Novel method to control release of lipophilic drugs with high potency from silicone

Silicone has been utilized as a carrier material for sustained release system of lipophilic drugs. Extensive studies revealed that drug release rate is influenced by factors such as physicochemical properties of the drug and additives.(1-5)) When a lipophilic drug is highly potent at low concentrations, the drug release rate should be strictly controlled so as to avoid side effects. In this study, using vitamin D(3) (VD(3)) as an example of such drugs, we investigated novel method to suppress initial burst and to modify drug release rate from silicone matrix. As a result, it was found that (a). addition of human serum albumin (HSA) suppressed initial burst and enhanced release rate in the later stage, resulting constant release of VD(3), (b). covering a matrix formulation with a membrane of low diffusivity (core-rod formulation) suppressed initial burst and released drug in a constant rate, and (3) using materials for which the drug has high affinity as dissolution solvent (reservoir formulation), the drug release rate was reduced.     

An improvement in the bending ability of a hinged trisaccharide with the assistance of a sugar-sugar interaction

Hinged di- and trisaccharides incorporating 2,4-diamino-beta-D-xylopyranoside as a hinge unit (Hin) were synthesized. Bridging of the diamino group of Hin by carbonylation or chelation to a metal ion results in a conformational change from (4)C1 to (1)C4, which in turn causes a bending of the oligosaccharides. In this study, the bending abilities of the hinged oligosaccharides were compared, in terms of the reactivities toward carbonylation and chelation. Di- or trisaccharides containing a 6-O-glycosylated mannopyranoside or galactopyranoside at their reducing ends had bending abilities similar to that of the Hin monosaccharide, probably because there were neither attractive nor repulsive interactions between the reducing and nonreducing ends. However, when Hin was attached at O2 of methyl mannopyranoside (Man alphaMe), the bending ability was dependent on the nonreducing sugar and the reaction conditions. Typically, a disaccharide--Hin beta(1,2)Man alphaMe--was difficult to bend under all the tested reaction conditions, and the bent population in the presence of Zn(II) was only 4%. On the other hand, a trisaccharide--Man alpha(1,3)Hin beta(1,2)Man alphaMe--was bent immediately after the addition of Zn(II) or Hg(II), and the bent population reached 75%, much larger than those of all the other hinged trisaccharides ever tested (<40%). This excellent bending ability suggests an attractive interaction between the reducing and nonreducing ends. The extended conformation was recovered by the addition of triethylenetetramine, a metal ion chelator. Reversible, quick, and efficient bending of the hinged trisaccharide was thus achieved.     

Folding of Synthetic Homogeneous Glycoproteins in the Presence of a Glycoprotein Folding Sensor Enzyme

UDP‐glucose:glycoprotein glucosyltransferase (UGGT) plays a key role in recognizing folded and misfolded glycoproteins in the glycoprotein quality control system of the endoplasmic reticulum. UGGT detects misfolded glycoproteins and re‐glucosylates them as a tag for misfolded glycoproteins. A flexible model to reproduce in vitro folding of a glycoprotein in the presence of UGGT in a mixture containing correctly folded, folding intermediates, and misfolded glycoproteins is described. The data demonstrates that UGGT can re‐glucosylate all intermediates in the in vitro folding experiments, thus indicating that UGGT inspects not only final folded products, but also the glycoprotein folding intermediates.     

(Quasi‐)Racemic X‐ray Structures of Glycosylated and Non‐Glycosylated Forms of the Chemokine Ser‐CCL1 Prepared by Total Chemical Synthesis

Our goal was to obtain the X‐ray crystal structure of the glycosylated chemokine Ser‐CCL1. Glycoproteins can be hard to crystallize because of the heterogeneity of the oligosaccharide (glycan) moiety. We used glycosylated Ser‐CCL1 that had been prepared by total chemical synthesis as a homogeneous compound containing an N‐linked asialo biantennary nonasaccharide glycan moiety of defined covalent structure. Facile crystal formation occurred from a quasi‐racemic mixture consisting of glycosylated L ‐protein and non‐glycosylated‐D ‐protein, while no crystals were obtained from the glycosylated L ‐protein alone. The structure was solved at a resolution of 2.6–2.1 Å. However, the glycan moiety was disordered: only the N‐linked GlcNAc sugar was well‐defined in the electron density map. A racemic mixture of the protein enantiomers L ‐Ser‐CCL1 and D ‐Ser‐CCL1 was also crystallized, and the structure of the true racemate was solved at a resolution of 2.7–2.15 Å. Superimposition of the structures of the protein moieties of L ‐Ser‐CCL1 and glycosylated‐L ‐Ser‐CCL1 revealed there was no significant alteration of the protein structure by N‐glycosylation.     

Macroporous Morphology of the Titania Films Prepared by a Sol-Gel Dip-Coating Method from the System Containing Poly(Ethylene Glycol). III. Effect of Chemical Additives

The variation of macroporous morphology has been studied for the titania (TIO₂) films prepared by a sol-gel dip-coating method from the system containing poly(ethylene glycol) (PEG) under the addition of various types of organic solvents. The influence of externally-added solvent is interpreted by considering the compatibility between PEG and the solvent mixture, the volatility of the solvent mixture, and the polycondensation rate of titania oligomers. The macroscopic domain formation is remarkable when the compatibility between the solvent mixture and PEG is relatively poor and the boiling point of external solvent is relatively low.     

Multiple elliptic hypergeometric series. An approach from the Cauchy determinant

A multiple generalization of elliptic hypergeometric series is studied through the Cauchy determinant for the Weierstrass sigma function. In particular, a duality transformation for multiple hypergeometric series is proposed. As an application, two types of Bailey transformations for very well-poised multiple elliptic hypergeometric series are derived.     

Synthesis of Methyl 6′-Deoxy- and 6′-Thiolactosaminides and Their Inhibitory Activity Toward CMP-NeuNAc:D-galactoside-(2→6)-α-D-sialyltransferase

Abstract

Specific inhibitors of glycosyltransferases have become of interest1 not only for investigation of carbohydrate-participating cell-surface phenomena but also for practical use such as chemotherapeutic reagents. Glycosyltransferases catalyze the transfer of glycosyl moieties from nucleotide donors to oligosaccharide acceptors. Therefore, two kinds of substrate-analog inhibitors are possible. The donor analogs have been rather well studied, but are not specific. On the other hand, glycosyltransferases have in general smct acceptor specifkity. Recently, acceptor analogs which inhibit the corresponding glycosyltransferases were reported^2-5 and as expected were acceptor-specific inhibitors.