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Biomedical subjects

Y Letourneux

Publications and source records attributed to Y Letourneux.

At least 37 records · Page 2Linked to original sources
PubMed1996

Synthesis and evaluation of the anti-inflammatory effects of niflumic acid lipophilic prodrugs in brain edema.

Five new lipophilic prodrugs of the non-steroidal anti-inflammatory drug, niflumic acid (Nifluril, CAS 4394-00-7), were synthetized and evaluated on the experimental brain edema (injection of phospholipase A2). The effect of these drugs in comparison with dexamethasone which elicits a marked effect on clinical and experimental brain edema was evaluated. Niflumic acid was vectorised by cholesterol, hexadecanol and by three 1,3-diacylglycerols. The anti-inflammatory activity of these compounds on experimental brain edema was evaluated by determination of the prostaglandin E2 (PGE2) brain tissue concentration. Niflumic acid reduced the prostaglandin E2 production more significantly than dexamethasone. Niflumic acid prodrug forms (1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyl] glycerol and 1,3-dihexadecanoyl-2-[2-[3-(trifluoromethyl)anilino]nicotinoyloxybuta noyl] glycerol also showed a marked anti-inflammatory activity at low concentrations.

Animals↗
PubMed1995

Antibacterial activity of 7-aminocholesterol, a new sterol.

A new sterol, 7-aminocholesterol, which inhibits growth of Saccharomyces cerevisiae, also displayed antibiotic activity against Gram-positive bacteria. The 50% growth inhibitory concentration against strains of Listeria innocua, L. monocytogenes, Staphylococcus aureus, Enterococcus hirae and Bacillus cereus was 3 microM.

Anti-Bacterial Agents↗
PubMed1995

Influence of alkyl chain lengths in dialkylglycerophosphocholines towards phospholipase A2 inhibition in macrophages.

Rat peritoneal macrophages were cultured with a specific and potent phospholipase A2 activator A 23187, with 1-stearoyl-2-[3H]arachidonoyl-sn-GPC as source of [3H] arachidonic acid, and with a dialkyl-GPC, at 2, 10 or 20 microM. Four dialkyl-GPCs were prepared by chemical synthesis. Position 2 of rac-glycerol was alkylated with an alkane chain of 8 carbons and position 1 was alkylated with various alkane chains (8, 10, 12, or 16 carbons). [3H] arachidonic acid was split, then recovered with cell nonesterified fatty acids and nonphosphorous glycerolipids after endocellular phospholipase A2 activity. It was also recovered with fatty acids and eicosanoids isolated from culture medium. Inhibition of fatty acid release and eicosanoid synthesis depended on mixed chain dialkyl-GPC structures. The highest inhibitory effect on arachidonic acid release was reached with 1-decyl-2octyl-GPC and was practically as high in culture medium (IC50 at 5 microM) as in cells (IC50 at 4 microM). 1,2-di-octyl-GPC and 1-dodecyl-2-octyl-GPC had weaker inhibitory effects (but higher in culture medium than in cells). The asymmetrical 1-hexadecyl-2-octyl-GPC poorly affected enzyme activity.

Animals↗
PubMed1995

Synthesis and preliminary in vitro evaluation of antitumor nitrosoureido cholesterol derivatives.

A new class of chloroethyl nitrosourea analogues of cholesterol has been synthetized from the corresponding 7-amino and 7-aminoalkylcholesterol derivatives. Compounds III-V inhibited L1210 cell growth in culture much more effectively than N,N'-bis(2-chloroethyl)-N'-nitrosourea (BCNU) after 48 h incubation. Stability and cytotoxic activity of these prodrugs are promising for brain tumor treatments and as lymphotropic vectors for tumor cells spreading along the lymphatic pathways.

Animals↗
PubMed1994

Amino- and aminomethylcholesterol derivatives with fungicidal activity.

Among a series of aminocholesterol derivatives synthesized, 7-aminocholesterol is the strongest inhibitor of yeast cell growth. Using sterol auxotrophic mutant strains, we showed that this compound inhibits cell proliferation by interfering with ergosterol biosynthesis. The sterol pattern of treated cells revealed that 7-aminocholesterol inhibits delta 8-->delta 7-sterol isomerase and delta 14-sterol reductase as morpholine inhibitors. However, the novel feature of this compound is a strong cytotoxicity to yeast.

Cholesterol↗
PubMed1994

Synthesis and in vitro study of a diglyceride prodrug of a peptide.

A diglyceride derivative of a pentapeptide renin inhibitor, the 1,3-dipalmitoyl-[Iva-Phe-Nle-Sta-Ala-Sta-acetyl]-glycerol was synthesized and tested in vitro as a potential prodrug for oral administration. The ability of the diglyceride analog to inhibit the renin activity was equivalent to that of the parent peptide after predigestion with pancreatic lipase. Furthermore, the presence of the palmitoyl groups was found to induce, in vitro, an efficient protection of the peptide from gastric and intestinal hydrolysis. During incubation with intestinal and gastric fluids, and with alpha-chymotrypsin and pancreatic lipase, the glycerolipidic derivative was more stable than the peptide alone. These results support the use of glycerolipidic prodrug for oral administration of peptides.

Amino Acid Sequence↗
PubMed1994

Study of lymphotropic targeting and macrofilaricidal activity of a melphalan prodrug on the Molinema dessetae model.

This study deals with the design of a new macrofilaricidal drug derived from melphalan and having a lymphotropism to avoid the hepatic first pass effect and enhance bioavailability after oral administration. Melphalan was linked to a ligand leading to a prodrug called 1,3-dp-melphalan which has structural analogy to triglycerides. The Molinema dessetae/Proechimys oris model was used for antiparasitic evaluation. Melphalan was macrofilaricidal in vitro against Molinema dessetae at 1mM, inactive in vivo after an oral single dose at 164 mumol/kg while the prodrug 1,3-dp-melphalan was active against adult worms after a single dose at 82 mumol/kg. After an oral administration of the prodrug to rats, the maximum concentration and the cumulated quantities of melphalan in lymph were about 45-fold higher than those observed with the free drug under the same conditions. Moreover, the plasma concentration of melphalan was 2-fold higher than those observed after the administration of the free drug. These results are in favor of lymphotropic targeting as a novel approach to develop new orally active macrofilaricides.

Animals↗
PubMed1994

Synthesis and orally macrofilaricidal evaluation of niclosamide lymphotropic prodrugs.

The development of new macrofilaricidal drugs is described following a strategy for the promotion of the lymphatic transport of anthelminthic drugs by-passing the liver. The selected compound was niclosamide (CAS 50-65-7) which is very effective in vitro against infective larvae but has no significant antifilarial activity when orally administered at 200 mumol/kg. To estimate the interest of such an approach, the synthesis of 5 prodrugs was achieved in a first stage. The intrinsic antifilarial activity and the delayed effect of these compounds were evaluated in vitro. Then, in vivo tests were performed with Molinema dessetae infective larvae to select the best ligands. The prodrug V 1,3-dihexadecanamido-2-[4-chloro(2- chloro-4-nitroanilinocarbonyl)phenyloxy-carbonylpropanoyl oxy]propane (having a diamide function) was responsible for an in vitro delayed effect and an orally in vivo activity (200 mumol/kg when administered in a single dose). The biological improvement of this easily micellizable prodrug which is stable to intestinal enzymes in respect to Niclosamide confirms such a strategy.

Animals↗
PubMed1992

Synthesis of the orally macrofilaricidal and stable glycerolipidic prodrug of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl ycerol.

A new strategy is presented to develop macrofilaricidal compounds orally administered and able to concentrate in the lymphatic system. A diglyceride derivative of melphalan, 1,3-dipalmitoyl-2-(4'(bis(2''-chloroethyl)amino)phenylalaninoyl)gl y cerol, was synthesized. The esterification of melphalan by 1,3-dipalmitin allowed chemical stabilization of the alkylating agent in aqueous dispersion. No degradation of this prodrug was observed after a 3-month storage of an aqueous dispersion at 4 degrees C. The filaricidal activity of the prodrug was compared with those of melphalan in vitro against adults, infective larvae and microfilariae of Molinema dessetae, and evaluated in vivo on Molinema dessetae infected Proechimy oris. In vitro, melphalan and the glycerolipidic prodrug were inactive against microfilariae but active at 1 mmol/l against infective larvae and adults. In vivo studies were performed with rodents subcutaneously inoculated with infective larvae from Aedes aegypti. The number of macrofilariae was significantly reduced following treatment with a single oral dose of the alkylating agent prodrug (0.082 mmol/kg).

Aedes↗
PubMed1992

In vitro and in vivo evaluation of macrofilaricidal activity of GABA and 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: a diglyceride prodrug.

A new therapeutic target has been identified from the filaria Molinema dessetae: the gabaergic system. gamma-aminobutyric acid (GABA) itself showed antifilarial effect in vitro and a macrofilaricidal action in vivo at high dose by intraperitoneal route (10(-2) M). Nevertheless, no action was observed by oral route. The study we report here consists to obtain an antifilarial effect by oral route using a diglyceride prodrug. Such a strategy is based on the triglycerides metabolism. A diglyceride prodrug of gamma-aminobutyric acid has been synthesized and its filaricidal activity compared with that of GABA, in vitro on adults of Molinema dessetae and in vivo on Molinema dessetae infected Proechimys oris. In vitro, GABA at 2.5 x 10(-3) M induced a temporary paralysis and the ester drug at the same concentration was fully active on adults. In vivo, no significant activity was observed by oral administration of a daily dose of GABA (10(-2) M). A five day course of GABA at 10(-2) M via the intraperitoneal route induced a significant reduction of male and female worms. We did not find any activity of the prodrug in vivo, either by the oral route (10(-2) M) or after an intraperitoneal administration (10(-3) M). The interest of GABA and GABA derivatives as potential filaricidal drugs was discussed.

Animals↗
PubMed1989

Rationale for the synthesis and preliminary biological evaluation of highly active new antitumor nitrosoureido sugars.

Various new nitrosoureido derivatives of di- or trideoxy sugars were synthesized. The influence of the hydroxyl substitution pattern, the configuration at the anomeric center, and the absolute configuration of the sugar moiety on the antitumor activity of a series of nitrosoureido derivatives of di- and trideoxy sugars was studied. All compounds showed a very significant activity in vivo against L1210 leukemia, B16 melanocarcinoma, and Lewis lung carcinoma. Methyl 3-[3-(2-chloroethyl)-3-nitrosoureido]-2,3-dideoxy-alpha-D-arabino- hexopyranoside, 24 (NSC 609224), was found to be the most active compound. When treated with 24 (NSC 609224) at 20 mg/kg on day 1, at least 90% of the L1210 leukemia and B16 melanocarcinoma bearing mice showed a survival of over 60 days for a LD50 value for this compound of 42 mg/kg.

Amino Sugars↗
PubMed1989

In-vitro evaluation of filaricidal activity of GABA and 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: a diglyceride prodrug.

A diglyceride ester of gamma-aminobutyric acid (GABA) has been synthesized and its filaricidal activity compared with GABA, and progabide in-vitro, on infective larvae and microfilariae of Molinema dessetae, a rodent filaria. GABA induced paralysis in infective larvae but was inactive on microfilariae. There were interactions between the culture medium and GABA. The ester drug at 0.1 mmol L-1 (1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl) was as active as progabide on infective larvae and hundredfold more potent than GABA. Its microfilaricidal activity at 1 mmol L-1 was lower than that progabide at 0.1 mmol L-1 but a delayed effect was observed. The data confirm filariae sensitivity to GABA derivatives.

Animals↗
PubMed1976

Inhibition of the conversion of cholesterol to pregnenolone in bovine adrenocortical preparations.

The inhibition of the conversion of [4-14C] cholesterol to [4-14C] pregnenolone by a number of steroids has been studied in bovine adrenocortical mitochondrial acetonedried preparations. At equimolar substrate and inhibitor concentrations (3.3 muM) the most potent inhibitors were cholesterol derivatives containing a nitrogen function at c-22, followed by derivatives containing oxygen functions at c-22 or c-20 or both. The presence of a hydroxyl group at c-17 or the replacement of the 3beta-hydroxyl group by fluorine reduced the inhibitory efficacy. In the presence of inhibitors that were also relatively good substrates of the cholesterol side-chain cleavage system, such as some cholesterol derivatives hydroxylated in the side-chain,the rate of [4-14C] pregnenolone formation increased with time as the inhibitor was consumed. (20S)-20,21-Dihydroxycholesterol exerted such an effect on the kinetics of [4-14C]pregnenolone formation, and yielded 21-hydroxypregnenolone which was identified by gas chromatography-mass spectrometry. The synthesis of (20R)-22-ketocholesterol, of (20R,22R)-22hydroxycholesterol, (20R,22S)-hydroxycholesterol, and of (20S)-desmosterol is described.

Adrenal Cortex↗