ABSTRACT
Novel pyrone-derived quorum sensing (QS) ligands to inhibit the binding of OdDHL to the LasR of Pseudomonas aeruginosa were designed, synthesized and evaluated. Among the analogs, the most potent compound 8 exhibited strong in vitro inhibitory activities against biofilm formation and down-regulated OdDHL/LasR-associated genes by 35-67%. The binding mode of 8 in silico was highly similar to that of the crystal ligand OdDHL in the active site of LasR.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Biofilms/drug effects , Pseudomonas aeruginosa/drug effects , Pyrones/pharmacology , Quorum Sensing/drug effects , Trans-Activators/metabolism , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/metabolism , Anti-Bacterial Agents/chemistry , Homoserine/analogs & derivatives , Homoserine/metabolism , Humans , Molecular Docking Simulation , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Pseudomonas Infections/prevention & control , Pseudomonas aeruginosa/physiology , Pyrones/chemistry , Structure-Activity RelationshipABSTRACT
Adiponectin production during adipocyte differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) can be used to evaluate the pharmacological activity of anti-diabetic drugs to improve insulin sensitivity. Monoamine oxidase (MAO) inhibitors such as phenelzine and pargyline inhibit adipogenesis in murine pre-adipocytes. In this study, however, we found that selective MAO-A inhibitors, moclobemide and Ro41-1049, and a selective MAO-B inhibitor, selegiline, promoted adiponectin production during adipocyte differentiation in hBM-MSCs, which suggested the anti-diabetic potential of these drugs. In contrast, non-selective MAO inhibitors, phenelzine and tranylcypromine, inhibited adipocyte differentiation of hBM-MSCs. Concomitant treatments of MAO-A and MAO-B selective inhibitors did not change the stimulatory effect on adiponectin production in hBM-MSCs. Taken together, the opposite effects of isotype-selective MAO inhibitors on adiponectin production during adipogenesis in hBM-MSCs may not be directly associated with the inhibitory effects of MAO, suggested that the structure of MAO inhibitors may contain a novel anti-diabetic pharmacophore.
Subject(s)
Antidiuretic Agents/chemistry , Bone Marrow Cells/cytology , Mesenchymal Stem Cells/cytology , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase/chemistry , 3T3-L1 Cells , Adipogenesis/drug effects , Animals , Antidiuretic Agents/chemical synthesis , Antidiuretic Agents/pharmacology , Humans , Mice , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Phenelzine/chemistry , Phenelzine/pharmacology , Tranylcypromine/chemistry , Tranylcypromine/pharmacologyABSTRACT
Adiponectin and leptin are major adipocytokines that control crosstalk between adipose tissue and other organ systems. Hypoadiponectinemia and hypoleptinemia are associated with human metabolic diseases. Compounds with adipocytokine biosynthesis-stimulating activities could be developed as therapeutics against diverse metabolic conditions. In phenotypic screening with human bone marrow mesenchymal stem cells (hBM-MSCs), (E)-4-hydroxy-3-(3-(4-hydroxy-3-methoxyphenyl)acryloyl)-6-methyl-2H-pyran-2-one (1) was identified to increase adiponectin biosynthesis during adipogenesis and simultaneously to stimulate leptin production. Using the compound 1 structure, the structure-activity relationship study was performed to discover more potent compounds stimulating both adiponectin and leptin production. (E)-3-(3-(2-fluoropyridin-4-yl)acryloyl)-4-hydroxy-6-methyl-2H-pyran-2-one (11) exhibited the most potent adiponectin (EC50, 2.87 µM) and leptin (EC50, 2.82 µM) biosynthesis-stimulating activities in hBM-MSCs. In a target identification study, compound 11 was characterized as a dual modulator binding to both peroxisome proliferator-activated receptor (PPAR) γ and glucocorticoid receptor (GR). This study provides a novel pharmacophore for PPARγ/GR dual modulators with therapeutic potential against human metabolic diseases.