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Macrocyclic peptoids display remarkable biological activity thanks to their constitution and functionalization. This Review provides a systematic description of the bioactivities discovered so far, together with a complete structure-function relationship rationalization. Utilizing a strategic design for the synthesis of cyclic peptoids represents the starting point for further developments of these peptidomimetics as drug candidates.

Abstract

Cyclic N-substituted glycines oligomers, also known as cyclic peptoids, constitute a promising class of novel peptidomimetics, capable of simulating bioactive effectors with enhanced proteolytical stability and cell permeability as crucial bonuses. The macrocyclic constraint, essential for the induction of stable secondary structures, determines the biomimetic potential of such molecules, which act as antimicrobials, cytotoxic agents, siderophores, glycosidases inhibitors and so on. The bioactivity can be either attributed to the macrocyclic core (especially chelation) or to the side-chains (when endowed with specific groups or pharmacophores). The structure-bioactivity correlations emerging for this class of peptidomimetics, based on the study of conformational order and morphology of the backbone architecture, unravel interesting avenues for the rational design of more effective cyclooligomeric biomimics.

Pd^II-catalyzed β-C(sp³)−H lactamization of aliphatic amides is reported. This protocol features the use of practical and inexpensive oxidants and protecting groups, mild conditions, and reliable scalability. Further derivatization of β-lactam products enables synthesis of a range of biologically important motifs such as β-amino acid, γ-amino alcohol, and azetidine.

Abstract

The development of C(sp³)−H functionalization reactions that use common protecting groups and practical oxidants remains a significant challenge. Herein we report a monoprotected aminoethyl thioether (MPAThio) ligand-enabled β-C(sp³)−H lactamization of tosyl-protected aliphatic amides using tert-butyl hydrogen peroxide (TBHP) as the sole oxidant. This protocol features exceedingly mild reaction conditions, reliable scalability, and the use of practical oxidants and protecting groups. Further derivatization of the β-lactam products enables the synthesis of a range of biologically important motifs including β-amino acids, γ-amino alcohols, and azetidines.

An amine-functionalized naphthotube featuring a cavity with both hydrogen bonding sites and hydrophobic surfaces has been developed that traps aldehydes in bulk aqueous solution through the formation of hemiaminals. Dehydration of the hemiaminal to the imine is favored by the release of water from the hydrophobic microenvironment. Both the hemiaminals and imines could be detected by NMR spectroscopy and mass spectrometry at room temperature.

Abstract

Stabilizing water-sensitive reaction intermediates is challenging but desirable for guiding reactions to desired products in water. Herein, we report that labile imine and hemiaminal functional groups can be stabilized inside a synthetic container compound, a water-soluble naphthotube. The naphthotube features a primary amine group anchored in a cavity with both hydrogen bonding sites and hydrophobic surfaces. Aldehydes in bulk aqueous solution are trapped in the cavity by the amine to form hemiaminals stabilized through hydrogen bonding and hydrophobic effects. Dehydration of the hemiaminal to the imine is favored by the release of water from the hydrophobic microenvironment. Both the hemiaminals and imines can be detected at room temperature by NMR spectroscopy and mass spectrometry.

Catalysis by radical enzymes dependent on coenzyme B 12 (AdoCbl) relies on the reactive primary 5’-deoxy-5’adenosyl radical, which originates from reversible Co-C bond homolysis of AdoCbl. This bond homolysis is accelerated roughly 10 12 -fold upon binding the enzyme substrate. The structural basis for this activation is still strikingly enigmatic. As revealed here, a displaced firm adenosine binding cavity in substrate-loaded glutamate mutase (GM) causes a structural misfit for intact AdoCbl that is relieved by the homolytic Co-C bond cleavage. Strategically interacting adjacent adenosine- and substrate-binding protein cavities provide a tight caged radical reaction space, controlling the entire radical path. The GM active site is perfectly structured for promoting radical catalysis including ‘negative catalysis’, a paradigm for AdoCbl-dependent mutases.

Computational approaches to organocatalysis: This review is focused on the different computational approaches that have been applied within the organocatalysis field. A huge effort from the theoretical chemistry field has been made in order to prove that de novo design of effective catalysts for different types of reactions is a long-term target, yet a palpable phenomenon.

Abstract

It is clear that the field of organocatalysis is continuously expanding during the last decades. With increasing computational capacity and new techniques, computational methods have provided a more economic approach to explore different chemical systems. This review offers a broad yet concise overview of current state-of-the-art studies that have employed novel strategies for catalyst design. The evolution of the all different theoretical approaches most commonly used within organocatalysis is discussed, from the traditional approach, manual-driven, to the most recent one, machine-driven.

Chemoselective conjugation to the multitude of functional groups at the surface of proteins is challenging. Most commonly lysine, cysteine or tyrosine are targeted, however in recent years a range of innovative methods have been developed to selectively target other amino acids at proteins and these methods are the focus of this review.

Abstract

Protein bioconjugates are in high demand for applications in biomedicine, diagnostics, chemical biology and bionanotechnology. Proteins are large and sensitive molecules containing multiple different functional groups and in particular nucleophilic groups. In bioconjugation reactions it can therefore be challenging to obtain a homogeneous product in high yield. Numerous strategies for protein conjugation have been developed, of which a vast majority target lysine, cysteine and to a lesser extend tyrosine. Likewise, several methods that involve recombinantly engineered protein tags have been reported. In recent years a number of methods have emerged for chemical bioconjugation to other amino acids and in this review, we present the progress in this area.