Current Organic Chemistry - Volume 10, Issue 14, 2006

The progress achieved both in the solid and liquid phase of the synthetic methodologies for peptides, permitted the application of various chemistries for preparing totally synthetic proteins and protein-like macromolecules of branched architecture. Polypeptides with molecular masses in the 10-25 kDa range have been successfully prepared using either the step by step and fragment condensation or the chemoselective ligation methods. Amide, thioether, disulfide, thioester, hydrazone, oxime and thiazolidine linkages have been employed in such syntheses. Fully active proteins or macromolecules mimicking particular protein properties especially in immunology have been synthesized in high purity and large quantities. The branched constructs have found numerous applications in immunology due to their contribution in overcoming the very low ability of short linear peptides to react specifically with antibodies or to induce an immune response. The advantages over almost all the other methods of using synthetic carriers for developing potent antigens and immunogens have placed this approach at the center of extensive research activities. This review focuses on the concept and synthetic strategies suitable for assembling proteins or protein-like macromolecules of branched architecture with application in protein function studies and immunology.

Thiooligosaccharides display inhibitory activity against glycoside hydrolases and they constitute a valuable tool for structural biology. The construction of the interglycosidic linkage, in which the oxygen atom is replaced by sulfur, usually involves one of the following reactions: i) nucleophilic displacement of good leaving groups in a carbohydrate moiety by a sugar thiol, ii) Michael and Michael-type additions of sugar thiols to unsaturated acceptors, iii) ring-opening of aziridines and oxiranes by thiosugars, iv) enzyme-catalyzed couplings of thiosugar moieties. The application of these reactions for the syntheses of thiooligosaccharides are surveyed, and the biological activities of the resulting products briefly described. Carbohydrate structures incorporating three-bond glycosidic linkages with two heteroatoms are uncommon in Nature. The -N-O- interglycosidic bond in the oligosaccharide part of enediyne antibiotics is partly responsible for their potent antitumor activities. The disulfide bond which plays an essential role in proteins has recently been introduced as an interglycosidic connecting motif. The sulfenamide functionality is the sulfur analog of the hydroxylamine type glycosidic linkages in calicheamicins. Novel glycosylation strategies have recently been developed by taking advantage of unconventional, three-bond glycosidic linkages to construct neoglycoproteins and other glycoconjugates which are increasingly important tools in glycobiology and drug discovery. To explore conformational preferences and molecular flexibility in these structures NMR spectroscopy, chiroptical methods and X-ray crystallography are being used, supplemented by molecular modelling calculations. The structural features will be briefly discussed with relevance to biological interactions such as enzyme binding.

Degenerative joint diseases (e.g. rheumatoid arthritis or osteoarthritis) represent a major cause of disability and early retirements in the industrialised countries. These diseases affect primarily the cartilage of the larger joints and destroy its macromolecular constituents. Cartilage covers the ends of the bones acting as a weight bearing, low friction, wear resistant tissue. It is known that the composition of cartilage is crucial for its function and forming the complex matrix network: This matrix consists primarily of collagen and acidic polysaccharides (the glycosaminoglycans) that form in combination with proteins the so-called proteoglycans. This review is dedicated to the molecular organization of cartilage and its components in health and disease with the emphasis on the interactions between the individual polymeric components. Therefore, some physico-chemical methods used in cartilage research will be also discussed. The focus will be on methods of nuclear magnetic resonance spectroscopy (NMR) that allow a clear differentiation and characterization of the components of cartilage. It is one aim to prove that besides classical methods of biochemistry, biophysical techniques are also useful to study cartilage structure and function. Both, basic sciences and medical applications will be considered. Finally, future prospects will be provided how modern NMR techniques may help to assess the quality of bioengineered cartilage.

The fixation of ligands onto molecules, surfaces and materials by use of reactions using a simple and unified chemistry is among the everlasting desires of chemists. Besides the general insensitivity with respect to the chemical structures of the ligand, the completeness of the reaction as well as the insensitivity from external reaction parameters (i.e.: solvents, ambient temperature) is wished. The copper(I)-catalysed azide/alkyne “click”-reaction (also termed Sharpless “click”-reaction, a variation of the Huisgen 1,3-dipolar cycloaddition reaction between terminal acetylenes and azides) is a recent re-discovery of a reaction fulfilling these requirements. Extremely high yields (usually above 95%) are combined with a high tolerance of functional groups and reactions running at moderate temperatures (25°C - 70 °C). The present review assembles recent literature for applications of these reactions in the field of material science, in particular on surfaces, polymers, and for the ligation of ligands to larger biomolecules, including own publications in this field. Since this is an extremely fast developing area, this review offers important knowledge to the interested reader. A number of >64 references are included.

The lithiation electrophilic substitution sequence of aromatic compounds has become very a common methodology for ortho-introduction of a long list of substituents in general. In particular, it was centered around the orthosubstitution of aromatic carboxylic acids via their masked forms. Till now, long list of reviews concerning tertiary amides or oxazolines as directing groups has been referred. On the other hand, secondary amides, even historically first masked function of aromatic carboxylic acids, were discussed in much smaller extent. In here, the scope of this methodology and the application of the secondary amide function in organic synthesis is presented.

The stereoselective formation of chiral tertiary alcohols is of great importance for the synthesis of enantiomerically pure natural products and pharmaceuticals. The simplest approach for the preparation of chiral alcohols is the enantioselective addition of organometallic reagents to carbonyl compounds. Hundreds of catalysts promote nucleophilic additions of organometallic compounds to aldehydes with high enantioselectivities. However, the use of ketones as group acceptors under similar conditions has proven much more challenging. The chemistry of catalytic asymmetric additions to ketones is progressing, especially since 1998. This review attempts to cover advances in this field which have occurred between 1994-2004. Particular attention is paid to chiral auxiliaries, reagents and catalysts used for the addition to different kinds of ketones (aromatic and aliphatic ketones, α, β-unsaturated ketones, α-ketoesters) as well as the enantiomeric excesses of the chiral tertiary alcohols obtained for each case. In addition, a discussion about the progress in the catalytic asymmetric addition to ketoimines in order to generate enantiomerically enriched tertiary amines will be presented. Finally, recent applications of the asymmetric addition to ketones chemistry in the synthesis of natural products and related compounds are reported.