Comprehensive Coordination Chemistry II. 10‐volume set. Edited by Jon A. McCleverty and Thomas J. Meyer.

In this contribution, we provide a comprehensive overview of acyclic twisted amides, covering the literature since 1993 (the year of the first recognized report on acyclic twisted amides) through June 2020. The review focuses on classes of acyclic twisted amides and their key structural properties, such as amide bond twist and nitrogen pyramidalization, which are primarily responsible for disrupting nN to π*C═O conjugation. Through discussing acyclic twisted amides in comparison with the classic bridged lactams and conformationally restricted cyclic fused amides, the reader is provided with an overview of amidic distortion that results in novel conformational features of acyclic amides that can be exploited in various fields of chemistry ranging from organic synthesis and polymers to biochemistry and structural chemistry and the current position of acyclic twisted amides in modern chemistry.

Acyclic Twisted Amides.

New chemical inhibitors of protein-protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction. The β-catenin:TCF interaction plays a critical role in the Wnt signaling pathway which is over-activated in multiple cancers, including prostate cancer. Using the Rosetta suite of protein design algorithms, we evaluate how different macrocycle structures can bind a pocket on β-catenin that associates with TCF. The in silico designed macrocycles are screened in vitro using luciferase reporters to identify promising compounds. The most active macrocycle inhibits both Wnt and AR-signaling in prostate cancer cell lines, and markedly diminishes their proliferation. In vivo potential is demonstrated through a zebrafish model, in which Wnt signaling is potently inhibited.

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Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer

A simple and practical molecular iodine-mediated method for the efficient construction of thiocarbamates from isocyanides, thiols and water under metal-free and mild conditions has been developed. A variety of thiocarbamates were easily synthesized through this methodology, which has the advantages of simple operation, eco-friendly conditions, good functional group tolerance, and readily accessible raw materials.

Molecular iodine-mediated synthesis of thiocarbamates from thiols, isocyanides and water under metal-free conditions

In the past few decades, heterocyclic compounds and their derivatives have gained popularity due to their prominent medicinal importance. The versatile and synthetically accessible 2-aminobenzothiazole scaffolds are quite fascinating for multiple applications in both synthetic organic chemistry and biological fields due to their potent pharmacological activities. A large number of efforts have been made to develop a wide range of methodologies for the synthesis of 2-aminobenzothiazole and its derivatives. Moreover, 2-aminobenzothiazole significantly serves as a reactant or a reaction intermediate for affording various fused heterocycles since NH2 and endocyclic N functions of 2-aminobenzothiazole are suitable to assist reactions with common bis electrophilic reagents to form a diverse fused heterocyclic scaffold. This review highlights various synthetic methodologies and chemical reactions of 2-aminobenzothiazole.

Contemporary progress in the synthesis and reactions of 2-aminobenzothiazole: a review

Peptoids that are oligomers of N-substituted glycines represent a class of peptide mimics with great potential in areas ranging from medicinal chemistry to biomaterial science. Controlling the equilibria between the cis and trans conformations of their backbone amides is the major hurdle to overcome for the construction of discrete folded structures, particularly for the development of all-cis polyproline type I (PPI) helices, as tools for modulating biological functions. The prominent role of backbone to side chain electronic interactions (n → π*) and side chains bulkiness in promoting cis-amides was essentially investigated with peptoid aromatic side chains, among which the chiral 1-naphthylethyl (1npe) group yielded the best results. We have explored for the first time the possibility to achieve similar performances with a sterically hindered α-chiral aliphatic side chain. Herein, we report on the synthesis and detailed conformational analysis of a series of (S)-N-(1-tert-butylethyl)glycine (Ns1tbe) peptoid homo-oligomers. The X-ray crystal structure of an Ns1tbe pentamer revealed an all-cis PPI helix, and the CD curves of the Ns1tbe oligomers also resemble those of PPI peptide helices. Interestingly, the CD data reported here are the first for any conformationally homogeneous helical peptoids containing only α-chiral aliphatic side chains. Finally we also synthesized and analyzed two mixed oligomers composed of NtBu and Ns1tbe monomers. Strikingly, the solid state structure of the mixed oligomer Ac-(tBu)2-(s1tbe)4-(tBu)2-COOtBu, the longest to be solved for any linear peptoid, revealed a PPI helix of great regularity despite the presence of only 50% of chiral side chain in the sequence.

Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains.

An iodine-catalyzed formation of substituted 2-aminobenzothiazole derivatives is herein described using hydrogen peroxide as an oxidant in PEG400. The method enabled an efficient environmentally sound access to this valuable scaffold in moderate to excellent yields under metal-free conditions.

Iodine-catalyzed formation of substituted 2-aminobenzothiazole derivatives in PEG400

The synthesis and conformational preferences of a set of new synthetic foldamers that combine both the α,β-peptoid backbone and side chains that alternately promote cis- and trans-amide bond geometries have been achieved and addressed jointly by experiment and molecular modeling. Four sequence patterns were thus designed and referred to as cis-β-trans-α, cis-α-trans-β, trans-β-cis-α, and trans-α-cis-β. α- and βNtBu monomers were used to enforce cis-amide bond geometries and α- and βNPh monomers to promote trans-amides. NOESY and molecular modeling reveal that the trans-α-cis-β and cis-β-trans-α tetramers show a similar pattern of intramolecular weak interactions. The same holds for the cis-α-trans-β and trans-β-cis-α tetramers, but the interactions are different in nature than those identified in the trans-α-cis-β-based oligomers. Interestingly, the trans-α-cis-β peptoid architecture allows establishment of a larger amount of structure-stabilizing intramolecular interactions.

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Exploring the Conformation of Mixed Cis- Trans α,β-Oligopeptoids: A Joint Experimental and Computational Study.

Abscisic acid (ABA) is a natural product, which is a well-known phytohormone. However, this molecule has recently exhibited interesting biological activities, emphasizing the need for a simple and direct access to new analogues based on the ABA framework. Our strategy relies on a pallado-catalyzed Mizoroki-Heck cross-coupling as key reaction performed in solvent and ligand free conditions. After a careful optimization, we succeeded in accessing various (E/Z)-dienes and (E/E/Z)-trienes in moderate to good yields without isomerization and applied the same approach to the synthesis of ABA in an environmentally sound manner.

https://www.mdpi.com/2073-4344/8/3/115/pdf

Solvent-Free Mizoroki-Heck Reaction Applied to the Synthesis of Abscisic Acid and Some Derivatives

This review describes the various synthetic methods commonly used to obtain molecules possessing conjugated dienes. We focus on methods involving cross-coupling reactions using various metals such as nickel, palladium, ruthenium, cobalt, cobalt/zinc, manganese, zirconium, or iron, mainly through examples that aimed to access natural molecules or their analogues. Among the natural molecules covered in this review, we discuss the total synthesis of a phytohormone, Acid Abscisic (ABA), carried out by our team involving the development of a conjugated diene chain.

https://www.mdpi.com/2073-4344/12/1/86/pdf?version=1642071630

Geoffrey Dumonteil

Papers

Homogeneous and Robust Polyproline Type I Helices from Peptoids with Nonaromatic α-Chiral Side Chains.

Iodine-catalyzed formation of substituted 2-aminobenzothiazole derivatives in PEG400

Exploring the Conformation of Mixed Cis- Trans α,β-Oligopeptoids: A Joint Experimental and Computational Study.

Solvent-Free Mizoroki-Heck Reaction Applied to the Synthesis of Abscisic Acid and Some Derivatives

Synthesis of Conjugated Dienes in Natural Compounds