Helen M. I. Osborn

The asymmetric synthesis of aziridines

The report contains an overview of methods available for asymmetric preparation of a range of 1H- aziridines and their N-substituted analogues

Flavonoids as prospective compounds for anti-cancer therapy.

Flavonoids, which are polyphenolic compounds, are a class of plant secondary metabolites possessing a broad spectrum of pharmacological activity including anti-cancer activities. They have been reported to interfere in the initiation, promotion and progression of cancer by modulating different enzymes and receptors in signal transduction pathways related to cellular proliferation, differentiation, apoptosis, inflammation, angiogenesis, metastasis and reversal of multidrug resistance. Due to their multiple molecular mechanisms of action, flavonoids (both natural and synthetic analogs) are being investigated for their potential applications in anti-cancer therapies. In this review article, the main molecular mechanisms of action of flavonoids attributing to their potential anti-cancer activities have been discussed and the key structural features required for their activity are highlighted.

Recent developments in polymer supported syntheses of oligosaccharides and glycopeptides

Abstract A review of methods available for the polymer supported syntheses of oligosaccharides and glycopeptides is presented. The range of polymers and linkers, oligosaccharide assembly strategies, and analytical techniques employed in recent syntheses are described.

Alterations in Receptor Binding Properties of Recent Human Influenza H3N2 Viruses Are Associated with Reduced Natural Killer Cell Lysis of Infected Cells

ABSTRACT Natural killer (NK) cell recognition of influenza virus-infected cells involves hemagglutinin (HA) binding to sialic acid (SA) on activating NK receptors. SA also acts as a receptor for the binding of influenza virus to its target host cells. The SA binding properties of H3N2 influenza viruses have been observed to change during circulation in humans: recent isolates are unable to agglutinate chicken red blood cells and show reduced affinity for synthetic glycopolymers representing SA-α-2,3-lactose (3′SL-PAA) and SA-α-2,6-N-acetyl lactosamine (6′SLN-PAA) carbohydrates. Here, NK lysis of cells infected with human H3N2 influenza viruses isolated between 1969 and 2003 was analyzed. Cells infected with recent isolates (1999 to 2003) were found to be lysed less effectively than cells infected with older isolates (1969 to 1996). This change occurred concurrently with the acquisition of two new potential glycosylation site motifs in HA. Deletion of the potential glycosylation site motif at 133 to 135 in HA1 from a recent isolate partially restored the agglutination phenotype to a recombinant virus, indicating that the HA-SA interaction is inhibited by the glycosylation modification. Deletion of either of the recently acquired potential glycosylation sites from HA led to increased NK lysis of cells infected with recombinant viruses carrying modified HA. These results indicate that alterations in HA glycosylation may affect NK cell recognition of influenza virus-infected cells in addition to virus binding to host cells.

Regioselective C-3-O-acylation and O-methylation of 4,6-O-benzylidene-β-d-gluco- and galactopyranosides displaying a range of anomeric substituents

The regioselective C-3-O-acylation and O-methylation of a range of 4,6-O-benzylidene-beta-D-gluco- and galactopyranosides has been studied. Regioselectivity is achieved by forming the copper chelate of the 2,3-diol using either sodium hydride and copper(II) chloride, or copper(II) acetylacetanoate, or copper(II) acetate, prior to introduction of the acylating or methylating agent.

Synthesis and analysis of urea and carbamate prodrugs as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT)

The suitability of 4-di(2-chloroethyl)aminoanilino-4-hydroxyphenethylaminomethanone 2 to act as a prodrug for melanocyte-directed enzyme prodrug therapy (MDEPT) is assessed. Thus its synthesis, ability to generate a cytotoxic agent upon exposure to tyrosinase, and stability within different sera are reported. A comparison is made to illustrate that the new urea prodrug 2 is a more suitable candidate for MDEPT than the corresponding carbamate prodrug 1.

Melanocyte-Directed enzyme prodrug therapy (MDEPT): development of second generation prodrugs for targeted treatment of malignant melanoma.

Evaluation of second generation prodrugs for MDEPT, by oximetry, has highlighted structural properties that are advantageous and disadvantageous for efficient oxidation using mushroom tyrosinase. In particular, a sterically undemanding prodrug bis-(2-chloroethyl)amino-4-hydroxyphenylaminomethanone 28 was synthesised and found to be oxidised by mushroom tyrosinase at a superior rate to tyrosine methyl ester, the carboxylic acid of which is the natural substrate for tyrosinase. The more sterically demanding phenyl mustard prodrugs 9 and 10 were oxidised by mushroom tyrosinase at a similar rate to tyrosine methyl ester. In contrast, tyramine chain elongation via heteroatom insertion was detrimental and the rate of mushroom tyrosinase oxidation of phenyl mustard prodrugs 21 and 22 decreased by 10 nanomol/min.

Analysis of polysaccharides and monosaccharides in the root mucilage of maize (Zea mays L.) by gas chromatography

Root mucilage of maize (Zea mays L.) was purified using Sephadex size-exclusion chromatography to allow subsequent analysis of the polysaccharides derived from this mucilage. Hydrolysis of the polysaccharides to their constituent monosaccharides and conversion of these monomers to volatile peracetate derivatives allowed analysis of these derivatives using gas chromatography. This permitted identification and broad quantification of the major components of the polysaccharides. Two methods have been developed: (1) a two-step hydrolysis/acetylation procedure and (2) a one-step acetolysis. Gas chromatograms obtained using the latter procedure are far simpler due to the formation of predominantly one anomer for each monomer component. In both cases, the major monosaccharide components of the polysaccharides were identified as fucose, arabinose, galactose and glucose. Analysis of the crude maize mucilage demonstrated that monosaccharides co-exist with polysaccharides. The monosaccharides were again converted to their peracetates and gas chromatography identified the major monosaccharide component as glucose.

Melanocyte-directed enzyme prodrug therapy (MDEPT): development of a targeted treatment for malignant melanoma.

A novel prodrug rationally designed to function as a tyrosinase substrate has been synthesised to allow targeted treatment of malignant melanoma. This agent has been evaluated for tyrosinase-mediated drug release, and has been shown to act in the desired manner. Furthermore, differential cytotoxicity has been demonstrated in cell lines which express tyrosinase and those which do not.

Carbohydrate-based therapeutics

In recent years there has been a resurgence of interest in the biological roles of carbohydrates and as a result it is now known that carbohydrates are involved in a vast array of disease processes. This review summarises progress in the development of carbohydrate‐based therapeutics that involve: inhibition of carbohydrate‐lectin interactions; immunisation, using monoclonal antibodies for carbohydrate antigens; inhibition of enzymes that synthesise disease‐associated carbohydrates; replacement of carbohydrate‐processing enzymes; targeting of drugs to specific disease cells via carbohydrate‐lectin interactions; carbohydrate based anti‐thrombotic agents.