Gilbert Schlewer

Allergic contact dermatitis due to sesquiterpene lactones

Several compounds containing the α‐methylene‐γ‐butyrolactone moiety have been tested on human volunteers and on guinea‐pigs; the animals were experimentally sensitized by alantolactone, iso‐alantolactone and laurel oil. Of the two new lactones, spirolactone was the more reactive: this was confirmed by both animal and human testing. The synthetic lactones are less reactive than natural ones. α‐Methylene‐γ‐butyrolactone itself does not elicit cross‐reactions in guinea‐pigs sensitive either to alantolactone or to isoalantolactone, or in patients sensitive to sesquiterpene lactones. The α‐methylene‐γ‐butyrolactone group is necessary for cross‐reaction, but to be active, it has first to be substituted. It was also found that isoalantolactone, allegedly not allergenic, is in fact a sensitizer and cross‐reacts with alantolactone. The cross‐reaction between laurel and Frullania, found in man, also occurs in guinea‐pigs. It is more evident when sesquiterpene lactone is the sensitizer and laurel used to elicit reaction.

Ionization state of myo-inositol 1,4,5-trisphosphate: correlation with binding properties

The comparison between the ionization state and the binding properties on brain membrane receptors of the synthetized myo-inositol 1,4,5-trisphosphate lead to the conclusion that the biological active species may be either the monoprotonated or the fully deprotonated trisphosphate.

Complexation studies on inositol-phosphates. V. Cu2+, Zn2+, Fe2+ and Fe3+ complexes of some myo-inositol triphosphates

Potentiometry and 31P NMR spectroscopy have been used to study the protonation and complexation properties of some myo-inositol triphosphates (Ins(1,2,6)P3, Ins(1,3,5)P3, and Ins(2,4,6)P3) with Cu2+, Zn2+, Fe2+, and Fe3+. The study was performed for all the ligands at 25°C in a 0.1 M tetrabutylammonium bromide solution (medium 1) and in addition, for Ins(1,2,6)P3, at 37°C in a 0.2 M KCl medium (medium 2). The position of the phosphate groups around the inositol ring largely influences the basicity of the ligand. Log β011 has the highest value for Ins(1,2,6)P3 which displays three vicinal phosphates. When no interfering cations such as K+ are present, M2HL, M2L, MHL, ML, and MOHL complexes were found for most of the systems. Although the stability of the complexes follows the Irving-Williams rule, i.e., Cu(II) > Zn(II) > Fe(II), no real selectivity of complexation is observed. A 31P NMR titration was performed for the Zn2+-H+-Ins(1,2,6)P3 system. The resulting titration curves, compared with those obtained in the absence of metal showed two opposite effects: i) a downfield shift due to the competition of the metal with the proton, ii) an upfield shift corresponding to the binding of Zn2+. From these curves it can, in addition, be concluded that the cation in the mononuclear species is mainly coordinated to P1 and P2 whereas the second cation of the homodinuclear complex is stabilized by P6.

Total syntheses of chiral sn-myo-inositol-1,4,5-trisphosphate1 and its enantiomer

Abstract sn-myo-Inositol-1,4,5-trisphophate (Ins(1,4,5)P3) and its enantiomers are prepared by synthesis of suitably protected myo-inositols, separation of enantiomers via the formation of D-mannose diastereomeric derivatives and selective phosphorylations.

Allergic contact dermatitis to α-methylene-γ-butyrolactones: Preparation of alantolactone-protein conjugates and induction of contact sensitivity in the guinea pig by an alantolactone-skin protein conjugate

Abstract Sesquiterpene lactones have been implicated as causative agents of allergic contact dermatitis to plants of the Compositae family. It has been postulated that these compounds undergo nucleophilic addition through their α-methylene-γ-butyrolactone conjugated system and that this mechanism accounts for their covalent attachment to carrier molecule(s). The present report presents evidence of covalent bond formation between alantolactone, a typical sesquiterpene lactone, and model proteins. Evidence of alantolactone-ribonuclease A adduct formation has been obtained from release of alantolactone under thermal treatment of the adduct in a gas Chromatograph and in a mass spectrometer and from comparative fingerprint analysis. We also report that alantolactone rapidly inhibits the enzymic activity of aspartate β-semialdehyde dehydrogenase, by reaction with a cysteinyl residue of the enzyme. An adduct of alantolactone-guinea pig skin proteins induces, in guinea pigs, a state of delayed hypersensitivity to alantolactone and cross-reaction to other natural or synthetic α-methylene-γ-butyrolactones, as assessed by epicutaneous tests to the haptens.

Complexation studies on inositol-phosphates. II. Alkali-metal complexes of D-myo-inositol 1,2,6 trisphosphate

The complexation properties of the D-myo-inositol 1,2,6 trisphosphate (Ins(1,2,6)P3) towards Li+, Na+, K+, Rb+, and Cs+ cations were studied at 25 degrees C in a 0.1 M tetra-n-butylammonium bromide medium. For all cations, mononuclear and protonated species were found. For smaller cations (Li+, Na+, and K+) a dinuclear complex was also put into evidence. The main characteristic of the complexes is its high stability; and of the ligand, its nonselectivity. The Ins(1,2,6)P3-K system was ascertained using Sammartanos method which additionally enabled the influence of various K+ concentrations on the protonations constants to be considered.

Complexation studies on inositol-phosphates, VI. Al3+ complexes of DL-myo-inositol 1,4,5-triphosphate and D-myo-inositol 1,2,6-triphosphate

Abstract Aluminum complexes of D- myo -inositol 1,2,6-triphosphate (Ins(1,2,6)P 3 ) and DL- myo -inositol 1,4,5-triphosphate (Ins(1,4,5)P 3 ) have been studied by potentiometry at 25°C in a 0.1 M tetrabutylammonium bromide medium. Both ligands form AlHL, AlL, and AlOHL species whereas Ins(1,2,6)P 3 forms, in addition, an Al 2 L complex and Ins(1,4,5)P 3 an Al(OH) 2 L species. In an attempt to assess the biological significance of the Al 3+ binding to Ins(1,4,5)P 3 , the results were compared to the Al 3+ -ATP complexes that have been found in similar medium conditions. Taking into account the relative stability of the complexes of both systems, it appears likely that the intracellular second messenger system involving Ins(1,4,5)P 3 may be disturbed by the presence of the aluminum cation.

COMPLEXATION OF SPERMINE AND SPERMIDINE BY MYO-INOSITOL 1,4,5-TRIS(PHOSPHATE) AND RELATED COMPOUNDS : BIOLOGICAL SIGNIFICANCE

D myo-inositol 1,4,5-tris(phosphate) (Ins(1,4,5)P3) displays a multicoordination site arrangement that allows strong interactions with polycationic species such as the naturally occurring polyamines spermine and spermidine. In the present work, the complexation of these polyamines by Ins(1,4,5)P3 and related compounds was quantitatively investigated. The study was performed in a 0.1 M tetramethylammonium p-toluenesulfonate (Me4NOTs) solution at 25 degrees C. For purpose of comparison, the complexation of the polyamine-ATP systems were also considered in the same experimental conditions. 31P-NMR experiments showed for Ins(1,4,5)P3 and its analogues, the formation of complexes of a 1:1 stoichiometry. As expected, the most stable complexes are formed between the most charged partners. In addition, the basicity of the phosphate groups seems to govern the stability of the complexes. If both ATP and Ins(1,4,5)P3 are present at the same concentration, the latter interacts preferably with the polyamines. Ins(1,4,5)P3-spermine complex formation provides a possible simple explanation for the inhibition by spermine of Ins(1,4,5)P3-induced Ca2+ release. Spermine will undoubtedly compete with metallic cations such as Ca2+ in the intracellular medium and consequently, may play a regulatory role in the signal transduction mediated by Ins(1,4,5)P3.

Complexation studies on inositol-phosphates: IV. Ca(II) complexes of myo-inositol 1,4,5-trisphosphate

The stability constants of the complexes formed between Ca2+ and the myo-inositol 1,4,5-triphosphate (Ins(1,4,5)P3) were determined by potentiometric titration in two different media and temperature conditions (medium 1: I = 0.1 M But4NBr, 25 degrees C; medium 2: I = 0.2 M KCl, 37 degrees C). Mainly because of the presence of potassium the results obtained in these media show large differences in both the nature and the stability of the complexes. In medium 1, MH2L and M2L species are formed along with the ML and MHL species which also exist in medium 2. In addition, the stability of the latter species decreases by more than one log unit in going from medium 1 to medium 2. In an attempt to assess the biological significance of the metal binding to Ins(1,4,5)P3, the results were compared to the Ca2+-ATP complexes that form in the same media conditions. Taking into account the relative stability of the complexes of both systems, it is likely that the action or metabolism of Ins(1,4,5)P3 may be influenced by coordination of either alkali or alkali-earth cations.

Synthesis of arylalkylmonofluorophosphonates as myo-inositol monophosphatase ligands

Abstract Arylalkylmonofluorophosphonates were prepared by condensation of arylalkylaldehydes with the lithium salt of diethyl 1-fluoro-1-(trimethylsilyl)-methylphosphonate. Reduction and hydrolysis sequences gave the final products. These compounds do not inhibit the myo -inositol monophosphatase.