SYNTHESIS OF PEPTIDOMIMETIC LIGANDS TARGETING CELL-SURFACE RECEPTORS INVOLVED IN TUMOR ANGIOGENESIS

In the first part of the Thesis, the synthesis of different classes of peptidomimetics targeting integrin receptors is described. Both simple ligands and drug conjugates were synthesized and tested to assess their biological activity. In cancer therapy, peptides and peptidomimetics targeting integrins are employed as carriers to deliver cytotoxic drugs at the tumor site, taking advantage of integrin over-expression on the surface of tumor cells. Within this frame, synthetic efforts have been focused on the synthesis and on the conjugation to the cytotoxic agent paclitaxel of isoDGR-based integrin ligands to effect drug-targeting to integrin over-expressing tumor cells. The second part of the Thesis deals with the vascular endothelial growth factor receptors and their ligands. In particular, the interaction of VEGF-C with VEGFRs has been considered, focusing the attention on the reason why this growth factor was considered a privileged candidate for the preparation of a small library of VEGFR-selective peptides. These peptides have been synthesized by introducing systematic modifications in the natural portion of the growth factor and evaluated as VEGFR binders and anti-angiogenic agents in vitro.