Covering: up to 2009 Sugar-nucleotides are essential intermediates in carbohydrate metabolism and glycoconjugate biosynthesis. Structurally, sugar-nucleotides are composed of a sugar or sugar derivative and a nucleoside mono- or diphosphate. Numerous combinations of sugars and nucleotides are found in nature, and although only nine different sugar-nucleotides have so far been identified in mammalian cells, this number is much greater in other organisms. Naturally occurring sugar-nucleotides, as well as structural analogues, are of great interest as substrates for enzymatic reactions in carbohydrate synthesis, as enzyme inhibitors, as tools for assay development and for the study of glycoconjugate biosynthesis. Therefore, methods for the efficient preparation of natural and non-natural sugar-nucleotides are of considerable importance for synthetic, biological and medicinal chemistry. The synthesis of sugar-nucleotides is non-trivial and complicated by a number of factors: the low solubility of sugar-nucleotides in organic solvents, the presence of several polar or charged functional groups, and the susceptibility of the glycosidic and pyrophosphate bonds to hydrolytic cleavage. To address these issues, both chemical and enzymatic strategies have been pursued. Here we present an overview of current methods for the chemical synthesis of NDP- and NMP-sugars, including recently developed protocols for the direct chemical manipulation of unprotected sugar-nucleotides.

The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-α monoclonal antibody), Adalimumab (recombinant human anti-human TNF-α monoclonal antibody) and Anakinra (recombinant form of human interleukin 1β (IL-1) receptor antagonist) [1-3]. The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1β and TNF-α to be validated targets [4] However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1β and TNF-α signalling network at both the transcriptional and translational level [5, 6]. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-α and IL-1β production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.

Phytopharmaceuticals prepared from flowerheads of Arnica montana of Spanish origin and of the new type ”Arbo”, which can be easily and economically cultivated, were studied for their capability to impair activation of the transcription factors NF-κB and NF-AT. Both proteins are responsible for the transcription of genes encoding various inflammatory mediators. Additionally, their influence on the release of the cytokines IL-1 and TNF-α were examined. The inhibitory activities correlate with their quantitative and qualitative content of sesquiterpene lactones (Sls). Moreover, it was shown that the inhibitory potency of 11α,13-dihydrohelenalin derivatives being the main Sls in the Spanish flowers depend on their esterfication. Compounds with unsaturated acyl moieties, such as methacrylate and tiglinate, exhibited a stronger activity in the NF-κB EMSA as well as in the croton oil ear test in mice than the acetate derivative. Arbo tincture:tincture prepared from Arnica flowerheads type Arbo AP-1:activator protein 1 BSA:bovine serum albumen c.p.m.:counts per minute DTT:dithiothreitol EDTA:ethylenediaminetetraacetic acid EGTA:ethylene glycol-bis(β-aminoethyl ether)- N,N,N′,N′-tetraacetic acid EMSA:electrophoretic mobility shift assay FCS:fetal calf serum HEPES:N-[2-hydroxyethyl]-piperazine-N′- [2-ethanesulfonic acid] IL:interleukin NP-40:nonylphenoxypolyethoxyethanol NF-AT:nuclear factor of activated T cells BPS:phosphate buffered saline PMA:phorbol myristate acetate PMSF:phenylmethylsulfonyl fluoride Poly (dI-dC):polydeoxyinosinicdeoxycytidylic acid, double-stranded alternating copolymer Spanish tincture:tincture prepared from Spanish Arnica flowerheads Sl:sesquiterpene lactone TNF-α:tumor necrosis factor alpha 1 Partly presented at the 3^rd International Congress on Phytomedicine, 2000, Munich, Germany.