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.

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics / A.M. Caramiello, M.C. Bellucci, G. Cristina, C. Castellano, F. Meneghetti, M. Mori, F. Secundo, F. Viani, A. Sacchetti, A. Volonterio. - In: JOURNAL OF ORGANIC CHEMISTRY. - ISSN 0022-3263. - (2022), pp. 1-22. [Epub ahead of print] [10.1021/acs.joc.2c01903]

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics

M.C. Bellucci
Secondo
;
C. Castellano;F. Meneghetti;M. Mori;
2022

Abstract

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.
Settore CHIM/06 - Chimica Organica
Settore CHIM/08 - Chimica Farmaceutica
Settore CHIM/03 - Chimica Generale e Inorganica
13-ott-2022
Article (author)
File in questo prodotto:
File Dimensione Formato  
acs.joc.2c01903.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 5.61 MB
Formato Adobe PDF
5.61 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/943308
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus ND
  • ???jsp.display-item.citation.isi??? ND
social impact