biology Symposia Third Edition: A Branch of Science in its Explosive Phase.

This symposium is the third PSL (Paris Sciences & Lettres) Chemical Biology meeting (2016, 2019, 2023) held at Institut Curie. This initiative originally started at Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette (2013, 2014), under the directorship of Professor Max Malacria, with a strong focus on chemistry. It was then continued at the Institut Curie (2015) covering a larger scope, before becoming the official PSL Chemical Biology meeting.

The covalent reactivity of functionalized 5-hydroxy-butyrolactams is the basis for targeting of fatty acid binding protein 5 (FABP5) by the neurotrophic agent MT-21.

Covalently acting compounds experience a strong interest within chemical biology both as molecular probes in studies of fundamental biological mechanisms and/or as novel drug candidates. In this context, the identification of new classes of reactive groups is particularly important as these can expose novel reactivity modes and, consequently, expand the ligandable proteome. Here, we investigated the electrophilic reactivity of the 3-acyl-5-hydroxy-1,5-dihydro-2-pyrrole-2-one (AHPO) scaffold, a heterocyclic motif that is present in various bioactive natural products.

Detection of cutaneous malignant melanoma using RNA sampled by tape strips: A study protocol.

Background: Cutaneous malignant melanoma (CMM) is curable if detected in its early stages. However, the clinical recognition of CMM is challenging. An American research group has shown promising results in detecting CMM based on RNA profiles sampled from suspicious lesions with tape strips.

Triculamin: An Unusual Lasso Peptide with Potent Antimycobacterial Activity.

Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) produced by microorganisms. Here we show that the two natural products triculamin and alboverticillin, originally isolated in 1967 and 1958, respectively, with potent and specific activity against mycobacteria are in fact the same lasso peptide. We solved the structure using 2D NMR spectroscopy and expanded on the previously reported bioactivity.

The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity.

The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO).

Identification of potential autoantigens in anti-CCP-positive and anti-CCP-negative rheumatoid arthritis using citrulline-specific protein arrays.

The presence or absence of autoantibodies against citrullinated proteins (ACPAs) distinguishes two main groups of rheumatoid arthritis (RA) patients with different etiologies, prognoses, disease severities, and, presumably, disease pathogenesis. The heterogeneous responses of RA patients to various biologics, even among ACPA-positive patients, emphasize the need for further stratification of the patients. We used high-density protein array technology for fingerprinting of ACPA reactivity.

Forward Chemical Genetic Screen for Oxygen-Dependent Cytotoxins Uncovers New Covalent Fragments that Target GPX4.

The identification of growth inhibitory compounds with the ability to selectively target the cellular oxygenation state may be of therapeutic interest. Here, a phenotypic screen of a covalent fragment library revealed diverse compounds containing propiolamide warheads with selective toxicity for liver cancer cells in normoxic conditions. Target identification and validation through CETSA and direct pulldown experiments demonstrated that several compounds target glutathione peroxidase 4 (GPX4) and induce ferroptotic cell death.

Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS-STING Pathway.

The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (-)-vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity.

Pharmacological Insights into Halophyte Bioactive Extract Action on Anti-Inflammatory, Pain Relief and Antibiotics-Type Mechanisms.

The pharmacological activities in bioactive plant extracts play an increasing role in sustainable resources for valorization and biomedical applications. Bioactive phytochemicals, including natural compounds, secondary metabolites and their derivatives, have attracted significant attention for use in both medicinal products and cosmetic products. Our review highlights the pharmacological mode-of-action and current biomedical applications of key bioactive compounds applied as anti-inflammatory, bactericidal with antibiotics effects, and pain relief purposes in controlled clinical studies or preclinical studies.

Organocatalytic Asymmetric Multicomponent Cascade Reaction for the Synthesis of Contiguously Substituted Tetrahydronaphthols.

Isobenzopyrylium ions are unique, highly reactive, aromatic intermediates which are largely unexplored in asymmetric catalysis despite their high potential synthetic utility. In this study, an organocatalytic asymmetric multicomponent cascade via dienamine catalysis, involving a cycloaddition, a nucleophilic addition, and a ring-opening reaction, is disclosed. The reaction furnishes chiral tetrahydronaphthols containing four contiguous stereocenters in good to high yield, high diastereoselectivity (up to >20:1), and excellent enantioselectivity (93-98% ee).

Actinic keratoses contiguous with squamous cell carcinomas are mostly non-hyperkeratotic and with severe dysplasia.

Aims: Actinic keratosis (AK) is a precursor of cutaneous squamous cell carcinoma (SCC). No validated parameters can predict which AKs will progress into SCCs, but especially thick AKs are under suspicion. The clinical and histopathological thickness of AKs is strongly correlated.

Photophysics of a protein-bound derivative of malachite green that sensitizes the production of singlet oxygen.

Genetically encodable proteins that photosensitize the production of singlet oxygen, O(aΔ), will play an increasingly important role in elucidating mechanisms of cellular processes modulated by reactive oxygen species, ROS, and changes in redox balance. In the development of such tools, it is essential to characterize the oxygen-dependent photophysics of the protein-encased chromophore. Of the O(aΔ)-photosensitizing systems recently developed, a protein-bound derivative of Malachite Green has several desirable features: (1) it absorbs light at wavelengths longer than those typically absorbed by endogenous molecules, and (2) the chromophore becomes a viable sensitizer only when bound to the activating protein.

Total Synthesis of Natural Products Containing Enamine or Enol Ether Derivatives.

Enamine and enol ethers are nucleophilic functional groups that are well known to most chemists. When enamine or enol ethers are present in natural products, they are nearly exclusively found as derivatives having a direct connection to electron-withdrawing groups for stabilization, and the resulting larger entities, such as enamides or enol acylates, can be further extended or modified in the framework of natural products. The restricted conformational space that is associated with even simple enamine and enol ether derivatives can be a strong determinant of the overall molecular structure, and the more polarized derivatives can endow some natural products with electrophilic properties and thus facilitate covalent interactions with biological targets.

Concise Asymmetric Syntheses of Streptazone A and Abikoviromycin*.

Streptazone A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazone B , using a rhodium-catalyzed distal selective allene-ynamide Pauson-Khand reaction.

Expanding the antibacterial selectivity of polyether ionophore antibiotics through diversity-focused semisynthesis.

Polyether ionophores are complex natural products capable of transporting cations across biological membranes. Many polyether ionophores possess potent antimicrobial activity and a few selected compounds have the ability to target aggressive cancer cells. Nevertheless, ionophore function is believed to be associated with idiosyncratic cellular toxicity and, consequently, human clinical development has not been pursued.