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. Here, we studied the natural chalcone MF-14 and the corresponding dihydrochalcone MF-15 from Melodorum fruticosum, for modulating the biosynthesis of LM including leukotrienes, prostaglandins, SPM and their 12/15-LOX-derived precursors in human monocyte-derived macrophage (MDM) M1- and M2-like phenotypes. In MDM challenged with Staphylococcus aureus-derived exotoxins both compounds (10 µM) significantly suppressed 5-LOX product formation but increased the biosynthesis of 12/15-LOX products, especially in M2-MDM. Intriguingly, in resting M2-MDM, MF-14 and MF-15 strikingly evoked generation of 12/15-LOX products and of SPMs from liberated PUFAs, along with translocation of 15-LOX-1 to membranous compartments. Enhanced 12/15-LOX product formation by the chalcones was evident also when exogenous PUFAs were supplied, excluding increased substrate supply as sole underlying mechanism. Rather, MF-14 and MF-15 stimulate the activity of 15-LOX-1, supported by experiments with HEK293 cells transfected with either 5-LOX, 15-LOX-1 or 15-LOX-2. Together, the natural chalcone MF-14 and the dihydrochalcone MF-15 favorably modulate LM biosynthesis in human macrophages by suppressing pro-inflammatory leukotrienes but stimulating formation of SPMs by differential interference with 5-LOX and 15-LOX-1

29th Annual GP2A Medicinal Chemistry Conference

The 29th Annual GP2A (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. Like previous editions, the conference was a real success, with high-level scientific discussions on cutting-edge advances in the fields of pharmaceutical chemistry

Synthèse et évaluation biologique de dérivés phénoliques polyfonctionnalisés

Une voie d'accès rapide et efficace au motif ortho-(2-hydroxy-3-méthylbut-3-ényl)phénol a été développée via une séquence photooxygénation-réduction appliquée au précurseur prénylé correspondant. En réalisant la photoxydation à -30C, nous avons mis en évidence la formation de deux hydroperoxydes, secondaire et tertiaire. Ce dernier est instable et se dégrade lors du retour à température ambiante. Cette caractéristique a alors été mise à profit en réalisant la séquence photooxygénation-réduction à 15C. Dans ces conditions, seul le de rivé alcool allylique secondaire est obtenu. Cette méthodologie a ensuite été appliquée à des composés prénylés appartenant à des séries différentes (acétophénone, phénol, coumarine, xanthone) et les dérivés de type ortho-(2-hydroxy-3-méthylbut-3-ényl)phénol sont obtenus avec des rendements compris entre 8% et 84%. La synthèse de motifs 2-isopropényl-2,3-dihydrobenzofuraniques a été réalisée à partir de dérivés ortho-(2-hydroxy-3-méthylbut-3-ényl)phénols placés dans les conditions de Mitsunobu. Dans un cas particulier, cette réaction fournit également des composés à structure dihydrobenzoxépinique, résultant d'un mécanisme de type Sn2'. Par la suite, la synthèse du motif 2-(1-hydroxy-1-méthyléthyl)-3-méthoxy-2,3-dihydrobenzofuranique a été envisagée via l'ouverture en milieu basique de dérivés sulfates cycliques. Dans ces conditions opératoires, ces derniers subissent un réarrangement original et conduisent à une structure de type 3-(1-hydroxy-1-méthyléthyl)-2-méthoxy-2,3-dihydrobenzofuranique, régioisomère de la structure désirée. De plus, la cycloperoxymercuriation de dérivés hydroperoxydes allyliques tertiaires a permis la synthèse de motifs 1,2-dioxolaniques. Le groupement bromomercurique est ensuite substitué par hydridodémercuriation en présence de borohydrure de sodium ou par bromodémercuriation en présence de dibrome. L'activité biologique de différents composés synthétisés a été évaluée dans trois domaines pharmacologiques principaux : cytotoxique, antifongique, antipaludique.ANGERS-BU Médecine-Pharmacie (490072105) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

“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

Semisynthesis of natural formylated tocotrienols

International audienc

δ-garcinoic acid, a platform to tocotrienol derivatives isolated from barks of New Caledonian endemics plants

International audienc

δ-garcinoic acid, a platform to tocotrienol derivatives isolated from barks of New Caledonian endemics plants

International audienc

Semisynthetics Pathways Starting from δ-Garcinoic Acid towards Anti-Inflammatory Tocotrienols Isolated from New-Caledonian Endemic Plants

International audienc

Crystal Structure of Ethoxidine, A Synthetic Quaternary Benzo[c]phenanthridine

International audienceThe complete structure of N-methyl-12-ethoxy-2,3,8,9-tetramethoxybenzo[c]phenanthridinium methylsulfonate salt 1, also named ethoxidine, was established by a single-crystal X-ray analysis. The crystal is triclinic, space group P1− with a = 14.1836 (11), b = 14.2803 (11), c = 14.3073 (12) Å, β = 77.699 (5)°, V = 2422.3 (3) Å3, Z = 4, 2 C25H29NO8S, D c = 1.381 g/cm3, μ (CuKα) = 1.5418 Å, S = 1.036, F (000) = 1064.00, R = 0.0594 and wR = 0.1446. In the unit cell, there are two independent molecules. Solid-state data could be used to enlighten the biological mechanism of action.</p

Hémisynthèse de nouveaux analogues de la vitamine E à visée anti-inflammatoire

International audienc