Synthesis and PPAR-.GAMMA. Ligand-Binding Activity of the New Series of 2'-Hydroxychalcone and Thiazolidinedione Derivatives

Abstract

Peroxisome proliferator-activated receptor (PPAR)-g is a member of the PPAR family and has been the subject of extensive research due to its mechanistic importance in glucose and lipid homeostasis.1) It is the predominant molecular target for the insulin-sensitizing thiazolidinedione (TZD) drugs such as troglitazone, pioglitazone, and rosiglitazone. 2,3) Those TZD derivatives can activate PPAR-g and improve insulin resistance by increasing the number of small adipocytes resulting in normal function as differentiated from preadipocytes and inducing apoptosis in large adipocytes, which produce and secrete adipocytokines such as leptin, tumor necrosis factor (TNF)-a, and free fatty acid.4) Recently, it has been reported that novel sulfonylurea or TZD derivatives containing a flavonoid ring system have antidiabetic activity. 5,6) Chalcones, originally isolated from natural plant sources, have been reported to have a variety of biological properties including antioxidant, antiinflammatory, and anticancer activities 7) and several synthetic chalcone derivatives are known to have inhibitory activity against diabetic complications. 8,9)It was envisaged that compounds containing these moieties in the same molecule may show enhanced biological activity. It was therefore of interest to synthesize some TZDs with a chalcone moiety (chalconylidene-TZDs) as a substituent at the C-5 position.In this study, we selected a group of 2Ј-hydroxychalcones (3-17) and chalconyl-TZDs (18-20) and tested them for PPAR-g ligand-binding activity in the transient reporter assay. ChemistryAs depicted in Chart 1, the chalcones (c) were synthesized by Winget's condensation of an aromatic acetophenone (a) with the appropriate aromatic aldehyde (b).10) The olefin parts of these chalcones were confirmed to have trans geometry based on the 1 H-NMR spectrum, in which the coupling constant between the two vinylic protons appearing at 6.9-7.2 and 7.8-8.3 ppm is approximately 15 Hz. A comparison of the physical and spectroscopic data of the synthesized compounds with the reported values showed good agreement.The chalconylidene-TZDs (18-20) were synthesized as shown in Chart 2. First, dicarboxybenzaldehyde (d) was condensed with TZD with anhydrous sodium acetate in acetic acid to form p-carboxybenzylidene-TZD (e, mp 155-157°C) (i.e., by Knoevenagel reaction). The Winget condensation gave products that were insoluble yellowish polymers made from d. On the other hand, the reaction of appropriate (a) compared with aldehyde (e) using Winget's condensation gave chalconylidene-TZDs (f). In the literature, it was reported that unsubstituted imidazolidinediones and benzaldehydes in acetic medium gave mainly the Z isomer. 11)In this study, only one isomer was obtained. However, due to the low solubility of the compounds and the difficulties of obtaining suitable crystals for X-ray analysis, the isomer could not be analyzed structurally in detail. Results and DiscussionThe results of the PPAR-g ligand-binding activity of 2Ј-hydroxychalcone and chalconylidene-TZD d...

Hydroxylated chalcones with dual properties: Xanthine oxidase inhibitors and radical scavengers

“…For the synthesis of di-, tri-, tetra-, penta-, and hexasubstituted chalcones, a three-step route was utilized (Figure 2). More specifically, the hydroxyl groups in aldehydes or acetophenones were protected by MOMO groups under basic reflux conditions [64]. Claisen-Schmidt condensation of these protected aldehydes and acetophenones provided enones [65, 66].…”

2-Bromo-4′-methoxychalcone and 2-Iodo-4′-methoxychalcone Prevent Progression of Hyperglycemia and Obesity via 5′-Adenosine-Monophosphate-Activated Protein Kinase in Diet-Induced Obese Mice

“…Halogen-containing secondary metabolites have attracted recent attention due to their potent biological activities, which are attributed to the unique electronic and steric environment created by the presence of halogen atoms [ 4 ]. Using a simple synthetic method, we have been able to produce different halogen-containing chalcone derivatives [ 6 , 12 ].…”

Chalcones and their therapeutic targets for the management of diabetes: Structural and pharmacological perspectives

“…When cells were treated with insulin in the presence of compound (80), noticeable improvement of insulin-stimulated glucose uptake was observed. Compound (81) showed the most potent sensitization. Substitution by acidic or highly polar groups abolishes the activity completely [103].…”

“…Jung et al have synthesized and evaluated a series of chalcones and thiazolidinedione derived chalcones (61e63) which showed PPAR-g agonist activity [81]. …”