Synthesis and biological evaluation of thioglycosylated porphyrins for an application in photodynamic therapy.

The aim of this work is the synthesis of a new family of glycosylated porphyrins in which the sugar moieties are linked to the tetrapyrrole ring by a thioglycosidic bond. Two series have been designed. The first one corresponds to meso-aryl porphyrin derivatives.

Antithyroid action of tamoxifen in the rat: in vivo and in vitro studies.

The influence of administration of tamoxifen (TAM) on thyroid metabolism was investigated. The potential action of TAM on iodine in the thyroid gland was evaluated by determination of the equilibrium constant of the charge transfer complex formed with molecular iodine and by computational studies. Adverse effects of TAM on thyroid function parameters were also investigated in female Wistar rats.

Influence of dietary iodine on drug-induced hypothyrodism in the rat.

Several compounds of pharmaceutical importance from a variety of chemical families, for example chlorpromazine and clomipramine, have been found to form charge-transfer complexes with iodine. We have investigated the influence of dietary iodine on thyroid-gland dysfunction induced by clomipramine, chlorpromazine or 2-thiazoline-2-thiol. We suggest that iodine is partly diverted from its metabolic pathway by complexation with drugs, and so the urinary concentration of iodide is increased.

[Analgesic and anti-inflammatory activity of saponins of Argania spinoza].

We studied analgesic and antiinflammatory actions of saponins of Argania spinosa cakes in mice and rats. With oral doses of 50 to 300 mg/kg, we found peripheric analgesic actions equivalent to the acetyl salicylic acid ones. The maximum protection was obtained with 500 mg/kg per os.

Thyroid accumulation and adverse effects of imipramine and desipramine in rats after long-term administration.

The respective adverse effects of imipramine and desipramine on serum thyroid hormone levels and their accumulation in thyroid were investigated in male Wistar rats. Two groups of 30 rats were gavaged for 4 weeks with 30 mg/kg/day imipramine hydrochloride (IMI) or desipramine hydrochloride (DESI), while the control group (12 rats) received the arabic gum vehicle only. In the IMI-treated group, the serum thyroxine (T4) level significantly decreased (by 13%) and IMI and its metabolite DESI were accumulated in the thyroid, as pointed out by mean thyroid-to-serum concentration ratios close to 12 and 8, respectively.

Anti-inflammatory action of methimazole.

The anti-inflammatory activity of 1-methylimidazole-2-thiol (methimazole), the most widely used antithyroid drug, was investigated. Methimazole had a marked inhibitory action on prostaglandin H synthase (IC50 = 10 mumol/l), inhibiting the peroxidase (IC50 = 330 mumol/l), although the cyclo-oxygenase was slightly activated. Methimazole was less potent than indometacin (IC50 = 1.

Methimazole inhibits peripheral lymphocyte proliferation by inducing S-quiescent phase arrest.

The influence of methimazole (MTI) on the mitogenic proliferation of human blood lymphocytes was studied in vitro to evaluate the potential immunomodulatory activity of this antithyroid drug. The effects of the drug on the lymphocyte cell cycle were assessed by multiparametric flow cytometry. Although MTI induced an increase in the number of lymphocytes in the synthesis and G2M compartments, it failed to stimulate proliferation as the cells tended to accumulate in the quiescent S compartment.

Synthesis and inhibitory effects of 2-pyridyl-2-thiobenzoxazole and 2-pyridyl-2-thiobenzimidazole derivatives on arachidonic acid metabolism.

A series of new 2-pyridyl-2-thiobenzoxazole and 2-pyridyl-2-thiobenzimidazole compounds was prepared and investigated by a number of in vitro methods in order to determine their prostaglandin synthesis inhibitory activity. The most active compound decreases prostaglandin production and carrageenin edema, but has a less platelet antiaggregatory activity.

Lymphoproliferative activity of methimazole: free SH group dependency.

1. The comparative effects of methimazole (MTI), an antithyroid drug, and its S-methyl derivate (MMTI), were studied in vitro on the lymphoproliferative response to lectin in order to point out the free SH group importance. The cell cycle analysis was performed by flow cytometry after cellular DNA staining by propidium iodide.

Synthesis and antithyroid activity of 1,4,5-trialkyl 2-thioimidazole derivatives.

A series of compounds based on the structure of MTI (1-methyl-2-thioimidazole) were synthesized by condensation of alpha-hydroxyketones and alkylthioureas. The alpha-hydroxyketones were obtained by a radical reaction in the presence of sodium and the alkyl ester, while the alkylthioureas were prepared by nucleophilic addition of ammonia on an alkylisothiocyanate. The antithyroid activity of the 13 compounds prepared was evaluated in vitro by determination of the concentrations which led to a 50% inhibition (IC50) of the activity of thyroid peroxidase, and in vivo by assay of thyroid hormones levels and histological examination of the thyroid gland in rats treated chronically with the compounds.

Synthesis and inhibitory effects of 1,4,5-trialkyl-2-thioimidazole derivatives on platelet aggregation.

New 1,4,5-trialkyl-2-thioimidazole have been synthesized by the condensation of alpha-hydroxyketones and alkylthioureas. The in vitro platelet aggregation inhibiting effect of prepared compounds on human platelets was studied in the presence of ADP and collagen as inducers. The formation of thromboxane B2(TXB2) was inhibited.

1,4,5-trialkyl imidazole system anti-inflammatory properties of new substituted derivatives.

In an investigation of the anti-inflammatory properties of five-membered ring nitrogen-containing heterocyclic compounds, two series of derivatives of imidazole were prepared by altering the sites of substitution and by joining aliphatic chains to the nitrogen atom in the 1 position of the imidazole ring. Some of them were more potent inhibitors of carrageenan-induced edema than indomethacin. An electron spin resonance study indicated that these compounds possess anti-radical activity.

Antithyroid action of ketoconazole: in-vitro studies and rat in-vivo studies.

Inspection of the chemical structure of ketoconazole indicates that it may have antithyroid activity. The antithyroid action of this drug was demonstrated in-vitro and in-vivo. In-vitro, it was found to form a complex with iodine (formation constant Kc 141 L mol-1), and to inhibit lactoperoxidase (IC50 2 x 10(-4) M).

Biological evaluation of compounds with -NCS- group or derived from thiazole and imidazole. Activity on prostaglandin synthetase complex.

The effects of compounds with activity against thyroid peroxidase were tested on the activity of hydroperoxidase and cyclo-oxygenase of the prostaglandin synthetase complex in-vitro. Active compounds were found to inhibit the peroxidase, and the cyclo-oxygenase function. These compounds were also found to have anti-inflammatory activity as demonstrated by the reduction of carrageenan-induced oedema of the hind paw of the rat.

Synthesis and antithyroid activity of pyridine, pyrimidine and pyrazine derivatives of thiazole-2-thiol and 2-thiazoline-2-thiol.

A series of compounds was synthesized by linking various derivatives of pyridine, pyrimidine or pyrazine to thiazole-2-thiol or to its partially hydrogenated derivative 2-thiazoline-2-thiol. The reactions of the compounds with molecular iodine and lactoperoxidase were examined in vitro. Their antithyroid activity was also examined in vivo in the rat.

[Antibacterial sulfonamides, antiparasitic and antifungal derivatives of imidazole: evaluation of their antithyroid effects in the rat].

Antithyroid action of some antibacterial, antiparasitic or antifungal agents, was studied by 2 in vitro and 3 in vivo experimentations in the rat. These drugs can upset thyroid hormone synthesis by forming a molecular complex with iodine, and/or by inhibiting thyroid peroxidase activity. Rats treated with these drugs showed an hypothyroidism, demonstrated both by a decrease in T4 concentration and an hyperactivity of thyroid gland by positive feed-back, whose consequence was the presence of cylindrical cells.

Synthesis and anti-inflammatory activity of 2-pyridyl-2-thiobenzothiazole derivatives.

A series of novel 2-pyridyl-2-thiobenzothiazole compounds was prepared and investigated by a number of in vitro methods in order to determine their anti-inflammatory properties. Results are discussed with reference to well known NSAIDs. (3-carboxy-2-pyridyl)-2-thiobenzothiazole had the most potent anti-inflammatory activity, being 1.

Synthesis and inhibitory effects of 1,2,4-triazole derivatives on platelet aggregation.

Various derivatives of triazole substituted in the 2-position were prepared, and their activity on platelet aggregation tested. Compounds 4 and 14 had the most powerful action. These agents were thought to inhibit platelet aggregation via an inhibition of the cyclo-oxygenase-peroxidase complex (PGS complex), preventing synthesis of prostaglandins.

Sites of action of 2-thiazoline-2-thiol on biogenesis of thyroid hormones.

2-Thiazoline-2-thiol is an antithyroid agent that strongly reduces thyroid hormone levels. Synthesis of these hormones is catalyzed in vivo by thyroid peroxidase. The interaction of this drug with molecular iodine and its effect on peroxidase activity were investigated.

Formation of molecular iodine during oxidation of iodide by the peroxidase/H2O2 system. Implications for antithyroid therapy.

The first step in the biogenesis of thyroid hormones is the oxidation of iodides taken up by the thyroid gland. Oxidation of I- by the H2O2/peroxidase system leads to the formation of iodinium ions I+ which bond to thyroglobulin by electrophilic substitution. However, it is not clear whether I- is transformed directly to I+ or whether it passes through a molecular iodine intermediate.

Spectroscopic analysis of charge transfer complexes between morpholine and iodine.

It has been demonstrated spectroscopically that many nitrogen-containing heterocyclic compounds can form charge transfer complexes with iodine. The complexes of morpholine with iodine were shown to be of the n-sigma type with a 1:1 stoichiometry. A strong donor-acceptor interaction was found (Kc = 1261 +/- 12 mol-1 at 20 degrees C in CCl4), considerably higher than those of complexes of aromatic compounds with iodine.

The mechanism of action of synthetic antithyroid drugs: iodine complexation during oxidation of iodide.

A number of compounds of pharmaceutical importance from a variety of chemical families, including thiocyanates, isothiocyanates, thiourea and derivatives, imidazoles, and various amines, were found to form charge transfer complexes with iodine. Parallel studies were carried out to investigate the actions of these drugs on lactoperoxidase and thyroid activity in vivo in the rat (assays of T3 and T4 and histology of the thyroid gland). The results showed that there was a good correlation between the value of Kc (the formation constant of the iodinated complex) and antithyroid activity in vivo.

[Apropos of a fatal case of poisoning by household aerosol].

The authors present a case of abusive use of nitrogen in aerosol. It produced an acute edema primarily toxic bringing a hypoxemia amidst the coronarian network already partially occluded. It is rapidly followed by a subendocardiac infarct of the myocardium with left ventricular failure.