Synthesis and biological evaluation of 2-heteroarylthioalkanoic acid analogues of clofibric acid as peroxisome proliferator-activated receptor alpha agonists.

A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.

The excitation-contraction coupling on C2C12 skeletal muscle myotubes was modulated by NO-donor ester of gemfibrozil.

The excitation-contraction coupling in skeletal muscle is modulated by nitric oxide via redox status modification of ryanodine receptor on sarcoplasmic reticulum during events that lead to muscle contraction. We have synthesized a derivative of antilipidemic drug, gemfibrozil, in which a NO-donor furoxan moiety is joined to the fibrate by an ester linkage. Aim of the present study was to determine if the NO released from the above compound is capable of influencing the NO-sensible E-C coupling steps in skeletal muscle and if this effect could be potentially utilised for physiopathological studies and pharmaceutical applications. To obtain this goal we decided to study some of the excitation-contraction mechanisms in the presence of NO-releasing derivative of gemfibrozil in skeletal muscle C2C12 cell line.

Candida rugosa lipase-catalysed kinetic resolution of 2-substituted-aryloxyacetic esters with dimethylsulfoxide and isopropanol as additives.

Candida rugosa lipase-catalysed hydrolysis of three different 2-substituted-aryloxyacetic esters was performed in aqueous buffer containing dimethyl sulphoxide and isopropanol from 0 to 80% v/v as additives, in order to obtain an enhancement of the enantioselectivity. For 2-(p-chlorophenoxy)acetic acid and 2-n-butyl-2-(p-chlorophenoxy)acetic acid ethyl esters, DMSO enhanced enzyme enantioselectivity more than IPA with an opposite enzymatic enantiopreference. The cosolvents moderately improved Candida rugosa lipase enantioselectivity for 2-phenyl-2-(p-chlorophenoxy)acetic acid ethyl ester.

Enantiomeric separation of some demethylated analogues of clofibric acid by capillary zone electrophoresis and nano-liquid chromatography.

The enantiomeric separation of some demethylated analogues of clofibric acid, namely 2-(6-chloro-benzothiazol-2-ylsulfanyl)-, 2-(6-methoxy-benzothiazol-2-ylsulfanyl)-, 2-(quinolin-2-yloxy)-, 2-(6-chloro-quinolin-2-yloxy)-, 2-(7-chloro-quinolin-4-yloxy)-propionic acid (compounds A-E, respectively), has been studied by CZE and nano-LC using for the first technique two beta-CD derivatives and vancomycin added to the BGE and vancomycin-modified silica particles for the second one, with the aim to find the optimum experimental conditions for the baseline resolution. The type and the concentration of the chiral selector added to the BGE, the buffer pH, the type of organic modifier and its concentration, the capillary temperature and the applied voltage played a very important role in the enantioresolution of the analysed compounds. The use of 6-monodeoxy-6-monoamino-beta-CD allowed to achieve baseline resolution of four of five clofibric acid derivatives in less than 10 min while heptakis-(2,3,6-tri-O-methyl)-beta-CD partially resolved the same compounds in their enantiomers. Employing vancomycin as the chiral selector in CZE, the counter-current partial filling method was chosen achieving baseline resolution of four analytes. All the studied compounds were enantioresolved employing a capillary column packed with vancomycin stationary phase by nano-LC, and the resolution was strongly influenced by the concentration of the organic modifier and by the pH of the mobile phase. The best results were achieved at pH 4.5 in presence of 60% of methanol (MeOH). However, longer analysis times were observed in the experiments carried out by nano-LC.

Enantiomeric separation of gemfibrozil chiral analogues by capillary electrophoresis with heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin as chiral selector.

The enantiomeric separation of gemfibrozil chiral analogues was performed by capillary zone electrophoresis (CZE). Resolution of the enantiomers was achieved using heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TM-beta-CD) as chiral selector dissolved into a buffer solution. In order to optimize the separation conditions, type, pH and concentration of running buffer and chiral selector concentration were varied. For each pH value, the optimum chiral selector concentration that produced the resolution of the isomers was found. The migration order of labile diastereoisomers formed was valued at the optimum experimental conditions by adding a pure optical isomer to the racemic mixture. Data from 1H NMR studies confirmed host-guest interaction between TM-beta-CD and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid sodium salt. The hypothesized stoichiometry host:guest was 1:1. An apparent equilibrium constant (Ka) was estimated monitoring the chemical shift variation as a function of TM-beta-CD concentration. Salt effect on complexation equilibrium constant was also investigated.

Synthesis and antiplatelet activity of thioaryloxyacids analogues of clofibric acid.

The thiophene-, benzothiazole- and pyridine-thioaryloxyacids analogues of clofibric acid were synthesized and their antiplatelet activity was screened. Some compounds exhibited antiaggregating properties. The platelet-related haemostasis was measured on a PFA-100 analyzer using bull blood.

Synthesis and antibacterial evaluation of oxazolidin-2-ones structurally related to linezolid.

Compounds structurally related to the known antimicrobial drug linezolid were selected in order to evaluate the influence of electron-withdrawing properties and altered geometric features as a result of the N-substituent modification. After a preliminary study of molecular modeling, cinnamoyl-, pyridin- and pyrimidinoxazolidin-2-ones were synthesized. None of the new compounds showed antibacterial activity.

Synthesis and antiplatelet activity of gemfibrozil chiral analogues.

The chiral analogues of gemfibrozil 5-(2,5-dimethylphenoxy)-2-methylpentanoic acid and 5-(2,5-dimethylphenoxy)-2-ethylpentanoic acid were synthesized in optically active form using (S)-4-(1-methylethyl)-2-oxazolidinone as chiral auxiliary. All compounds inhibit human platelet aggregation. From these data, one can surmise that all tested compounds and gemfibrozil act at the platelet level with different mechanism than that of ASA, even if with a different potency.