Development of a New Family of Conformationally Restricted Peptides as Potent Nucleators of β-Turns. Design, Synthesis, Structure, and Biological Evaluation of a β-Lactam Peptide Analogue of Melanostatin

Novel enantiopure (i)-(β-lactam)-(Gly)-(i+3) peptide models, defined by the presence of a central α-alkyl-α-amino-β-lactam ring placed as the (i+1) residue, have been synthesized in a totally stereocontrolled way by α-alkylation of suitable N-[bis(trimethylsilyl)methyl]-β-lactams. The structural properties of these β-lactam pseudopeptides have been studied by X-ray crystallography, Molecular Dynamics simulation, and NOESY-restrained NMR simulated annealing techniques, showing a strong tendency to form stable type II or type II‘ β-turns either in the solid state or in highly coordinating DMSO solutions. Tetrapeptide models containing syn- or anti-α,β-dialkyl-α-amino-β-lactam rings have also been synthesized and their conformations analyzed, revealing that α-alkyl substitution is essential for β-turn stabilization. A β-lactam analogue of melanostatin (PLG amide) has also been prepared, characterized as a type-II β-turn in DMSO-d6 solution, and tested by competitive binding assay as a dopaminergic D2 modulator in rat neuron cultured cells, displaying moderate agonist activity in the micromolar concentration range. On the basis of these results, a novel peptidomimetic design concept, based on the separation of constraint and recognition elements, is proposed.