Synthesis and in vitro studies of pyrone derivatives as scavengers of active oxygen species.

The antioxidant properties of eleven alpha-pyrones and four gamma-pyrones were evaluated by means of three different tests: reduction of the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide anion scavenging assay and lipid peroxidation assay. In the DPPH test, 6-aryl-5,6-dihydro-4-hydroxypyran-2-ones (3) and 4-hydroxypyran-2-one (5f) were the most active derivatives with IC50 values ranging from 36.7 to 394 mumol/l. Potent superoxide anion scavenging properties appeared in derivatives possessing phenol moieties. Thus phenolic pyrones 5e and 5f exhibited a noteworthy activity (IC50 = 0.180 and 0.488 mmol/l, respectively) when reference compound, ascorbic acid, demonstrated only 24% inhibition at a concentration of 1 mg/ml. In addition derivative 5f significantly inhibited the Fe2+/ADP/ascorbate-induced lipid peroxidation of rat liver microsomes with an IC50 value of 0.069 mmol/l. Due to its multiple mechanism of protective action, compound 5f may be useful for the treatment of oxidative tissue injury in human disease.

Antioxidant properties of novel lipophilic ascorbic acid analogues.

Structural modifications of ascorbic acid by the introduction of lipophilic moieties has led to derivatives with increased stability against thermal and oxidative degradation. Two series of new lipophilic ascorbic analogues were synthesized to obtain antioxidants devoid of autooxidant properties: 4-benzoyl-3-hydroxyfuran-2(5H)-ones (3a-j) and 4-acetyl-5-aryl-3,4-dihydrofuran-2(5H)ones (5a-f). These compounds were submitted to three different tests: reduction of the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH); superoxide-anion scavenging assay; and lipid-peroxidation assay. Most compounds interacted with DPPH: at a concentration of 5 x 10(-3) M, the reducing activity of 4-benzoyl derivatives, 3c and 3h, was more than 50%; under the same conditions, the rate of inhibition for 4-acetylbutanolides, 5a and 5f, reached 60.6% and 87.3%, respectively; 93.3% inhibition was observed with ascorbic acid. In the superoxide-anion scavenging assay, at a concentration of 1 mg mL(-1), 4-benzoyl derivatives, 3g and 3i, exhibited a good activity, with IC50 (dose resulting in 50% inhibition) values of 1.45 and 1.35 x 10(-3) M, respectively. 4-Acetylbutanolide, 5f, significantly inhibited the Fe2+/ADP/ascorbate-induced lipid peroxidation of rat liver microsomes with an IC50 of 4.9 x 10(-4) M. This study demonstrates that enol functions in the structure of ascorbic acid analogues are not absolutely essential to bring about antioxidant effects.

High-performance liquid chromatographic determination of paclitaxel in rat serum: application to a toxicokinetic study.

A simple and sensitive high-performance liquid chromatographic method is described for the determination of paclitaxel (Taxol) at 230 nm using a Nucleosil C18 (5 microm) column and a methanol-water (70:30, v/v) mobile phase following a single-step extraction from serum with dichloromethane. The assay was validated against the classical criteria and was applied to a toxicokinetic study in rats after one or five, one per week) intraperitoneal administrations of 16 mg/kg Taxol.

Effect of tolcapone on plasma and striatal apomorphine disposition in rats.

The influence of tolcapone, an inhibitor of catechol-O-methyl transferase, was evaluated on the disposition of apomorphine, a dopamine agonist used to treat Parkinson's disease, to explain a previously observed increase of duration of the effect of apomorphine associated with tolcapone. Sampling was performed in rats before and at different times after administration of apomorphine and following that of tolcapone or saline. Both in plasma and striatum, times to reach maximal-concentration and maximal concentrations did not significantly differ between the two groups but the elimination half-life times and areas under the curve were significantly greater following tolcapone treatment than in the saline group. These results show that tolcapone can increase plasma apomorphine bioavailability by modifying its liver catabolism.

Effect on free radical processes of some ascorbic acid analogues.

Ascorbic acid, present in plasma from humans at concentrations of 50 to 200 mumol/l, has multiple antioxidant properties. Structural modification of this vitamin by the introduction of lipophilic moieties has allowed to the development of ascorbate esters and ethers active as free radical quenchers. Thus, a new series of ascorbic acid analogues possessing one or two aromatic rings was prepared in an attempt to synthesize potent antioxidants with lipophilic properties. Substituted 3-hydroxy furan-2 (5H)-ones and in some cases, dihydrofuro[3,4-b]pyrones were prepared. The synthesized compounds were evaluated for their antioxidant activity in vitro. So, 4-(4-methoxybenzoyl)-3-hydroxy-5-phenylfuran-2(5H)-one 3e (IC50 = 3.06 x 10(-4) M) was found to be the most effective in scavenging the superoxide anion, whereas 4-benzoyl-3-hydroxy-5-(3,4-dimethoxyphenyl)furan- 2(5H)-one 3d (IC50 = 1.38 x 10(-4) M) was the most active in inhibiting, lipid peroxidation.

Synthesis and aldose reductase inhibitory activity of triazine derivatives possessing acetic acid group.

N-Acetic acid derivatives of 6-aryl-pyrazolo-triazin-4-ones were synthesized for evaluation as new aldose reductase inhibitors. The intrinsic activity of each compound was assessed by measuring the inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All the prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-6) M less than or equal to IC50 less than or equal to 10(-4) M). Furthermore, biological activity (log 1/IC50) for most of the data sets could be correlated directly to electronic and steric parameters. Finally, spatial configuration of the most active derivative 6c (IC50 = 2 x 10(-6) M) was compared with that of tolrestat and with pharmacophor requirements of the aldose reductase inhibitor site using a molecular modeling system.

Synthesis and aldose reductase inhibitory activity of pyridazine derivatives possessing acetic acid group.

N-acetic acid and S-acetic acid derivatives of 5-arylidene pyridazines were synthesized for evaluation as new aldose reductase inhibitors. Intrinsic activity for each compound was assessed by measuring inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-5) M less than or equal IC50 less than or equal to 10(-4) M). It was found that lipophilicity was important in increasing activity. Furthermore, this activity (log 1/IC50) could be correlated directly to a lipophilic parameter (log kw) for the whole data set.

Compared plasma and brain pharmacokinetics of clomipramine and its metabolite demethylclomipramine in two strains of mice (NMRI and CD1).

The fate of clomipramine (CMI) and its main demethylated metabolite demethylclomipramine (DCMI) was studied in two strains of Swiss mice (NMRI and CD1) after intraperitoneal injection. A study of its distribution among various tissues showed that fixation was most marked in lungs, perirenal fat and kidneys, and only moderate in the brain. The pharmacokinetic parameters of both molecules were determined in brain tissue and plasma. Absorption was rapid (tmax CMI = 14 min), metabolism prompt (tmax DCMI = 17 or 18 min according to the breed) and elimination rapid from both plasma and brain tissue. The first two stages were similar in the two strains, but elimination of CMI from both plasma and brain was faster in the NMRI mice (plasma t1/2 = 53 min against 165 min in the CD1 mice). Both values were well below that reported for man (mean plasma t1/2 = 24 h). The data presented can serve as a basis for designing true chronic administration protocol in animals.

[Synthesis and evaluation of the aldose reductase inhibitory activity of new diaryl pyridazine-3-ones]. / Synthèse et évaluation de l'activité inhibitrice d'aldose réductase de nouvelles diaryl pyridazin-3-ones.

It has been possible to prepare from 4,6-diaryl pyridazinones a series of derivatives substituted in the 2-position by chains of various lengths bearing a carboxylic acid function. Pig lens aldose reductase inhibitory activity was evaluated for all compounds. N-acetic acid derivative 3c with a chlorine atom on the phenyl nucleus at the 6-position on the pyridazin ring was the most active pyridazinone with an IC50 value of 1.2 x 10(-5) M. Furthermore, it has been shown that lipophilicity and spatial configuration of the synthesized compounds took a prominent part on enzymatic activity.