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Synthesis of clusters containing lactose and their biological and structural evaluation

Final Activity Report Summary - LACCLUSTERS (synthesis of clusters containing lactose and their biological and structural evaluation)

a) Accomplishment of research objectives as presented in the original proposal
synthetic multivalent carbohydrates are effectors of biological processes and promote clustering of receptors and the organisation of the receptors has been shown to influence signalling and cellular responses. The crosslinking of multivalent carbohydrates on cell surfaces with lectins (carbohydrate binding proteins) has been proposed to lead to formation of assemblies that have roles in signal transduction. Such carbohydrate-lectin interactions are important in cancer metastasis (migration of cancer cells to new tissues) and apoptosis. Understanding the relationship between structure and biological activity of multivalent sugars may lead to a better understanding of how to manipulate the 'sugar code' and lead to new approaches to development of drugs. The purpose of this work was to synthesis bivalent ligands containing a lactose sugar for crosslinking with lectins. Two new ligands with particular topology have been obtained in eight and nine synthetic steps. Those compounds will be evaluated for their inhibitory effects on lactose-bearing clusters in a solid-phase assay with surface-immobilised lactosylated BSA and different sugar receptors and for their inhibition of haemagglutination and lectin binding to tumour cell surfaces.

b) New objectives established during the course of work and new lines of research
As the previous targets have been obtained, we focused our work on two other projects which allowed me to develop some new skills in the fields of glycolipid and azasugars synthesis.
The first project was concerned with the synthesis of a glycolipid that would elucidate the mechanism of action of the protein thermogenin (UCP1). This protein is the basis of non-shivering thermogenesis under exposure to cold conditions. Understanding the mechanism of action of the UCP family proteins will facilitate the identification of molecules able to increase energy expenditure in adult humans (anti-obesity drugs).
Synthetic methods have been developed to obtain the targets and this work has recently been published in Carbohydrate research. Biological tests have been carried out under the supervision of Dr Richard K. Porter in Trinity College Dublin. Results of this work on the elucidation of the mechanism of action of UCP1 have recently been submitted for publication.

The second project was about the synthesis of somatostatin peptidomimetics. Somatostatin is a peptide hormone that has found to be secreted by a broad range of tissues, including pancreas, and regions of the central nervous system. It has numerous functions but its therapeutic application as a drug (such as anti-cancer applications) is limited because of its short half-life (less than three minutes) and oral bioavailability.

iminosugars such as deoxynojirimycin (DNJ) and deoxymannojirimycin (DMJ) and related compounds are analogues of glucose where nitrogen replaces the ring oxygen and such sugars have proven extremely interesting as leads for development of therapeutics for diabetes, HIV infection and neurodegenerative disease due to their glycosidase inhibitory activity. Indeed some are in clinical use.

Iminosugars have been rarely considered as platforms for peptidomimetic drug development, presumably because of greater difficulties in their preparation We have synthesised a new ligand for based on iminosugar scaffold and test its affinity for the somatostatin receptors (SST). The compound was able to bind a subtype of somatostatin receptor (SST4) in the micromolar range and has shown selectivity for this receptor against SST5. The synthetic methodology and the binding assays have been published in the Journal Of Organic Chemistry.

These preliminary results provide a basis for investigating the suitability of iminosugar peptidomimetics as ligands for somatostatin receptors. In addition one can envisage the development of other novel peptidomimetics which is an area of great potential for the pharmaceutical industry.