| Summary: | The first Chapter deals with the biological properties of the RGD motif which has been identified as the recognition site in adhesive interactions between integrin cell surface receptors and extra-cellular glycoproteins such as fibronectin or associated with inhibition of platelet aggregation by snake venom peptides. Chapter II gives an account of structure-activity relationship studies of low molecular weight RGD antagonists which have been reported in the recent literature to probe the structural requirements determining RGD affinity and specificity for integrins. In our approach, a cyclic pentapeptide directly derived from the active site of fibronectin, cyclo[RGDSK], was chosen as model template in an attempt to mimic the putative bioactive structure. Fmoc-t-butyl polyamide solid-phase strategy reviewed briefly in Chapter III was employed for the preparation of the linear precursor which was then cyclized in solution-phase under dilute conditions. Optimization of the synthesis of cyclo[RGDSK] is reported in Chapter IV. The subsequent analogues were designed to improve the bioactivity of the initial template while maintaining its selectivity towards integrins, either by replacing aspartic acid with an unusual residue γ-carboxyglutamic acid (Gla) that binds to integrin calcium sites triggering platelet aggregation, or by inserting the binding motif in a hydrophobic ring. The syntheses of cyclo[RG-<i>DL</i>-Gla-SK] and cyclo[RGDFF] are detailed in Chapter V. Chapter VI deals with the preparation of a depsipeptide mimetic, cyclo[RGD-Phlac_2], designed to increase the backbone flexibility of the last analogue by incorporation of two depside links. Finally, the structural and biological analyses of these cyclopeptides and cyclodepsipeptides discussed in Chapter VII should provide more insights into the active conformation of the RGD motif.
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