Dongyue Xin

A Multifaceted Secondary Structure Mimic Based On Piperidine‐piperidinones

Minimalist secondary structure mimics are typically made to resemble one interface in a protein-protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1, simulation of its solution-state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side-chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non-ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus DLD-1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol(-1) above the minimum energy solution state.

A chemoselective route to β-enamino esters and thioesters.

Conditions were developed for syntheses of β-enamino esters, thioesters, and amides. These reactions involve hydroxybenzotriazole derivatives in buffered media. Illustrative syntheses of some heterocyclic systems are given, including some related to protein–protein interface mimics.

Expanding the Scope of Oligo-pyrrolinone–Pyrrolidines as Protein–Protein Interface Mimics

Oligo-pyrrolinone-pyrrolidines (generic structure 1) have the potential to interfere with protein-protein interactions (PPIs), but to reduce this to practice it is necessary to be able to synthesize these structures with a variety of different side chains corresponding to genetically encoded proteins. This paper describes expansion of the synthetic scope of 1, the difficulties encountered in this process, particularly issues with epimerization and slow coupling rates, and methods to overcome them. Finally, spectroscopic and physicochemical properties as well as proteolytic stabilities of molecules in this series were measured; these data highlight the suitability of oligo-pyrrolinone-pyrrolidines for the development of pharmacological probes or pharmaceutical leads.

Protein-protein interface mimicry by an oxazoline piperidine-2,4-dione.

Representative minimalist mimics 1 were prepared from amino acids. Scaffold 1 was not designed to mimic any particular secondary structure, but simulated accessible conformations of this material were compared with common ideal secondary structures and with >125,000 different protein-protein interaction (PPI) interfaces. This data mining exercise indicates that scaffolds 1 can mimic features of sheet-turn-sheets, somewhat fewer helical motifs, and numerous PPI interface regions that do not resemble any particular secondary structure.

Extended Piperidine–Piperidinone Protein Interface Mimics

Minimalist structures, H and I, were designed as protein interface mimics. Attributes of these chemotypes are (i) greater rigidity than conventional peptides, (ii) chiral and nonplanar heterocyclic backbones that are less prone to the hydrophobic aggregation effects, and (iii) potential to be prepared with a variety of side chains corresponding to natural amino acids. Intermediates, however, in the oligo(pyrrolidinone-piperidine)s H syntheses were vulnerable to epimerization. The origins of this epimerization were determined, then the study was focused on oligo(piperidinone-piperidine) compounds I. Mimics I were prepared via iterative couplings; a penta(piperidinone-piperidine) was prepared in this way. A series of lower homologues of this pentamer were crystallized and studied (single crystal X-ray), and four of them were used in a circular dichroism (CD) study. Thus, an estimate of 36 Å for the N-to-C distance of a typical conformation of the penta(piperidinone-piperidine) was made. CD spectra of four progressively longer oligomers allowed assignment of elipticity changes around 300 nm that can be attributed to increased conformational ordering of the longer oligomers in solution.

Interplay Of Stereochemistry, Conformational Rigidity, And Ease Of Synthesis For 13-Membered Cyclic Peptidomimetics Containing APC Residues

As part of a program to design small molecules that bind proteins, we require cyclic peptides (or peptidomimetics) that are severely constrained such that they adopt one predominant conformation in solution. This paper describes syntheses of the 13-membered cyclic tetrapeptides 1 containing aminopyrrolidine carboxyl (APC) residues. A linear precursor was prepared and used to determine optimal conditions for cyclization of that substrate. A special linker was prepared to enable cyclization of similar linear peptidomimetics on a solid phase, and the solution-phase cyclization conditions were shown to be appropriate for this too. Stereochemical variations were then used to determine the ideal APC configuration for cyclization of the linear precursors (on a solid phase, using the conditions identified previously). Consequently, a series of compounds were prepared that are representative of compounds 1. Conformational studies of representative compounds in DMSO solution were performed primarily using (i) NOE studies, (ii) quenched molecular dynamics simulations using no constraints from experiment, and (iii) MacroModel calculations with NMR constraints. All three strategies converged to the same conclusion: the backbone of molecules based on 1 tends to adopt one preferential conformation in solution and that conformation can be predicted from the stereochemistries of the α-amino acids involved.

Heterogeneous Phase Transfer Catalysis in Solid Phase Syntheses of Anth-Cyclic Tetrapeptides.

This study features solid phase syntheses of cyclic tetrapeptides containing anthranilic acid (Anth) on relatively inexpensive resins derived from polystyrene. It proved to be difficult to hydrolyze a supported Anth-methyl ester unless a phase transfer catalyst was added to facilitate transport of hydroxide into the swollen hydrophobic gel state of the resin. We suggest this may be an under-appreciated strategy for improving syntheses on polystyrene supports.