Novel solid-phase synthesis of azapeptides and azapeptoides via Fmoc-strategy and its application in the synthesis of RGD-mimetics

The cell adhesion motif Arg-Gly-Asp (RGD) has been used as a starting point for the development of several antagonists for the alpha IIb beta 3 and alpha v beta 3 integrins, which are implicated in various pathological processes. In this paper, an efficient method for the solid-phase synthesis and biological evaluation of linear RGD-mimetics containing an azaamino acid instead of glycine are described. Activation of the Fmoc-protected hydrazines 1, 4, and 6 with a solution of phosgene in toluene provided Fmoc-protected activated azaglycine (2), azasarcosine (5), and azaalanine (7) in high yields. Six aza-RGD-mimetics have been synthesized on solid support using Fmoc peptide synthesis and individually optimized reaction conditions for the incorporation of activated azabuilding blocks. Due to orthogonal anchoring and side-chain protection, our strategy yielded TentaGel-bound RGD-mimetics, which meet all requirements of the one-bead-one-compound concept. We observed differing activity and selectivity in bioassays for the alpha IIb beta 3- and alpha v beta 3-integrin receptor depending on the substitution pattern of the azabuilding blocks. Our biological data suggest that azapeptides and azapeptoides can be employed as selectivity- and activity-inducing templates in pseudobio-oligomers.