Spirocyclic Peptidomimetics Featuring 2,3-Methanoamino Acids

Abstract

The spirocyclic peptidomimetics cyclo-[{(2S,3S)-cyclo-R}GD{(2S,3S)-cyclo-R}GD] (3) and cyclo-[{(2R,3S)-cyclo-R}GD{(2R,3S)-cyclo-R}GD] (4), containing 2,3-methanoarginine (cyclo-Arg‘) residues, were prepared. Conformations of these molecules were studied via a combination of CD and 1D and 2D NMR, and these data were interfaced with extensive molecular simulations. Conformational biases for molecules 3 and 4 were thereby deduced and were compared with conclusions previously obtained (Burgess, K.; Lim, D.; Mousa, S. A. J. Med. Chem. 1996, 39, 4520) for cyclo-[RGDRGD] (2). Molecule 3 has a relatively clear conformational bias toward a structure with a type II β-turn between the Gly CO and Gly NH atoms, but 4 is more flexible, existing in conformers wherein the Asp and Arg side chains tend to be on opposite faces of the backbone cyclic structure. These conclusions were used to interpret the relative affinities of 2−4 with respect to the vitronectin receptor.