Synthesis of integrin inhibitors

A series of azabicycloalkane amino acids, which can be regarded as conformationally restricted substitutes for Phe-Pro dipeptide units have been synthesized. These bicyclic scaffolds are used as intermediates in the synthesis of biologically active cyclic peptidomimetic compounds comprising the sequence RGD (Arg- Gly-Asp). The most active cyclopentapeptide of the series was 1-RGD, which shows biological activity as selective ®v¯3 and ®v¯5 integrin inhibitor. The high affinity of 1-RGD towards ®v¯3 and ®v¯5 receptors, involved in tumor angiogenesis, led us to functionalize the azabicycloalkane scaffold with a suitable linker to which bioactive compounds could be appended; thus it would be possible to perform selective delivery of therapeutics and imaging agents to the tumor vasculature. Our work was focused on the synthesis of lactams 2a, 2b or 3, 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.