Synthesis of Integrin Inhibitors

During our research studies, we performed the synthesis of a series of azabicycloalkane amino acids, which can be regarded as conformationally restricted substitutes for Phe-Pro dipeptide units. Computational and spectroscopic studies have revealed that these bicyclic scaffolds can mimic reverse-turn motifs. The replacement of the D-Phe-Val dipeptide in the reference compound cyclo(RGDfV) with such azabicycloalkane scaffolds leads to a new cyclopentapeptide. This compound, matter of an International Patent, shows biological activity as selective αv β3 and αv β5 integrin inhibitor. Future perspectives to employ this compound as potential antitumor drug, lead us to functionalize the azabicycloalkane scaffold in a position located far from the RGD region. Thus, it would be possible to create a bond with citotoxic molecules (doxorubicin, paclitaxel) or to even use it for diagnostic purposes, creating a bond with radiolabeled molecules or contrast agents, useful in techniques like PET or TAC respectively. Our researches were focused on the synthesis of new lactams endowed with a vinyl moiety on a 7,5-fused 1-aza-2-oxo-bicycloalkane. Two different approaches exploiting as a key step either a Ring Closing Enyne Metahesis (RCEYM) or an intramolecular Sakurai reaction, have been studied, and optimization of the various synthetic pathways is still in progress.