Revisiting N-to-O Acyl Shift for Synthesis of Natural Product-like Cyclic Depsipeptides

Abstract

Despite the prevalence of head-to-side chain threonine linkages in natural products, their incorporation has been underexplored in synthetic cyclic peptides. Herein we investigate a cyclic peptide scaffold able to undergo an N-O acyl rearrangement. Upon acylation of the amine with diverse carboxylic acids, the resulting cyclic depsipeptides displayed favorable cellular permeability and a conformation similar to the parent peptide. The rearrangement was found to be scaffold and conformation dependent as evidenced by molecular dynamics experiments.

Probing the Physicochemical Boundaries of Cell Permeability and Oral Bioavailability in Lipophilic Macrocycles Inspired by Natural Products

“…54 The library of 14 hybrid macrocycles demonstrated a wide range of permeabilities in a 5 h PAMPA incubation, consistent with previously established models relating passive permeability to conformation-dependent phenomena (e.g., the ability to form internal hydrogen bonds. 15,17,[21][22][23]26,47,48,55 For comparison, we included the cyclic hexapeptide 1NMe3, 15 a cellpermeable and orally bioavailable compound that we discovered previously. Compounds 3, 6, 12, and 14 demonstrated excellent passive permeability, comparable to that of the propranolol control.…”

“…This observation is consistent with other reports showing that conformation can outweigh the effect of polar functionality in determining passive permeability and that three-dimensional structural models are required to predict membrane permeability among compounds of similar composition. 4,15,17,25,26,43,47,48 Compounds 8 and 9, which had the poorest % recovery in the PAMPA assay (indicative of plate adherence or sequestration in the artificial membrane), also showed very low permeabilities, although poor PAMPA permeability did not necessarily correspond to low recovery (e.g., 5).…”

“…We sampled the conformations of 1 , 4 , 5 , 6 , and 14 using a computational algorithm that we had previously developed to predict loops in proteins and modified to accommodate macrocycles . Conformers within 5 kcal/mol of the global minimum for each structure were retained, clustered by backbone rmsd, and used as input into the “distribution of solution conformations” (DISCON) ,, algorithm, which fits NMR-derived distance and dihedral information to weighted ensembles of conformers rather than assuming a single well-defined conformer. In all but one case, DISCON yielded a single conformer as the best fit to the NOESY and J -coupling data (Figure and Table S5).…”

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

“…Intramolecular acyl transfer between hydroxy and amino groups has been investigated since the early 1920s on aminophenol derivatives, serine/threonine, and peptides . The N‐to‐O acyl shift takes place under strongly acidic conditions at which the carbonyl group is protonated, which promotes the formation of a five‐membered cyclic intermediate that is eventually converted into an ester product (Scheme ).…”

“…Intramolecular acyl transfer between hydroxy and amino groups has been investigated since the early 1920s on aminophenol derivatives, serine/threonine, and peptides. [1][2][3][4][5][6][7][8][9][10][11] The Nto-O acyl shiftt akes place under strongly acidic conditions at which the carbonyl group is protonated, which promotes the formation of af ive-membered cyclic intermediate that is eventually converted into an ester product (Scheme 1). The resulting amino group is complexedw ith the acid as as alt form, which provides sufficient chemical stabilityt oa llow its handling and applications.…”