METHODS FOR STEREOSELECTIVE SYNTHESIS OF GLYCOPYRANOSYLAMIDE LINKAGE

Glycoproteins play an important role in biological processes including intercellular communication, cell-cell recognition, and cell growth regulation. The study of cellular processes is often limited by the availability of glycopeptides or glycoproteins from natural sources. The advances in carbohydrate and peptide chemistry in the last decade have created generally applicable methodologies for the synthesis of glycopeptides. The crucial step of any synthesis of a glycopeptide is the introduction of the carbohydrate residue to the amino acid or peptide in a stereoselective manner under conditions which are compatible with glycosidic linkages and common protecting groups for peptide synthesis. A novel synthesis of glycopyranosyl isoxazolines has been developed employing readily available 2-acetoxy-glycosyl azides and triphenylphosphine. The synthesis of the isoxazolines proceeded via epimerization of a beta-phosphorimine to the alpha-phosphorimine followed by cyclization to provide the isoxazoline. This methodology has been employed to synthesize glucopyranosyl, galactopyranosyl, and mannopyranosyl isoxazoline derivatives. The methodology has also been extended with di- and trisaccharide azides. The stereoselective synthesis of the glycosylamide linkage has been developed utilizing in situ generated glycosyl isoxazolines. Results of the coupling studies demonstrated that the optimum conditions for the synthesis of glycosylamides involved the coupling of the isoxazoline with a 2-pyridyl thioester in the presence of copper(II) chloride. The stereoselective syntheses of alpha-glucosylamide and beta-mannosylamide have been accomplished in high yields. Isoxazoline couplings were applied to the synthesis of alpha-glucosyl amino acids derivatives also; particularly noteworthy was the coupling with differentially protected aspartic acid analogs. It was shown that the coupling conditions are compatible with different protection strategies used in peptide couplings. Treatment of 2-NAc- or 2-NPhth-2-deoxyglucopyranosyl azides gave phosphorimine intermediates that failed to cyclize to imidazoline in analogy with the isoxazoline. The phosphorimines, however, coupled efficiently with thiopyridyl esters to provide the glycosyl-beta-amide linkage. The yields in these couplings were superior to the yields from the traditional Staudinger reactions utilizing carboxylic acids. Coupling of these phosphorimines with the thiopyridyl ester of asparagine derivatives has proven to be a superior method for the synthesis of N-linked glycopeptide derivatives

Starch nanoparticles for delivery of the histone deacetylase inhibitor CG-1521 in breast cancer treatment

Esma Alp,1–4 Fehmi Damkaci,2 Eylem Guven,1 Martin Tenniswood3,4 1Department of Nanotechnology and Nanomedicine, Hacettepe University, Beytepe, Ankara 06800, Turkey; 2Department of Chemistry, State University of New York at Oswego, Oswego, NY 13126, USA; 3Cancer Research Center, Rensselaer, NY 12144, USA; 4Department of Biomedical Sciences, State University of New York, University at Albany, Rensselaer, NY 12144, USA Background: The efficacy of epigenetic drugs, such as histone deacetylase inhibitors, is often diminished by poor aqueous solubility resulting in limited bioavailability and a low therapeutic index. To overcome the suboptimal therapeutic index, we have developed a biocompatible starch nanoparticle formulation of CG-1521, a histone deacetylase inhibitor in preclinical development for hard-to-treat breast cancers, which improves its bioavailability and half-life. Methods: The physicochemical parameters (size, zeta potential, morphology, loading, and release kinetics) of these nanoparticles (CG-NPs) have been optimized and their cytotoxic and apoptotic capacities measured in MCF-7 breast cancer cell line. The mechanism of action of the encapsulated drug was compared with the free drug at molecular level. Results: We show that encapsulation of CG-1521 substantially reduces the release rate of drug and provides a significantly enhanced cytotoxic ability of nanoparticles compared with equivalent dose of free CG-1521. CG-NPs induced cell cycle arrest and significant apoptosis in MCF-7 cells in vitro. The biological action of encapsulated drug has the similar impact with free drug on gene expression.Conclusion: The findings suggest that encapsulation of CG-1521 into starch nanoparticles can improve drug delivery of histone deacetylase inhibitors for breast cancer therapy without interfering with the mechanism of action of the drug. Keywords: cell cycle, apoptosis, DNA fragmentation, gene expression, epigenetics, MCF-7 &nbsp

Synthesis of 1,3,4-oxadiazole and 1,2,4-triazole-3-thione derivatives

WOS: 00043146040225