Jean-François Robert

Analysis of the progesterone displacement of its human serum albumin binding site by β-estradiol using biochromatographic approaches: effect of two salt modifiers

The mechanisms of (i) the binding of two sex-hormones (i.e. progesterone and beta-estradiol) to human serum albumin (HSA) and (ii) the progesterone displacement of its HSA binding cavity by beta-estradiol were studied by biochromatography using three different methods. In the first time, zonal elution method was used to prove the direct competition effect between the two sex-hormone. In the second time, the competition effect between beta-estradiol and progesterone to bound on the same HSA site was analysed by the competitive bi-Langmuir approach. Finally, the thermodynamic data of these two binding processes were studied. The Gibbs free energy value (Delta(approximately)G degrees) of the displacement equilibrium was negative demonstrating that beta-estradiol displaced progesterone of its HSA binding cavity. Moreover, the effect of two chloride modifiers (i.e. Na(+), Mg(2+)) on these two binding processes were analysed. Results showed that in the salt biological concentration ranges, the Mg(2+) cation enhanced strongly the bioavailable progesterone, whereas the Na(+) cation interacted slowly on the progesterone displacement of its HSA binding site by beta-estradiol. This study showed that it must be useful to carry out more in vivo test on the magnesium supplementation effect for women who suffer from estrogen dominance syndrome.

Role of the magnesium cation on antihypertensive molecule-human serum albumin binding: affinity chromatography approach.

The role of the Mg2+ cation on antihypertensive molecule binding on human serum albumin (HSA) was studied by affinity chromatography. The thermodynamic data corresponding to this binding were determined for a wide range of Mg2+ concentrations (c). For the nifedipine molecule, an increase in the Mg2+ concentration produced a decrease in binding due to a decrease in the electrostatic interactions. For verapamil and diltiazem, which have the highest solvent accessible surface area, the solute binding on HSA was divided into two Mg2+ concentration regions. For a low c value below c(c) (approximately 1.6 mmol/l), the binding dependence with c was similar to that of nifedipine. For c above c(c) the hydrophobic effect created in the bulk solvent associated with a decrease in the van der Waals interactions between the solute molecule and the HSA implied a decrease in its binding. These results showed that for patients with hypertension, an Mg2+ supplementation during treatment with these antihypertensive molecules can increase the active pharmacological molecule concentration.

Imidazo[2,1-b]thiazole derivatives. XI: Modulation of the CD2-receptor of human T trypsinized lymphocytes by several imidazo[2,1-b]thiazoles

Abstract About 40 substituted imidazo[2,1-b]thiazoles were obtained in order to study their in vitro immunological effect on the modulation of the expression of human T trypsinized lymphocytes by the CD2 receptor. A synthetic program was developed to introduce either an oxygenated function, such as ester (11, 14), acid (12) and arylketonic groups (9, 13, 15), or two groups, such as an aryl and an ester (1, 6, 8), an acid (3, 7) or a hydrazide (2). These compounds were examined by an E-rosette-forming-cell test, and display a positive drug efficacity index, suggesting a regeneration effect on the expression of CD2 receptors. The following structural parameters are favourable: an aryl moiety on the C-6 with a methoxy or nitro group; and an ethyl ester on the C-3, a double bond to the 2,3-position (the 5,6-position is ineffective). Acid and hydrazide functions or the loss of phenyl group on the C-6 decrease this activity. If the aryl group is on the C-3 or C-2 side chain, the activity is weaker and more so for the latter. However, the most interesting derivatives are less immunostimulating than levamisole hydrochloride.

Reanalysis of the testosterone displacement from its HSA binding site by DHEA using competitive Langmuir isotherm

In a previous manuscript [C. Andre, A. Berthelot, J.F. Robert, M. Thomassin, Y.C. Guillaume, J. Pharm. Bio. Med., in press], the Mg(2+) effect on the testosterone displacement equilibrium from its human serum albumin (HSA) binding site by DHEA was investigated using a thermodynamic approach. In this paper, a novel concept based on the competitive Langmuir distribution isotherms was proposed to calculate the association constant of the HSA-hormone binding and to confirm the Mg(2+) role on the testosterone displacement equilibrium from its HSA binding site by DHEA. Thus, both the HSA-hormone binding and the displacement equilibrium processes were reanalysed. The results obtained confirmed that:

Etudes infrarouge et NMR d'aryl-2 dihydro-1,2 (4H) thiéno[2,3-c]benzo[e]pyrannones-4

Abstract The spectroscopic properties (i.r., NMR) of 2-aryl-1,2-dihydro (4H) thieno[2,3-c]benzo[e]pyrane-4-ones have been studied. Chemical shifts and coupling constants of dihydrothienylic protons are affected by substitutions on the aryl ring and on homocycle 2′, 8 and 9 positions to give a conformational approach of these new compounds. The crystal structure of 2-phenyl dihydrothienocoumarine agrees the results of the spectroscopic study.

Dérivés de l'imidazo(2,1-b)thiazole—VI. Etudes i.r. et PMR (ASIS, LIS et NOE) du phénacylidène-3 tétrahydro-2,3,5,6 imidazo(2,1-b)thiazole

Resume The 3-phenacyl 5,6-dihydroimidazo(2,1-b)thiazole hydrobromide 3 gives the 3-phenacylidene 2,3,5,6-tetrahydroimidazo(2,1-b)thiazole 4 under action of bases with allylic transposition. The structure of 4 is determined by i.r. and PMR study (ASIS, LIS and NOE). The transoide configuration and s cis conformation explain the retro allylic transposition with formation of 3 by acidification. Both these compounds show interesting fungicidal properties.

An efficient two-step synthesis of 4-methyl-1,2,3,5,6,10b-hexahydropyrimido〔5,4-c〕quinoline-2,5-diones via biginelli reaction

An efficient two-step synthesis of 4-methyl-l,2,3,5,6,10b-hexahydropyrimido[5,4-c]quinoline-2,5-diones is presented. It consists of the reactions of appropriate aldehyde, urea and ethyl acetoacetate according to Biginelli reaction, followed by cyclisation with ammonia.

Etude i.r. et NMR de diaryl-2,4 diéthoxycarbonyl-5,5Δ1 pyrrolines

Abstract The spectroscopic properties (i.r., NMR) of 2,4-diaryl-5,5 diethoxycarbonyl Δ 1 pyrrolines has been studied. Chemical shifts and coupling constants of pyrrolinic protons are affected by effect of substitution on phenyl rings. In all cases, we have noted the conservation of magnetic non-equivalence of ethyl ester and methylene groups. Examination of these NMR data gives conformational approach of these pyrrolines.