Alain Xicluna

Substituted benzopyranobenzothiazinones. Synthesis and estrogenic activity on MCF-7 breast carcinoma cells

In the search for new agents with estrogenic activity mediated by estrogen receptors (ER), six 6,12-dihydro-1-benzopyrano[3,4-b][1,4]benzothiazin-6-ones 3a-f were synthesized. These compounds were readily prepared by the addition of 2-aminothiophenol 2 to substituted 4-hydroxycoumarin derivatives 1a-e. The estrogenic effect has been evaluated on the proliferation of MCF-7 breast adenocarcinoma cells and the specificity of described compounds was evaluated by the inhibition of their effect by ICI 182,780, an antiestrogenic compound. Among the compounds tested, 6,12-dihydro-3-methoxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one 3e and 6,12-dihydro-3-hydroxy-1-benzopyrano[3,4-b][1,4]benzothiazin-6-one 3f exhibited an ER-dependent proliferation and a high binding affinity to ER, but a moderate capacity to activate the transcription of a reporter gene. Their pharmacological profiles are defined by their binding properties and their mechanism of action by computational modelling studies.

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:

Triazine-human serum albumin association: thermodynamic approach and sodium effect.

Human serum albumin (HSA) serves as a carrier protein to transport triazine herbicides to molecular targets. In this paper, a theoretical treatment was developed to describe the HSA-triazine herbicides association. A determination of the association constant, K, as well as the degree of complexation n(c) (the percent of complex guest) was carried out. Enthalpy-entropy compensation was also analyzed in relation to this mathematical model to confirm the herbicide complexation behavior with HSA. The role of the sodium cation (Na(+)) on this association was investigated. It was expected that the sodium ion would act on the herbicide-HSA association process by modifying the surface tension of the bulk solvent and increase the K and n(c) values. The results showed that for patients who suffer from Na(+) desequilibrium, the triazine-HSA binding would change and as well the toxicological effect of these herbicides.

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.

Viscosity‐Temperature Dependence on DNA Stretching: Slalom Chromatography Study

Abstract Slalom chromatography (SC) is a chromatographic procedure for the separation of polymers, which is based on a non equilibrium principle. A novel equation was recently developed to model the retention variation of linear double stranded DNA molecules with the mobile phase velocity under SC. This paper analyzes the effect of mobile phase viscosity and temperature on the constants of this equation and confirms that these two factors play a great role on the DNA fragment stretching.

Recherche de 99mTcO4- et de 99mTcO2- dans les solutions injectables de 99mTc-HMDP par HPTLC en phase inverse.

Resume La scintigraphie osseuse permet, grâce a l’administration intraveineuse d’un marqueur osseux complexe au technetium 99 metastable ( 99m Tc), le diagnostic de nombreuses pathologies associees a l’os. L’instabilite au contact de l’air de ces solutions injectables peut conduire a un melange de pertechnetate VII ( 99m TcO 4 – ) et de technetium IV ( 99m TcO 2 –, xH 2 O), sachant que seul le technetium IV complexe au marqueur fixe l’os. Un controle qualitatif de la purete de ces solutions s’avere par consequent important avant administration. Nous rapportons a travers cette etude la mise au point d’un nouveau test chromatographique base sur la chromatographie sur couche mince haute performance (HPTLC) en phase inverse. Ce test, simple, rapide et reproductible permet de detecter sans ambiguite la presence eventuelle de 99m TcO 4 – (VII) et de 99m TcO 2 – (IV), xH 2 O dans les solution injectables d’hydroxymethylene diphosphonate (HMDP) pretes a l’emploi.Bone scintigraphy allows the diagnostic of many pathologies related to bone through the intravenous administration of a phosphonate bone marker complexed to 99 metastable technetium (99mTc). The instability of these injectable solutions on contact with air can lead to a mixture of pertechnetate VII (99mTcO4-) and technetium IV (99mTcO2-, xH2O), technetium IV being the only derivative to fix bone. A qualitative control of the purity of these solutions proved to be consequently important before administration. We report here the perfecting of a new chromatographic test based on reverse phase high performance thin layer chromatography (HPTLC). This test, simple, rapid and reproductive allows without ambiguity the detection of 99mTcO4-(VII) and 99mTcO2-(IV), xH2O in hydroxymethylene diphosphonate (HMDP) injectable solutions ready to use.

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.