Linear and Cyclic Depsipeptidomimetics with ß-Lactam Cores: A Class of New αv ß3 Integrin Receptor Inhibitors.

ABSTRACT

The αv ß3 integrin receptor plays an important role in tumor metastasis and tumor-induced angiogenesis. The inhibition of this receptor with diverse ligands, antibodies, or cyclic peptides is a promising research field for the treatment of a variety of tumors. The replacement of Phe-(Me)Val dipeptide by a ß-lactam ring in Cilengitide has led to new products that show higher inhibitory activity than the parent cyclopeptide. In particular, substitution of a peptide bond ß-lactam-NH-Asp linkage by a ß-lactam-O-Asp ester linkage increases the activity of the new cyclodepsipeptide. In the same way it has been found that open-chain compounds of the form Asp-ß-lactam-Arg can interact with the receptor and inhibit its activity moderately. The integrin inhibitory activity of the synthesized compounds has been established by using the CGH array, a method that appears to be a more reliable trial than the classical adhesion test.