Shimona Geresh

Ex vivo bioadhesion and in vivo testosterone bioavailability study of different bioadhesive formulations based on starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures

Starch-g-poly(acrylic acid) copolymers or grafted starches synthesized by 60Co irradiation or chemical modification and co-freeze-dried starch/poly(acrylic acid) mixtures were evaluated on their ex vivo bioadhesion capacity. The buccal absorption of testosterone from a bioadhesive tablet formulated with the grafted starches or starch/poly(acrylic acid) mixtures was investigated. The results were compared to a reference formulation (physical mixture of 5% Carbopol 974P and 95% Drum Dried Waxy Maize). Rice starch-based irradiated grafted starches showed the best bioadhesion results. Partial neutralization of the acrylic acid with Ca(2+) ions resulted in significantly higher bioadhesion values compared to the reference. Ca(2+) and Mg(2+) partially neutralized maltodextrin-based irradiated grafted starches showed significantly higher bioadhesion values compared to the reference formulation. The chemically modified grafted starches showed significantly higher adhesion force values than for the reference tablet. None of the co-freeze-dried starch/poly(acrylic acid) mixtures showed significantly higher bioadhesion results than the reference (Bonferroni test, P<0.05). A chemically modified grafted starch could sustain the 3 ng/ml plasma testosterone target concentration during +/- 8 h (T(>3 ng/ml)). By lyophilization of a partially neutralized irradiated grafted starch, the in vivo adhesion time (22.0 +/- 7.2 h) and the T(>3 ng/ml) (13.5 +/- 1.3 h) could be increased. The absolute bioavailability of the lyophilized formulation approached the reference formulation. Some of the grafted starches showed to be promising buccal bioadhesive drug carriers for systemic delivery.

Structural requirements in chiral diphosphine-rhodium complexes: III. Small scale method for fresh preparation of cationic diop-rhodium complexes and comparison with neutral diop-rhodium complexes

Abstract (—)-2,3-Isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane (DIOP) was used in cationic rhodium(I)-diphosphine complexes, freshly prepared on a milligram scale, to catalyze the asymmetric hydrogenation of ( Z )-α-acetamidocinnamic acid. These cationic complexes were found not to be air stable over a period of time, but when utilized after storage under argon reproducible kinetic results were noted, and the optical purity of the reduction product was found to be independent of the age of the cationic complex. The cationic rhodium(I)DIOP complex was found to be a more reactive complex than the corresponding neutral chlororhodium(I)-DIOP complex when used in asymmetric hydrogenations, but both gave the same optical yield.

The role of the solvent in the asymmetric hydrogenation of β-keto esters with Ru-BINAP

The influence of the solvent on the asymmetric hydrogenation of methyl acetoacetate, as a representative β-keto esters, with Ru-BINAP was studied. The highest activities were measured when the reaction proceeded in methanol, ethanol or isopropanol. These solvents, which also act as proton donors, accelerate product release from the reaction intermediate. The presence of water in the reaction mixture has been found to be detrimental for both activity and enantioselectivity. All results could be explained by the existence of two different solvent dependent reaction pathways for product release.

Trypsin inhibition, calcium and zinc ion binding of starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures for peroral peptide drug delivery.

Newly synthesised starch-g-poly(acrylic acid) copolymers and starch/poly(acrylic acid) mixtures were evaluated for their in vitro inhibition potency towards the proteolytic enzyme trypsin. Their Ca2+ and Zn2+ binding capacity was measured. Carbopol 934P was used as reference polymer. Starch-g-poly(acrylic acid) copolymers were prepared by chemical grafting and 60Co irradiation, the starch/poly(acrylic acid) mixtures by freeze-drying. The influence of preparation method, the ratio starch:acrylic acid, the neutralisation degree and for the freeze-dried polymers the influence of heat treatment after freeze-drying was investigated. All freeze-dried polymers showed a higher inhibition factor (IF) than the chemically grafted and 60Co irradiated starches, which all showed significantly lower IF than Carbopol 934P. The heat treated freeze-dried polymer Amioca/poly(acrylic acid) (1:1) showed a significantly higher IF than the reference polymer (Mann-Whitney test, p<0.05). The Ca2+ and Zn2+ binding capacity of all chemically grafted starches was much lower than for Carbopol 934P. Only the 60Co irradiated starches and freeze-dried polymers with ratio 1:3 approached the binding capacity of the reference polymer. The freeze-dried polymers showed the highest proteolytic enzyme inhibition potency. Freeze-drying and 60Co irradiation could result in the highest ion binding capacity. This combination of proteolytic enzyme inhibition activity and ion binding capacity makes these polymers hopeful excipients for successful oral peptide delivery.

Isolation and characterization of poly- and oligosaccharides from the red microalga Porphyridium sp.

The current study forms part of an ongoing research effort focusing on the elucidation of the chemical structure of the sulfated extracellular polysaccharide of the red microalga Porphyridium sp. (UTEX 637). We report here on the chemical structure of a fraction separated from an acidic crude extract of the polysaccharide, as investigated by methylation analysis, carboxyl reduction-methylation analysis, desulfation-methylation analysis, partial acid hydrolysis, Smith degradation, together with 1D and 2D (1)H and (13)C NMR spectroscopy. This fraction with a molar mass of 2.39x10(5)g mol(-1) comprised D- and L-Gal, D-Glc, D-Xyl, D-GlcA, and sulfate groups in a molar ratio of 1.0:1.1:2.1:0.2:0.7. The almost linear backbone of the fraction is composed of (1-->2)- or (1-->4)-linked d-xylopyranosyl, (1-->3)-linked L-galactopyranosyl, (1-->3)-linked D-glucopyranosyl, and (1-->3)-linked D-glucopyranosyluronic acid and comprises a possible acidic building unit: [(2 or 4)-beta-D-Xylp-(L-->3)]m-alpha-D-Glcp-(1-->3)-alpha-D-GLCPA-(1-->3)-L-Galp(l-->. Attached to the backbone are sulfate groups and nonreducing terminal D-xylopyranosyl and galactopyranosyl residues, which occur at the O-6 positions of Glc-derived moieties in the main chain.

On the mechanism of intramolecular photocycloaddition of substituted o-allylphenols to cyclic ethers

Abstract Osmometric and NMR techniques were used in order to study the ionic mechanism for the intramolecular photocycloaddition reaction of o -allyl phenols ( 1 ) to give cyclic ethers ( 2 ) + ( 3 ). The role of the intramolecular H-bond between the OH group and the π-electrons of the allylic group was ascertained. based on the results of the photocyclization, osmometric and NMR measurements the substituents can be divided into 3 groups according to their effect on the above intramolecular interaction.

Fractionation and partial characterization of the sulphated polysaccharide of Porphyridium

Abstract The carbohydrate composition of the extracellular sulphated polysaccharide obtained from cultures of the unicellular red alga Porphyridium was determined. The polysaccharide was separated by anion-exchange chromatography into eight fractions. The major carbohydrate-containing fractions, accounting for ca 89% of the total carbohydrates, were the 0.5, 1.0 and 2.0 M NaCl fractions and the hot urea fraction. The NaCl-eluted fractions showed very similar neutral sugar compositions, with some differences in the contents of sulphate and uronic acid, which increased from the 0.5 M to the 2 M NaCl fraction. The hot urea fraction was apparently a xylan (about 86% xylose) and accounted for about 72% of the protein found in the whole polysaccharide. These findings indicate the presence of at least two different polysaccharides, one of which seems to be a proteoglycan. Amino acid analysis of the latter fraction was performed.

STRUCTURAL REQUIREMENTS IN CHIRAL DIPHOSPHINE-RHODIUM COMPLEXES. XI. ASYMMETRIC HOMOGENEOUS HYDROGENATION OF Z-α-ACYLAMINOCINNAMIC ACIDS AND ESTERS WITH (1S,2S)-TRANS-1,2-BIS(DIPHENYLPHOSPHINOMETHYL)CYCLOHEXANE/RHODIUM(I) COMPLEXES

Z-α-acylaminocinnamate esters were hydrogenated with neutral rhodium(I) complexes containing (1S, 2S)-trans-1,2-bis(diphenylphosphinomethyl)cyclohexane. Increasing the steric bulk of the alcohol moiety of the ester function results in increased enantioface differentiation in favor of the re-si prochiral face to yield an excess of the S-amino acid derivatives. In the series of N-acetylphenylalanine ester products (resulting from hydrogenation of Z-α-acetamidocinnamate esters) the optical purity increased from 1% ee-(R) [Me]; 20% ee-(S) [Et]; 47% ee-(S) [i-Pr]; to 58% ee-(S) [t-Bu]. Increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) favors the reduction of the si-re prochiral face [in the methyl ester substrates] to yield an excess of the R-amino acid derivatives. In the series of N-acylphenylalanine methyl ester products (resulting from hydrogenation of Z-methyl α-acylaminocinnamates) the optical purity increased from 1% ee-(R) [Me]; 13% ee-(R) [i-Pr]; to 15% ee-(R) [t-Bu and 1-adamantyl]. The α-formamido and α-benzamido substrates gave hydrogenation products having 22% ee-(R) [H] and 35% ee-(R) [Ph]. In the corresponding free acids, increasing the steric bulk of the acyl function (NHCOR, where R is an alkyl moiety) results in almost no change in the optical purity of the reduction products. In the series of N-acylphenyl-alanine products (resulting from hydrogenation of Z-α-acylaminocinnamic acids) the optical purity was 35% ee-(S) [Me]; 31% ee-(S) [i-Pr]; 33% ee-(S) [t-Bu]; and 35% ee-(S) [1-adamantyl]. The α-benzamido substrate gave a hydrogenation product having 8% ee-(S).

Biodegradation of the sulphated polysaccharide of Porphyridium by soil bacteria

Abstract In the absence of carbohydrolases capable of degrading the complex cell wall polysacchadde of red microalgae, its structure and composition have so far been studied solely by means of conventional chemical methods. Recently, a mixture of soil bacteria was isolated that can grow on and specifically degrade the polysaccharide of Porphyridium sp. In the present work this enzymatic activity was used for further study of this cell wall polysaccharide. Upon charge separation, the native and degraded polysaccharides showed similar patterns, except with regard to protein distribution. In the polysaccharide degraded with bacterial enzymes, protein appeared in the fraction eluted with water, whereas in the native polysaccharide it appeared in the fraction cluted with urea. By size separation of the polysaccharide degraded with bacterial enzymes, a single peak of 5–6 × 10 6 daltons was obtained as compared with a 7 × 10 6 daltons peak in the native polysaccharide. Although the main product of enzymatic bacterial activity had a relatively high molecular mass, its viscosity was very low compared with that of the native polysaccharide. The results indicate that the bacterial enzymes degraded the polysaccharide by cleaving proteins from the polysaccharide.

Intermediates in asymmetric hydrogenation : The structure and 31P NMR spectra of rhodium enamide complexes containing 1R, 2R-trans-1,2-bis (diphenylphosphinomethyl) cyclo buta

Abstract Hydrogenation of bicyclo[2.2.1]heptadiene-1R,2R-( trans -1,2- bis (diphenylphosphinomethyl)cyclbutane rhodium ( I ) tetrafluoroborate in methanol gives a solvent adduct which reacts with N-acyldehydroamino acids and their esters to give air-unstable scarlet to yellow complexes. Effects of structure variation in the enamide on the 31 P NMR spectra of these species are reported and discussed with reference to (a) the equilibrium between methanol and enamide complexes; (b) the ratio of diastereomeric enamide complexes formed; (c) the temperature dependence of this ratio; (d) the rate of complexation equilibria and (e) the structure of enamide complexes, which are normally bidentate with binding via the olefin and amide groups. In certain cases the complex may be terdentate and E -enamides bind through the olefin and carboxyl groups. Each mode of binding gives rise to characteristic 31 P NMR spectra with regard to P-P and P-Rh coupling constants.