posted on 2022-10-13, 12:09authored byAlessio
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.