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. 2023 Aug 4;88(15):10381-10402.
doi: 10.1021/acs.joc.2c01903. Epub 2022 Oct 13.

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics

Alessio M Caramiello  1 , Maria Cristina Bellucci  2 , Gaetano Cristina  1 , Carlo Castellano  3 , Fiorella Meneghetti  4 , Matteo Mori  4 , Francesco Secundo  5 , Fiorenza Viani  5 , Alessandro Sacchetti  1 , Alessandro Volonterio  1   5
Affiliations

Synthesis and Conformational Analysis of Hydantoin-Based Universal Peptidomimetics

Alessio M Caramiello et al. J Org Chem. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthetic Strategies for the Synthesis of Hydantoin-Based Universal Peptidomimetics
Scheme 2
Scheme 2. MC Process Leading to Hydantoin F
Scheme 3
Scheme 3. Synthesis of Hydantoin Intermediate 5h
Scheme 4
Scheme 4. Synthesis of Hydantoin Universal Peptidomimetics 8
Chart 1
Chart 1. Structures of Hydantoin Universal Peptidomimetics 8
Figure 1
Figure 1
β-Turn- and β-helix-like conformations of universal peptidomimetics 8.
Figure 2
Figure 2
(a) α-Helix (left)- and β-turn (right)-like conformations for representative compound 8r; (b) superimposition of 8r conformers with an α-helix model in orange (left), 310-helix model in orange (center), and β-turn in green (right). For the α-helix, the relevant i, i + 4, and i + 7 positions are highlighted.
Figure 3
Figure 3
DMSO titration experiments on substrates 8p, 8r.
Figure 4
Figure 4
CD spectra for peptidomimetics 8p, 8r.
Figure 5
Figure 5
ATR-FTIR spectrum of 8r.
Figure 6
Figure 6
ORTEP diagram of 8r, with the arbitrary atom-numbering scheme. Thermal ellipsoids are drawn at the 40% probability level.
Figure 7
Figure 7
(A) Stick model of 8r in an arbitrary orientation, evidencing the main H-bonds. (B) Stick model showing the crystal packing along the c axis. Hydrogen atoms are omitted for the sake of clarity.
Figure 8
Figure 8
(A) HS mapped over dnorm with a fixed color scale in the range −0.5808 au (red) to 2.9223 au (blue), based on the length of the intermolecular contacts with respect to the sum of the van der Waals radii (red: shorter; blue: longer; white: same). (B) HS mapped over the shape index (color scale: −0.9973 to 0.9977 au). Blue areas represent bumps, and red regions indicate hollows. (C) HS mapped over the curvedness (color scale: −4.4169 to 0.8187 au). Green represents flat regions, and blue indicates edges.
Figure 9
Figure 9
Two-dimensional Fingerprint plots of HS, providing a visual summary of the frequency of each combination of de and di across the HS. Points with a contribution to the surface are colored blue for a small contribution to green for a great contribution.
See this image and copyright information in PMC

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