Synthesis and evaluation of conformationally constrained aminopipecolic acids for the generation of new small-molecule integrin-targeted drugs

The synthesis of substituted cyclopropane pipecolic acids (CPAs) as conformationally restricted templates for peptidomimetics is reported. A variety of differently substituted (poly)hydroxy- and amino-2-azabicyclo[4.1.0]heptane-1-carboxylic acids were prepared via the Pd-catalyzed methoxycarbonylation of suitably functionalized lactam-derived vinyl phosphates, followed by OH-directed cyclopropanations. Cyclopropane amino acids have been extensively exploited to reduce conformational mobility in peptidomimetics. However, to our knowledge there were no reports on CPAs embodied in peptides. Hence, we employed various substituted CPAs to build linear and cyclic peptidomimetics. In particular, we synthesized two cyclic peptidomimetics bearing the RGD (Arginine-Glycine-Aspartic Acid) sequence, which displayed nanomolar affinity towards both alfa-v-beta-3 and alfa-5-beta-1 integrin subfamilies. These have received increasing attention as therapeutic targets because of their critical role in tumor-induced angiogenesis and metastasis diffusion. Thus, CPAs appear suitable for the generation of novel peptidomimetics for drug discovery.