Mechanism Insight into Direct Amidation Catalyzed by Zr Salts: Evidence of Zr Oxo Clusters as Active Species.

The capricious reactivity and speciation of earth-abundant metals (EAM) hinder the mechanistic understanding essential to boost their efficiency and versatility in catalysis. Moreover, metal's solution chemistry and reactivity are conventionally controlled using organic ligands, while their fundamental chemistry in operando conditions is often overlooked. However, in this study, we showcase how a better understanding of in operando conditions may result in improved catalytic reactions.

Phosphoester bond hydrolysis by a discrete zirconium-oxo cluster: mechanistic insights into the central role of the binuclear Zr-Zr active site.

Effective degradation of non-natural phosphate triesters (PTs) widely used in pesticides and warfare agents is of paramount relevance for human and environmental safety, particularly under acidic conditions where they are highly stable. Here, we present a detailed reactivity and mechanistic study pioneering discrete {ZrO} clusters, which are commonly employed as building blocks for Zr-MOFs and as non-classical soluble coordination compounds for the degradation of PTs using the pesticide ethyl paraoxon as a model. Combined computational studies, mechanistic experiments, and EXAFS analysis show that the reactivity of these clusters arises from their Zr-Zr bimetallic sites, which hydrolyze ethyl paraoxon under acidic conditions through an intramolecular pathway.

From Nanozymes to Multi-Purpose Nanomaterials: The Potential of Metal-Organic Frameworks for Proteomics Applications.

Metal-organic frameworks (MOFs) have the potential to revolutionize the biotechnological and medical landscapes due to their easily tunable crystalline porous structure. Herein, the study presents MOFs' potential impact on proteomics, unveiling the diverse roles MOFs can play to boost it. Although MOFs are excellent catalysts in other scientific disciplines, their role as catalysts in proteomics applications remains largely underexplored, despite protein cleavage being of crucial importance in proteomics protocols.

Green, Safe, and Reliable Synthesis of Bimetallic MOF-808 Nanozymes With Enhanced Aqueous Stability and Reactivity for Biological Applications.

Bimetallic metal-organic frameworks (MOFs) are promising nanomaterials whose reactivity towards biomolecules remains challenging due to issues related to synthesis, stability, control over metal oxidation state, phase purity, and atomic level characterization. Here, these shortcomings are rationally addressed through development of a synthesis of mixed metal Zr/Ce-MOFs in aqueous environment, overcoming significant hurdles in the development of MOF nanozymes, sufficiently stable on biologically relevant conditions. Specifically, a green and safe synthesis of Zr/Ce-MOF-808 is reported in water/acetic acid mixture which affords remarkably water-stable materials with reliable nanozymatic reactivity, including MOFs with a high Ce content previously reported to be unstable in water.

Exploring the Reactivity of Polyoxometalates toward Proteins: From Interactions to Mechanistic Insights.

The latest advances in the study of the reactivity of metal-oxo clusters toward proteins showcase how fundamental insights obtained so far open new opportunities in biotechnology and medicine. In this Perspective, these studies are discussed through the lens of the reactivity of a family of soluble anionic metal-oxo nanoclusters known as polyoxometalates (POMs). POMs act as catalysts in a wide range of reactions with several different types of biomolecules and have promising therapeutic applications due to their antiviral, antibacterial, and antitumor activities.

Regioselective protein oxidative cleavage enabled by enzyme-like recognition of an inorganic metal oxo cluster ligand.

Oxidative modifications of proteins are key to many applications in biotechnology. Metal-catalyzed oxidation reactions efficiently oxidize proteins but with low selectivity, and are highly dependent on the protein surface residues to direct the reaction. Herein, we demonstrate that discrete inorganic ligands such as polyoxometalates enable an efficient and selective protein oxidative cleavage.

Enhancing the Catalytic Activity of MOF-808 Towards Peptide Bond Hydrolysis through Synthetic Modulations.

The performance of MOFs in catalysis is largely derived from structural features, and much work has focused on introducing structural changes such as defects or ligand functionalisation to boost the reactivity of the MOF. However, the effects of different parameters chosen for the synthesis on the catalytic reactivity of the resulting MOF remains poorly understood. Here, we evaluate the role of metal precursor on the reactivity of Zr-based MOF-808 towards hydrolysis of the peptide bond in the glycylglycine model substrate.

Expanding the reactivity of inorganic clusters towards proteins: the interplay between the redox and hydrolytic activity of Ce(iv)-substituted polyoxometalates as artificial proteases.

The ability of soluble metal-oxo clusters to specifically interact with protein surfaces makes them attractive as potential inorganic drugs and as artificial enzymes. In particular, metal-substituted polyoxometalates (MS-POMs) are remarkably selective in hydrolyzing a range of different proteins. However, the influence of MS-POMs' redox chemistry on their proteolytic activity remains virtually unexplored.

Heterogeneous nanozymatic activity of Hf oxo-clusters embedded in a metal-organic framework towards peptide bond hydrolysis.

Materials with enzyme-like activities and proteolytic potential are emerging as a robust and effective alternative to natural enzymes. Herein, a HfO-based NU-1000 metal organic framework (Hf-MOF) is shown to act as a heterogeneous catalyst for the hydrolysis of peptide bonds under mild conditions. In the presence of Hf-MOF, a glycylglycine model dipeptide was hydrolysed with a rate constant of k = 8.

Interplay between structural parameters and reactivity of Zr-based MOFs as artificial proteases.

Structural parameters influencing the reactivity of metal-organic frameworks (MOF) are challenging to establish. However, understanding their effect is crucial to further develop their catalytic potential. Here, we uncovered a correlation between reaction kinetics and the morphological structure of MOF-nanozymes using the hydrolysis of a dipeptide under physiological pH as model reaction.

The Dawn of Metal-Oxo Clusters as Artificial Proteases: From Discovery to the Present and Beyond.

The selective cleavage of peptide bonds in proteins is of paramount importance in many areas of the biological and medical sciences, playing a key role in protein structure/function/folding analysis, protein engineering, and targeted proteolytic drug design. Current applications that depend on selective protein hydrolysis largely rely on costly proteases such as trypsin, which are sensitive to the pH, ionic strength, and temperature conditions. Moreover, >95% of peptides deposited in databases are generated from trypsin digests, restricting the information within the analyzed proteomes.

Diflunisal Derivatives as Modulators of ACMS Decarboxylase Targeting the Tryptophan-Kynurenine Pathway.

In the kynurenine pathway for tryptophan degradation, an unstable metabolic intermediate, α-amino-β-carboxymuconate-ε-semialdehyde (ACMS), can nonenzymatically cyclize to form quinolinic acid, the precursor for de novo biosynthesis of nicotinamide adenine dinucleotide (NAD). In a competing reaction, ACMS is decarboxylated by ACMS decarboxylase (ACMSD) for further metabolism and energy production. Therefore, the inhibition of ACMSD increases NAD levels.

Redox Activity of Ce(IV)-Substituted Polyoxometalates toward Amino Acids and Peptides.

Redox reactions between polyoxometalates (POMs) and biologically relevant molecules have been virtually unexplored but are important, considering the growing interest in the biological applications of POMs. In this work we give a detailed account on the redox behavior of Ce-substituted polyoxometalates (Ce-POMs) toward a range of amino acids and peptides. Ce-POMs have been shown to act as artificial proteases that promote the selective hydrolysis of peptide bonds.

Discrete Hf Metal-oxo Cluster as a Heterogeneous Nanozyme for Site-Specific Proteolysis.

The selective hydrolysis of proteins by non-enzymatic catalysis is difficult to achieve, yet it is crucial for applications in biotechnology and proteomics. Herein, we report that discrete hafnium metal-oxo cluster [Hf O (OH) (SO ) ⋅(H O) ] (Hf ), which is centred by the same hexamer motif found in many MOFs, acts as a heterogeneous catalyst for the efficient hydrolysis of horse heart myoglobin (HHM) in low buffer concentrations. Among 154 amino acids present in the sequence of HHM, strictly selective cleavage at only 6 solvent accessible aspartate residues was observed.

Connecting remote C-H bond functionalization and decarboxylative coupling using simple amines.

Transition metal-catalysed C-H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the past 30 years. Here, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a para-selective C-H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway that involves an uncommon Pd-catalysed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration.

Catalytic One-Step Deoxytrifluoromethylation of Alcohols.

A new bench-stable trifluoromethylation reagent, phenyl bromodifluoroacetate, converts readily available alcohols to trifluoromethanes in a Cu-catalyzed deoxytrifluoromethylation reaction. This reaction streamlines access to target biologically active molecules, and should be useful for a variety of medicinal, agricultural, and materials chemists.

Noncovalent Substrate-Directed Enantioselective Heck Reactions: Synthesis of S- and P-Stereogenic Heterocycles.

S- and P-Stereogenic heterocycles were synthesized by a remarkably simple enantioselective Heck desymmetrization reaction based on the unprecedented noncovalent directing effect of S=O and P=O functionalities. Selected prochiral symmetric substrates were efficiently arylated using the recently disclosed chiral PyraBOx ligand under mild and open-flask reaction conditions. Several five-membered aryl- sulfones, sulfoxides, and phosphine oxides were synthesized in good to excellent yields, in good to high diastereoselectivity, and enantiomeric ratios up to 98:2.

Co(III)-catalyzed C-H activation/formal SN-type reactions: selective and efficient cyanation, halogenation, and allylation.

The first cobalt-catalyzed cyanation, halogenation, and allylation via C-H activation have been realized. These formal SN-type reactions generate valuable (hetero)aryl/alkenyl nitriles, iodides, and bromides as well as allylated indoles using a bench-stable Co(III) catalyst. High regio- and mono-selectivity were achieved for these reactions.

The C-H activation/1,3-diyne strategy: highly selective direct synthesis of diverse bisheterocycles by Rh(III) catalysis.

The reactivity and selectivity of 1,3-diynes in transition-metal-catalyzed CH activation is exploited to quickly assemble diverse polysubstituted bisheterocycles, which are highly important but difficult to access. By using the CH activation/1,3-diyne strategy, we overcame the challenges of selectivity (chemo-, regio-, and mono-/diannulation) and constructed seven kinds of adjacent bisheterocycles through the formation of four strategic bonds with high efficiency and high selectivity.

Direct functionalization with complete and switchable positional control: free phenol as a role model.

PhenAll: Recent breakthroughs in site-selective and direct functionalization of free phenols by transition-metal-catalyzed C-O or C-H bond activation are highlighted here as role models for the complete and switchable positional control of transformations of important core structures.

α-MsO/TsO/Cl ketones as oxidized alkyne equivalents: redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles.

α-Halo and pseudohalo ketones are used for the first time as C(sp(3))-based electrophiles in transition-metal-catalyzed C-H activation and as oxidized alkyne equivalents in Rh(III)-catalyzed redox-neutral annulations to generate diverse N-heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated.