American Chemical Society
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Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics

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journal contribution
posted on 2022-10-13, 12:09 authored by Alessio M. Caramiello, Maria Cristina Bellucci, Gaetano Cristina, Carlo Castellano, Fiorella Meneghetti, Matteo Mori, Francesco Secundo, Fiorenza Viani, Alessandro Sacchetti, Alessandro Volonterio
The synthesis of a collection of enantiomerically pure, systematically substituted hydantoins as structural privileged universal mimetic scaffolds is presented. It relies on a chemoselective condensation/cyclization domino process between isocyanates of quaternary or unsubstituted α-amino esters and N-alkyl aspartic acid diesters followed by standard hydrolysis/coupling reactions with amines, using liquid–liquid acid/base extraction protocols for the purification of the intermediates. Besides the nature of the α carbon on the isocyanate moiety, either a quaternary carbon or a more flexible methylene group, conformational studies in silico (molecular modeling), in solution (NMR, circular dichroism (CD), Fourier transform infrared (FTIR)), and in solid state (X-ray) showed that the presented hydantoin-based peptidomimetics are able to project their substituents in positions superimposable to the side chains of common protein secondary structures such as α-helix and β-turn, being the open α-helix conformation slightly favorable according to molecular modeling, while the closed β-turn conformation preferred in solution and in solid state.