Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS

Final Activity Report Summary - CARBCLUSTERS (Receptor clustering promoted by restricted divalent ligands)

The main objective of the project was to investigate the importance that conformational constriction has on biological activity of divalent molecules:
We are particularly interested in lectins, a type of proteins that bind to carbohydrate ligands, that are involved in many biological processes such as cell communication with other cells and their surrounding environment. In order to study these processes, it is important to have precise information on the number of carbohydrate ligands (multivalency) and on their three-dimensional disposition when they interact with the lectin.

The use of conformationally constrained ligands simplifies this problem to some extent: these molecules have a restricted number of possible presentations of the ligands. By using structurally well-defined molecular scaffolds, information can be obtained on the bioactive conformations necessary for interaction between the protein and the ligands. This knowledge of the structural requirements for biological activity can lead to the design of ligands with improved affinities and potential therapeutic applications.

To this aim, we started the project by synthesizing a variety of macrocyclic and oligomeric scaffolds based on glucuronic acid amides. A variety of novel multivalent scaffolds presenting different degrees of conformational rigidity was prepared using metathesis reaction. The structure and conformational properties of the scaffolds were determined using different spectroscopic techniques, computational modelling and X-ray crystallography.

Based on these data, we selected a suitable conformationally constrained macrocyclic scaffold and modified it so as to graft the carbohydrate ligand on a specific position of the scaffold (in this case, the 3-OH of the glucuronic acid) through a glycosidation reaction. The more flexible acyclic analogues were also prepared so as to compare the influence of conformational restriction by macrocyclisation when evaluating the biological activity of the ligands. The first series of divalent ligands synthesised displayed a-D- mannopyrannoside moieties, which are the recognition motifs for the plant lectin Concavalin A.

Galectins are a type of lectins of particular importance due to their involvement in many processes in mammalian cells, such as tumour formation. They recognise b-D-lactoside moieties. With the experience acquired during the synthesis of the a-D- mannopyrannoside ligands, we proceeded to prepare a second series of divalent restricted macrocyclic ligands displaying b-D-lactoside moieties onto the 3-OH position of the glucuronic acid of the scaffold. The synthesis of the lactoside derivatives proved to be challenging and more troublesome than that of the mannopyrannoside ligands synthesized previously. The more flexible acyclic analogues were also prepared.

All the ligands synthesised, together with other related ligands prepared within the research group, have been sent for biological evaluation to the laboratory of Prof. H. J. Gabius and Dr. S. Andre in Ludwig-Maximilians Universitat, Munich (Germany). Every of these compounds should display the corresponding ligands in a distinct and three-dimensionally well-defined manner, and this should be reflected in the interaction patterns between the ligands and their lectins receptors.

As well as the main objective initially proposed, during the course of the project two new research interests were encountered: a) development of novel b-cyclodextrin mimics from macrocyclic scaffolds and b) development of novel a-helix peptidomimetics from very rigid macrocyclic scaffolds.

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