Synthesis and Library Construction of Privileged Tetra-Substituted Δ⁵-2-Oxopiperazine as β-Turn Structure Mimetics

Abstract

In this study, we developed an efficient and practical procedure for the synthesis of tetra-substituted Δ5-2-oxopiperazine that mimics the bioactive β-turn structural motif of proteins. This synthetic route is robust and modular enough to accommodate four different substituents to obtain a high level of molecular diversity without any deterioration in stereochemical enrichment of the natural and unnatural amino acids. Through the in silico studies, including a distance calculation of side chains and a conformational overlapping of our model compound with a native β-turn structure, we successfully demonstrated the conformational similarity of tetra-substituted Δ5-2-oxopiperazine to the β-turn motif. For the library construction in a high-throughput manner, the fluorous tag technology was adopted with the use of a solution-phase parallel synthesis platform. A 140-membered pilot library of tetra-substituted Δ5-2-oxopiperazines was achieved with an average purity of 90% without further purification.

Designing Peptidomimetics

“…This approach was further revised and extended to identify scaffolds suited for the synthesis of chemical libraries [240]. This method has been used to search for suitable scaffolds, among them the trans-pyrrolidine-3,4dicarboximide 98 (in Figure 10) [241]; oxopiperazines 99 (in Figure 10) [242] or spiroquinolines 100 (in Figure 10) [243].…”

Privileged Structures: Efficient Chemical “Navigators” toward Unexplored Biologically Relevant Chemical Spaces

“…Six novel core scaffolds extracted or designed from natural products and peptide mimetics: (a) diaza-bridged heterocycles (types I and II), (b) tetrahydro-β-carboline alkaloid (type III), (c) tetrahydro-1,4-bezodiazepine (type IV), and (d) Δ 5 -2-oxopiperazines (types V and VI). Reproduced with permission from refs and . Copyright 2012 Wiley-VCH, and 2014 American Chemical Society, respectively.…”

“…Finally, oxopiperazine moieties are constrained dipeptide mimetics commonly used as privileged structures for the construction of drug-like compound libraries. Specifically, they mimic the turn structures of proteins, , which are crucial recognition elements in protein–protein interactions, and thus can serve as an interesting molecular framework for the discovery of small-molecule modulators of protein–protein interactions. , Therefore, we developed new pDOS pathways for the synthesis of a trisubstituted Δ 5 -2-oxopiperazine that mimics the seven-membered hydrogen-bonding ring motif and the three side-chain residues in γ-turn structures (type V, Figure d) . Distinct from γ-turns, β-turn structures are composed of a 12-membered hydrogen-bonding ring motif and four side-chain residues.…”

β-Turn mimetic-based stabilizers of protein–protein interactions for the study of the non-canonical roles of leucyl-tRNA synthetase

“…In fact, few studies have reported successful and/or sufficiently potent PPI modulators because PPI modulators do not fully overlap with the criteria of drug-likeness based on FDA-approved orally available drugs 5,6,8. For the systematic perturbation of diverse PPIs, various synthetic strategies have been used to construct diverse molecular frameworks, such as polyheterocycles and macrocycles, with different characteristics compared to conventional inhibitors at the active site of druggable targets as substrate analogs 9–14…”