Polyyne Hybrid Compounds from Notopterygium incisum with Peroxisome Proliferator-Activated Receptor Gamma Agonistic Effects

[Image: see text] In the search for peroxisome proliferator-activated receptor gamma (PPARγ) active constituents from the roots and rhizomes of Notopterygium incisum, 11 new polyacetylene derivatives (1–11) were isolated. Their structures were elucidated by NMR and HRESIMS as new polyyne hybrid molecules of falcarindiol with sesquiterpenoid or phenylpropanoid moieties, named notoethers A–H (1–8) and notoincisols A–C (9–11), respectively. Notoincisol B (10) and notoincisol C (11) represent two new carbon skeletons. When tested for PPARγ activation in a luciferase reporter assay with HEK-293 cells, notoethers A–C (1–3), notoincisol A (9), and notoincisol B (10) showed promising agonistic activity (EC(50) values of 1.7 to 2.3 μM). In addition, notoincisol A (9) exhibited inhibitory activity on NO production of stimulated RAW 264.7 macrophages

Design, synthesis and antimycobacterial activities of 1-methyl-2-alkenyl-4(1H)-quinolones

A series of new 1-methyl-2-alkenyl-4(1H)-quinolones lacking carboxyl, fluorine and piperazinyl at position-3, -6 and -7, respectively, have been synthesized and tested in vitro against fast growing species of mycobacteria

Myeloperoxidase-Derived 2-Chlorohexadecanal Is Generated in Mouse Heart during Endotoxemia and Induces Modification of Distinct Cardiomyocyte Protein Subsets In Vitro

Sepsis is a major cause of mortality in critically ill patients and associated with cardiac dysfunction, a complication linked to immunological and metabolic aberrations. Cardiac neutrophil infiltration and subsequent release of myeloperoxidase (MPO) leads to the formation of the oxidant hypochlorous acid (HOCl) that is able to chemically modify plasmalogens (ether-phospholipids) abundantly present in the heart. This reaction gives rise to the formation of reactive lipid species including aldehydes and chlorinated fatty acids. During the present study, we tested whether endotoxemia increases MPO-dependent lipid oxidation/modification in the mouse heart. In hearts of lipopolysaccharide-injected mice, we observed significantly higher infiltration of MPO-positive cells, increased fatty acid content, and formation of 2-chlorohexadecanal (2-ClHDA), an MPO-derived plasmalogen modification product. Using murine HL-1 cardiomyocytes as in vitro model, we show that exogenously added HOCl attacks the cellular plasmalogen pool and gives rise to the formation of 2-ClHDA. Addition of 2-ClHDA to HL-1 cardiomyocytes resulted in conversion to 2-chlorohexadecanoic acid and 2-chlorohexadecanol, indicating fatty aldehyde dehydrogenase-mediated redox metabolism. However, a recovery of only 40% indicated the formation of non-extractable (protein) adducts. To identify protein targets, we used a clickable alkynyl analog, 2-chlorohexadec-15-yn-1-al (2-ClHDyA). After Huisgen 1,3-dipolar cycloaddition of 5-tetramethylrhodamine azide (N3-TAMRA) and two dimensional-gel electrophoresis (2D-GE), we were able to identify 51 proteins that form adducts with 2-ClHDyA. Gene ontology enrichment analyses revealed an overrepresentation of heat shock and chaperone, energy metabolism, and cytoskeletal proteins as major targets. Our observations in a murine endotoxemia model demonstrate formation of HOCl-modified lipids in the heart, while pathway analysis in vitro revealed that the chlorinated aldehyde targets specific protein subsets, which are central to cardiac function

Polyyne Hybrid Compounds from <i>Notopterygium incisum</i> with Peroxisome Proliferator-Activated Receptor Gamma Agonistic Effects

In the search for peroxisome proliferator-activated receptor gamma (PPARγ) active constituents from the roots and rhizomes of <i>Notopterygium incisum</i>, 11 new polyacetylene derivatives (<b>1</b>–<b>11</b>) were isolated. Their structures were elucidated by NMR and HRESIMS as new polyyne hybrid molecules of falcarindiol with sesquiterpenoid or phenylpropanoid moieties, named notoethers A–H (<b>1</b>–<b>8</b>) and notoincisols A–C (<b>9</b>–<b>11</b>), respectively. Notoincisol B (<b>10</b>) and notoincisol C (<b>11</b>) represent two new carbon skeletons. When tested for PPARγ activation in a luciferase reporter assay with HEK-293 cells, notoethers A–C (<b>1</b>–<b>3</b>), notoincisol A (<b>9</b>), and notoincisol B (<b>10</b>) showed promising agonistic activity (EC₅₀ values of 1.7 to 2.3 μM). In addition, notoincisol A (<b>9</b>) exhibited inhibitory activity on NO production of stimulated RAW 264.7 macrophages