Isabelle Viossat

Novel lipoic acid analogues that inhibit nitric oxide synthase.

The synthesis and biological activity of novel lipoic acid analogues are reported. Lipoic acid and structural homologues coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.

Effect of BN 52021, a specific PAF-acether antagonist, on cardiac anaphylaxis in Langendorff hearts isolated from passively sensitized guinea-pigs

Hartley guinea-pigs were sensitized passively with antiovalbumin rabbit serum. Their isolated perfused hearts responded to the specific antigen with a marked decrease in contractile force, increase in perfusion pressure, and rhythm disturbances. All these impairments except tachycardia were decreased by BN 52021, a specific PAF-acether receptor antagonist, applied in a constant infusion before ovalbumin challenge. These findings suggest that PAF-acether plays a major role as mediator in cardiac anaphylaxis, and BN 52021 may be a valuable therapeutic agent in allergic conditions.

Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of human farnesyltransferase, BIM‐46228

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a wide spectrum of human cancers (pancreas, thyroid, colon, non‐small‐cell lung cancer). Membrane anchorage of Ras, required for functional activity in signal transduction, is facilitated by post‐translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C‐terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel FTase inhibitor, BIM‐46228, which showed (i) specific inhibition of purified human FTase enzyme, (ii) inhibition of proliferation in vitro in a large spectrum of human tumor cell lines, (iii) inhibition of growth of human tumor xenografts in athymic nude mice treated by per os administration and (iv) the benefits of in vitro combination of its activity with chemotherapy or radiotherapy.

Endothelin-1 in patients with coronary heart disease undergoing cardiac catheterization

OBJECTIVES This study examined the possible association between endothelin and coronary atherosclerosis and evaluated the synthesis and release of endothelin in the presence of various stimuli that occur during cardiac catheterization. BACKGROUND Circulating endothelin has been reported to be increased in diffuse atherosclerosis and acute myocardial infarction. However, the relation between coronary artery disease and endothelin release remains unclear. METHODS We measured the plasma and urinary concentrations of endothelin immunoreactivity in 45 patients and 10 healthy control subjects. RESULTS In group IA (n = 9), simultaneous blood sampling in the coronary sinus and femoral artery during coronary angioplasty of the left anterior descending coronary artery demonstrated no immediate changes in plasma immunoreactive endothelin-1 (ir-ET-1) levels. In 11 patients in group IB undergoing coronary angioplasty of a major artery, we did not detect changes in peripheral plasma concentrations of ir-ET-1 within 24 h, but urinary ir-ET-1 levels increased from 9.2 +/- 2.3 to 18.6 +/- 4.9 pg/mg of creatinine a few hours after coronary angioplasty (mean +/- SEM, p < 0.05). This increase in urinary endothelin excretion persisted 24 h later. Group II patients (n = 12) had coronary angiography without coronary angioplasty. Levels of both plasma and urinary ir-ET-1 did not change during the 24-h follow-up period. There was no relation between the severity of coronary atherosclerosis and the plasma or urinary concentrations of ir-ET-1. Systolic aortic pressure correlated with basal urinary excretion of endothelin (r = 0.54, p = 0.03, n = 15). In group III (n = 13), levels of ir-ET-1 in patients undergoing right heart catheterization without angiography did not differ from those in the control group. CONCLUSIONS The presence or the severity, or both, of coronary atherosclerosis is not associated with a detectable increase in endothelin release. The diagnostic procedures of catheterization do not modify endothelin concentrations in plasma and urine. Vascular stretch or injury, or both, during coronary angioplasty increases urinary ir-ET-1 levels a few hours after the procedure. This increase persists for at least 24 h but is not detectable by brief sampling of peripheral or coronary sinus blood.

Inhibition of human tumor cell growth In vitro and In vivo by a specific inhibitor of human farnesyltransferase: BIM‐46068

Oncogenic mutations of the ras gene leading to constitutive activation of downstream effectors have been detected in a large spectrum of human cancers (pancreas, thyroid, colon and NSCLC). Membrane anchorage of Ras required for functional activity in signal transduction is facilitated by post‐translational modifications resulting in covalent attachment of a farnesyl group to the cysteine in the C‐terminal CAAX motif. This attachment is mediated by farnesyltransferase (FTase). Here, we report a novel series of potent FTase inhibitors, where the tetrapeptide CAAX motif has been modified by incorporation of a thiazolidine carboxylic acid moiety followed by reduction of the 1st and 2nd peptide bonds to a secondary and tertiary amine, respectively. The C‐terminal carboxylate was converted to esters for improved cellular penetration. These compounds showed specific inhibition of purified human FTase enzyme, inhibition of proliferation in vitro in a large spectrum of human tumor cell lines and inhibition of growth of human tumor xenografts in athymic nude mice. In addition, in regard to a panel of cell lines, using the Compare analysis to determine the Pearson coefficient correlation, the anti‐proliferative spectrum of BIM‐46068 has been shown to be distinct from the profile of typical chemotherapeutic agents. Int. J. Cancer 83:283–287, 1999.

Endothelin Receptor Regulation by Endothelin Synthesis in Vascular Smooth Muscle Cells: Effects of Dexamethasone and Phosphoramidon

One of the major biological effects of the endothelium-derived peptide endothelin-1 (ET-1) is its receptor-mediated constrictive action on vascular smooth muscle. In this study, we have examined the effects on the ET-1 pathway of 18 h exposure at 37 degrees C of cultured rat aortic smooth muscle cells to dexamethasone (DEX) and phosphoramidon. ET-1 synthesis was evaluated by radioimmunoassay, ET-1 binding characteristics were determined with [125I]iodo-ET-1, and ET-1-induced intracellular calcium mobilization was measured using fura-2-loaded cells. DEX (100 nM) led to a 2- to 3-fold-increase of ET-1 production, it down-regulated ET-1 receptors and reduced ET-1-stimulated calcium mobilization by 70%. In contrast, phosphoramidon (100 microM) inhibited ET-1 production by 60%, up-regulated ET-1 receptors and potentiated ET-1-induced calcium mobilization by 75%. These results indicate that the regulatory effects of DEX and phosphoramidon on ET-1 receptors are mediated via ET-1 production by the cells. This suggests an autocrine control of ET-1 receptors by endogenous ET-1 synthesis in vascular smooth muscle cells.

Novel inhibitors of neuronal nitric oxide synthase with potent antioxidant properties

A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.

Pseudopeptide farnesyl-protein transferase inhibitors containing 5,5-dimethylthiazolidine-4-carboxylic acid

Mutated ras genes are implicated in 20-30% of all human tumors, including 50% of colon, 30% of lung and 90% of pancreatic cancer [1,2]. The Ras protein is initially synthesized as an inactive cytosolic precursor that requires a series of posttranslational modifications in order to associate to the cell membrane and perform its normal and oncogenic functions. The key step in these modifications is farnesylation of a cysteine residue in the C-terminal motif of the Ras protein. Since this prenylation is catalyzed by farnesyl-protein transferase (FTase), inhibition of FTase should indirectly regulate oncogenic ras function. Therefore, inhibitors of FTase represent potential anticancer agents.