2-Benzodioxinylaminoethanols: a new class of beta-adrenergic blocking and antihypertensive agents.

Various 2-benzodioxinylaminoethanol derivatives were synthetized and investigated for beta-adrenergic blocking activity. Most compounds demonstrated a beta-blocking activity of a competitive type when evaluated in guinea pig atrial and tracheal preparations. Three compounds were more potent than practolol and propranolol. All compounds demonstrated antihypertensive properties in spontaneously hypertensive rats. The most active compound was 1-(1,4-benzodioxin-2-yl)-2-[N4-(2-methoxyphenyl)piperazino]ethanol (11), which at 2.5 mg/kg iv lowered blood pressure by 41%.

Implication of cell wall constituents in the sensitivity of Kluyveromyces lactis strains to amphotericin B.

In Kluyveromyces lactis, the cell wall compositions of Kl (ATCC 96897), a wild sensitive strain, and Klm (ATCC 96896), a strain resistant to amphotericin B (AmB), were shown to be very different, since the walls in the latter were significantly enriched in hexosamine, but had a reduced content in phosphate and amino acid. In both strains, the cell walls limited their sensitivity to this antifungal agent. The absence of cell wall increased the sensitivity of the cells to this polyene by 5 to 10-fold. When the cells were treated with enzymes such as pronase and chitinase in order to change the cell wall structure just before inoculation, the yeasts appeared more resistant to the antibiotic. However, treatments with chymopapain and phospholipase C did not significantly change the sensitivity of the two strains to this agent. Cells treated with acid phosphatase displayed a longer lag phase than the control cells. In addition, when cultured in the presence of AmB, the cells were less sensitive to this agent. The present results reveal that both a change in the ionic charges of the cell wall and an alteration in the cell wall structure modified the sensitivity of these yeast strains to AmB.

Molecular pharmacophore determination of lipid lowering drugs with the receptor mapping method.

Hypolipidemic pharmacophoric moieties of statins, fibrates, ACAT inhibitors and beta-sitosterol analog series were identified by computational modeling, and compared with the computed structure of new potential glycyrrhetinic acid derivatives lipid-lowering drugs. Their electronic and geometric domains, similar to those of fibrates, suggest a fibrate -like mechanism matching biochemical data.

Monometoxytrityl derivatives of uridine as inhibitors of a human recombinant UDP-glucuronosyltransferase: UGT1*6.

A series of inhibitors of the human liver recombinant UDP-glucuronosyltransferase 1*6 derived from uridine were synthetized as probes of the binding site of the cosubstrate, UDP-glucuronic acid. If triphenylmethanol or uridine alone failed to inhibit the glucuronidation of 4-methylumbelliferone, the trityl derivatives of uridine were found to be very effective inhibitors of the enzyme (Ki 4.4 to 73 microM). The type of inhibition (competitive or mixed) varied with the substitutions on the uracile or on the triphenylmethyl moiety by halogen atoms or methyl groups. Structural features for the binding of the cofactor are postulated.

Protein and enzyme release from human leukocytes: influence of phenothiazine derivatives.

We studied the influence of chlorpromazine on the release of enzymes (beta-glucuronidase, EC 3.2.1.31; lactate dehydrogenase, EC 1.1.1.27; pyruvate kinase, 2.7.1.40) and proteins using human granulocytes isolated and maintained at 37 degrees C. Chlorpromazine had a biphasic effect on enzyme release and the inhibition of the glycolytic pathway could be demonstrated only at high concentrations of chlorpromazine, after one hour's incubation. The NAD+/NADH ratio was significantly perturbed at all the concentrations. This effect is time dependent. The action of 4 other phenothiazine derivatives made it possible to establish a relationship between their physico-chemical properties and protein release. The results are compared with those from other studies using other biological materials.

Structure of the phosphopeptidomannans from flocculent and non-flocculent yeast Kluyveromyces lactis.

After extraction from whole cells, and purification by gel filtration, the chemical composition and molecular mass estimation of the cell-wall phosphopeptidomannan (PPM) showed no significant difference respectively between flocculent, weakly, very weakly and non-flocculent Kluyveromyces lactis yeast strains. However, when PPMs were tested as ligands of a lectin, extracted from the flocculent strain, the PPM isolated from the flocculent and weakly flocculent strain were recognized to a higher degree than those isolated from the non and very weakly flocculent strains. Acetolysis of PPM extracted from the four strains produced five oligosaccharide fractions corresponding to mono-, di-, tri-, penta-and hexa-saccharides. The flocculent strain was characterised by a high content of di-and penta-saccharides. The 1H NMR analysis of the oligosaccharides demonstrated that the flocculent strain contained equivalent levels of the two mannobioses: Man(alpha 1-->2)Man and Man(alpha 1-->3)Man and of the two mannotrioses Man(alpha 1-->2)Man(alpha 1-->2)Man and Man(alpha 1-->3)Man(alpha 1-->2)Man. In contrast, the non-flocculent and the very weakly flocculent strains contained a single type of mannobiose Man(alpha 1-->2)Man and one type of mannotriose Man(alpha 1-->2)Man(alpha 1-->2)Man.

Acetolysis and 1H NMR studies on mannans isolated from very flocculent and weakly flocculent cells of Pichia pastoris IFP 206.

Growth of the yeast Pichia pastoris IFP 206 in methanol- and glucose-containing media led respectively to very and weakly flocculent cells. Mannans from both kinds of cells were extracted and compared. Chemical analysis and molecular mass estimation showed some differences between the mannans from very and weakly flocculent cells, especially in quantitative amino acid content. 1H NMR analysis showed that both kinds of mannan contained alpha-1,2 and beta-1,2 linkages. Two acetolysis conditions, combined with 1H NMR analysis, revealed that mannans from both kinds of cells were composed of mannose, mannobiose, mannotriose, mannotetraose and mannopentaose side-chains with the following respective structures: Man; Man alpha 1---2Man; Man alpha 1----2Man alpha 1----2Man; Man beta 1----2Man alpha 1----2Man; Man beta 1----2Man beta 1----2Man alpha 1----2Man; Man alpha 1----2Man beta 1----2Man beta 1----2Man alpha 1----2Man. Additionally the beta-1,2 linkages of the non-reducing terminal residues of the mannotetraose were shown to be acetolysis-labile. The mannans from very flocculent cells were richer in mannopentaose than the mannans from weakly flocculent cells. According to these results, the extended conformations in the branching moieties of the mannan could be the basis of the higher degree of flocculation of the methanol-grown cells.

Drug interference in clinical chemistry: studies on ascorbic acid.

The expert group "Drug Interference in Clinical Chemistry" of the Bureau of Reference, Directorate General for Research, Science and Education of the Commission of the European Communities, consisting of one participant of each member of the European Communities, presents this first report on the final results of its activities. Within the framework of a first stage basic program, the paper describes interferences of therapeutic and elevated doses of ascorbic acid on commonly used clinical chemical methods. This is the result of a bipartite study that was jointly planned, carried out and evaluated. Local and personal influences have been eliminated, as have variations due to methodology, measurement equipment and reagents, in order to be able to present distinct causal effects of ascorbic acid. No definite influence of ascorbic acid on analytical values for urea, cholesterol, calcium, protein, bilirubin, aspartate aminotransferase and alkaline phosphatase could be detected. At therapeutic concentrations, ascorbic acid distinctly interferes with the analysis of glucose, uric acid, creatinine and inorganic phosphate. The extent and direction of interferences vary, depending on the type of reaction, kit and apparatus. In some cases the influence of ascorbic acid results in severe disturbance of the analytical methods leading to useless values.