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Since the milestone contribution by Chen and White in 2007, bioinspired non‐heme bis‐amino‐bis‐pyridylmethyl Fe complexes have been at the forefront of studies related to designing catalytic approaches for direct oxidative functionalization of aliphatic C−H bonds. This, however, has not developed into large‐scale synthetic applications to date. The present concept is aimed at briefly discussing the state‐of‐the‐art of non‐heme Fe catalyzed oxidations of organic molecules with H2O2, the current oxidant of choice of bioinspired oxidation catalysis, mostly focusing on C−H oxidations, and analyzing the peculiarities of their reactivity through the prism of potential applications in fine organic synthesis. [ABSTRACT FROM AUTHOR]

A bulky, tridentate phenolate ligand (ImPh2NNOtBu) was used to synthesise the first example of a mononuclear, facial, N,N,O‐bound iron(II) benzoylformate complex, [Fe(ImPh2NNOtBu)(BF)] (2). The X‐ray crystal structure of 2 reveals that the iron centre is pentacoordinate (τ=0.5), with a vacant site located cis to the bidentate BF ligand. The Mössbauer parameters of 2 are consistent with high‐spin iron(II), and are very close to those reported for α‐ketoglutarate‐bound non‐heme iron enzyme active sites. According to NMR and UV‐vis spectroscopies, the structural integrity of 2 is retained in both coordinating and non‐coordinating solvents. Cyclic voltammetry studies show that the iron centre has a very low oxidation potential and is more prone to electrochemical oxidation than the redox‐active phenolate ligand. Complex 2 reacts with NO to form a S=3/2 {FeNO}7 adduct in which NO binds directly to the iron centre, according to EPR, UV‐vis, IR spectroscopies and DFT analysis. Upon O2 exposure, 2 undergoes oxidative decarboxylation to form a diiron(III) benzoate complex, [Fe2(ImPh2NNOtBu)2(μ2‐OBz)(μ2‐OH)2]+ (3). A small amount of hydroxylated ligand was also observed by ESI‐MS, hinting at the formation of a high‐valent iron(IV)‐oxo intermediate. Initial reactivity studies show that 2 is capable of oxygen atom transfer reactivity with O2, converting methyl(p‐tolyl)sulfide to sulfoxide. [ABSTRACT FROM AUTHOR]

A self-assembled FeII4 L6 cage was synthesized with 12 internal amines in the cavity. The cage forms as the dodeca-ammonium salt, despite the cage carrying an overall 8+ charge at the metal centers, extracting protons from displaced water in the reaction. Despite this, the basicity of the internal amines is lower than their counterparts in free solution. The 12 amines have a sliding scale of basicity, with a ≈6 pKa unit difference between the first and last protons to be removed. This moderation of side-chain basicity in an active site is a hallmark of enzymatic catalysis.

Comprehensive Summary: Dehydration of serine/threonine residues necessitates the activity of a dehydratase enzyme (domain) during the biosynthesis of RiPP. Recently, it was reported that dehydration in the thioviridamide pathway relies on a distinct dehydratase complex that showcases the activities of a phosphotransferase TvaC for serine/threonine phosphorylation and a lyase TvaD for subsequent phosphate elimination. Herein, we report that dehydration reactions in the pathway of lantibiotic cacaoidin involves a similar dehydratase complex, CaoK/CaoY. Remarkably, this dehydratase complex exhibits flexible enzymatic activity and tolerates significant variations in its substrate peptide sequence. By binding with the leader peptide (LP) sequence of precursor peptide CaoA, the dehydration reactions proceed in a directional manner from the C‐terminus of the core peptide (CP) to the N‐terminus, and C‐terminally truncated variants of CP are acceptable. We show that fusing CaoK to CaoY in a 1 : 1 molar ratio enables the resulting enzyme CaoYK to exert enhanced dehydration activity. CaoK binds with the LP to improve its own solubility and to ensure the phosphate transfer activity, while CaoY functions in a manner independently of LP. This work advances our understanding of the dehydration process during cacaoidin formation, and provides useful enzymes and methods for the studies of the rapidly emerging RiPPs. [ABSTRACT FROM AUTHOR]

Nanoparticles exhibiting enzymatic functions have garnered considerable attention due to their structural robustness and the profusion of active sites that can be introduced to a single nanosized particle. Here we report that nanosized mixed‐metal zeolitic imidazolate frameworks (ZIFs) show a superoxide dismutase (SOD)‐like catalytic activity. We chose a ZIF composed of copper and zinc ions and 2‐methylimidazole, CuZn‐ZIF‐8, in which the Cu and Zn ions are bridged by an imidazolato ligand. This coordination geometry closely mimics the active site of CuZn superoxide dismutase (CuZnSOD). The CuZn‐ZIF‐8 nanoparticles exhibit potent SOD‐like activity, attributed to their porous nature and numerous copper active sites, and also possess exceptional recyclability. [ABSTRACT FROM AUTHOR]

We present a Nip site model of acetyl coenzyme-A synthase (ACS) within a de novo-designed trimer peptide that self-assembles to produce a homoleptic Ni(Cys)3 binding motif. Spectroscopic and kinetic studies of ligand binding demonstrate that Ni binding stabilizes the peptide assembly and produces a terminal NiI-CO complex. When the CO-bound state is reacted with a methyl donor, a new species is quickly produced with new spectral features. While the metal-bound CO is albeit unactivated, the presence of the methyl donor produces an activated metal-CO complex. Selective outer sphere steric modifications demonstrate that the physical properties of the ligand-bound states are altered differently depending on the location of the steric modification above or below the Ni site. [ABSTRACT FROM AUTHOR]

In class Ib ribonucleotide reductases (RNRs) a dimanganese(II) cluster activates superoxide (O2⋅−) rather than dioxygen (O2), to access a high valent MnIII−O2−MnIV species, responsible for the oxidation of tyrosine to tyrosyl radical. In a biomimetic approach, we report the synthesis of a thiolate‐bound dimanganese complex [MnII2(BPMT)(OAc)2](ClO)4 (BPMT=(2,6‐bis{[bis(2‐pyridylmethyl)amino]methyl}‐4‐methylthiophenolate) (1) and its reaction with O2⋅− to form a [(BPMT)MnO2Mn]2+ complex 2. Resonance Raman investigation revealed the presence of an O−O bond in 2, while EPR analysis displayed a 16‐line St=1/2 signal at g=2 typically associated with a MnIIIMnIV core, as detected in class Ib RNRs. Unlike all other previously reported Mn−O2−Mn complexes, generated by O2⋅− activation at Mn2 centers, 2 proved to be a capable electrophilic oxidant in aldehyde deformylation and phenol oxidation reactions, rendering it one of the best structural and functional models for class Ib RNRs. [ABSTRACT FROM AUTHOR]

[Display omitted] • Bromoacetyltryptamine (BAT) was more potent than Michael acceptor analogs in an AANAT enzymatic assay. • A two-carbon linker connecting bromoacetyl and bicycle of BAT was shown to be optimal for enzymatic potency. • In comparison with BAT, Michael acceptor analogs were much slower to react with CoASH. • Kinetic simulation was used to develop a mechanism of AANAT's alkyltransferase and acetyltransferase functions. Arylalkylamine N -acetyltransferase (AANAT) catalyzes the rate-limiting step in melatonin synthesis and is a potential target for disorders involving melatonin overproduction, such as seasonal affective disorder. Previously described AANAT inhibitor bromoacetyltryptamine (BAT) and benzothiophenes analogs were reported to react with CoASH to form potent bisubstrate inhibitors through AANAT's alkyltransferase function, which is secondary to its role as an acetyltransferase. We replaced the bromoacetyl group in BAT with various Michael acceptors to mitigate possible off-target activity of its bromoacetyl group. Additionally, we modified the length of the carbon linker between the Michael acceptor and indole bicycle of tryptamine to determine its effect on potency. An AANAT enzymatic assay showed a two-carbon linker present in BAT was optimal, while none of the new warheads had activity. Kinetic analysis indicated that these Michael acceptors reacted with CoASH much slower than BAT and not within the timeframe of our enzymatic assay. Additionally, we confirmed earlier reports that the acetyltransferase function of AANAT follows an ordered bi bi mechanism in which AcCoA binds before serotonin. In contrast, BAT's alkyltransferase kinetics revealed a bi uni mechanism in which BAT binds to AANAT before CoASH. Our model combines both functions of AANAT into one kinetic mechanism. [ABSTRACT FROM AUTHOR]

Mammalian nitric oxide synthase (NOS) mediates the two‐step O2‐dependent oxidative degradation of arginine, and has been linked to a medley of disease situations in humans. Nonetheless, its exact mechanism of action still remains unclear. This work presents the first NOS model system where biologically proposed heme superoxo and peroxo intermediates are assessed as active oxidants against oxime substrates. Markedly, heme peroxo intermediates engaged in a bioinspired oxime oxidation reaction pathway, converting oximes to ketones and nitroxyl anions (NO−). Detailed thermodynamic, kinetic, and mechanistic interrogations all evince a rate‐limiting step primarily driven by the nucleophilicity of the heme peroxo moiety. Coherent with other findings, 18O and 15N isotope substitution experiments herein suffice compelling evidence toward a detailed mechanism, which draw close parallels to one of the enzymatic proposals. Intriguingly, recent enzymatic studies also lend credence to these findings, and several relevant reaction intermediates have been observed during NOS turnover. [ABSTRACT FROM AUTHOR]

Disulfide formation generally involves a two-electron oxidation reaction between cysteine residues. Additionally, disulfide formation is an essential post-translational modification for the structural maturation of proteins. This oxidative folding is precisely controlled by an electron relay network constructed by protein disulfide isomerase (PDI), with a CGHC sequence as the redox-active site, and its family enzymes. Creating reagents that mimic the functions of these enzymes facilitates folding during chemical protein synthesis. In this study, we aimed to imitate a biological electron relay system using cyclic diselenide compounds as surrogates for endoplasmic reticulum oxidoreductin 1 (Ero1), which is responsible for the re-oxidation of PDI. Oxidized PDI (PDI ox ) introduces disulfide bonds into substrate proteins, resulting in its conversion to reduced PDI (PDI red ). The PDI red is then re-oxidized to PDI ox by a coexisting cyclic diselenide compound, thereby restoring the function of PDI as a disulfide-forming agent. The produced diselenol state is readily oxidized to the original diselenide state with molecular oxygen, continuously sustaining the PDI catalytic cycle. This artificial electron relay system regulating enzymatic PDI function effectively promotes the oxidative folding of disulfide-containing proteins, such as insulin - a hypoglycemic formulation - by enhancing both yield and reaction velocity., (© 2024 Wiley-VCH GmbH.)

The active site of particulate methane monooxygenase (pMMO) and its mechanism of action are not known. Recently, the CuC site emerged as a potential active site, but to date it lacks any study on biomimetic resemblance of the coordination environment provided by the enzyme. Here, the synthesis of a cage ligand providing such an environment is reported. Copper is incorporated, and coordination occurs by the two imidazole and one carboxylate group offered by the ligand. Depending on the oxidation state, it can adopt different coordination modes, as evidenced by the solid‐state structures and computational investigation. The copper(I) state readily reacts with dioxygen and thereby undergoes CH activation. Moreover, the catalytic aerobic oxidation of hydroquinones as ubiquinol mimics is shown. Clean one‐electron oxidation occurs under mild conditions and EPR analysis of the copper(II) state in the presence of water reveals striking similarities to the data obtained from pMMO. [ABSTRACT FROM AUTHOR]

Aiming at studying cooperativity effects between amino acids in easily accessible protein models, we have explored the chemistry of peptide dendrimers, which we obtain as pure products by solid-phase peptide synthesis using a branching diamino acid such as lysine at every second or third position in a peptide sequence, followed by reverse-phase HPLC purification. This article reviews discoveries driven by combinatorial library synthesis and screening, including enantioselective esterase and aldolase enzyme models, cobalamin binding and peroxidase dendrimers, glycopeptide dendrimer biofilm inhibitors and their X-ray crystal structures as complexes with lectins, antimicrobial peptide dendrimers active against multidrug resistant Gram-negative bacteria, and transfection reagents for siRNA and CRISPR-Cas9 plasmid DNA. Latest developments include cheminformatics and artificial intelligence for exploring the peptide chemical space, and the principle of stereorandomization to understand the role of peptide chirality in activity.

Abstract A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti‐cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure‐based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors.

The electron rich Fe2(pdt)(RNC)61 (pdt=CH2(CH2S−)2) has been used as starting point for a DFT multi‐functional study to assess the feasibility of designing a stable inverted (or rotated) disposition of the two FeL3 pyramidal moieties in the dimetallic core, a key feature of [FeFe]‐hydrogenase cofactor. The choice of 1 was motivated by the presence of a rotated form in solution, slightly less stable than the unrotated stereoisomer. Aimed to find an upgraded version of 1, featuring the rotated isomer as ground state, various combinations of factors have been tested, for their effect on the relative stability of rotated vs unrotated isomers. The general result is that combining coordination asymmetry, electron donor presence and isocyanides R substituents able to establish intramolecular interactions is effective in stabilizing the rotated isomer. Our DFT study may inspire the design of synthetic biomimetics, with improved resemblance to the natural system. [ABSTRACT FROM AUTHOR]

In pursuit of mimicking the ubiquitous 2H1C motif in mononuclear non‐heme iron enzymes, two new bioinspired N,N,O phenolate ligands, BenzImNNO and ImPh2NNO, are synthesised and their coordination chemistry with zinc(II) and iron(II) is explored. BenzImNNO coordinates by means of an anionic κ3‐N,N,O donor set and readily forms homoleptic bisligated complexes, also in the presence of equimolar amounts of metal salt. In contrast, the increased steric bulk of ImPh2NNO promotes the formation of dinuclear complexes, [M2(ImPh2NNO)2(OTf)2] (M=Fe, Zn), with facially opposing metal sites, as a result of its unique bridging μ2:κ2‐N,N:κ1‐O coordination mode. We investigate the robustness of the ligand's dinucleating coordination mode during oxidative transformations and demonstrate that its coordination mode is retained upon triflate substitution for a biorelevant thiophenolate co‐ligand. [ABSTRACT FROM AUTHOR]

As S-donor metalloligands, the dithiolato [NiN2S2] complexes are employed to synthesize the bimetallic model of the active site of [NiFe]-Hydrogenases ([NiFe]-H2ases). In this work, three [NiN2S2] complexes were used to react with [NiCl2(PNP)] (PNP = (Ph2PCH2)2NCH3), respectively, to find out the influences of [NiN2S2] ligands on the structure and property of model complexes. It's interesting to find dianion [Ni(phma)]2− (H4phma = N,N'-1,2-phenylenebis(2-mercaptoacetamide)) and [Ni(ema)]2− (H4ema = N,N'-1,2-ethylenebis(2-mercaptoacetamide)) could afford the desired dinuclear models [Ni(phma)(μ-S,S′)Ni(PNP)] (1) and [Ni(ema)(μ-S,S′)Ni(PNP)] (2), while the reaction of neutral [Ni(bme-dach)] (bme-dach = N,N′-bis-2-methyl-mercaptopropyl-1,4-diazacycloheptane) only yielded a trinuclear complex [Ni{Ni(bme-dach)(μ-S,S′)}2][BF4]2 (3). The structures of these complexes have been carefully characterized by NMR, high resolution mass spectrometry, elemental analysis, and X-ray diffraction structure analysis. As the model of [NiFe]-H2ases, complex 1 could electrocatalyze H2 evolution with a rate constant of 9.35 × 103 M−1 s−1 in the presence of CH3COOH. [ABSTRACT FROM AUTHOR]

The active site of [FeFe]‐hydrogenase (H2ase) is preorganized with an amine (azadithiolate) as a proton relay and a [4Fe4S] subunit as an electron reservoir, which together lower the overpotential for proton reduction and hydrogen oxidation by multiple‐site concerted proton–electron transfer (MS‐CPET). Herein, we report a mononuclear manganese complex, fac‐[Mn(CO)3(6‐(2‐hydroxyphenol)‐2‐pyridine‐2‐quinoline) Br] (1), as a rare model to fully mimic the functions of the H2ase. In 1, a redox‐active bidentate ligand with a pendent phenol replicates the roles of the electron reservoir and the proton relay in the enzyme. Experimental and theoretical studies revealed two consecutive MS‐CPET processes in the catalytic cycle, in each of which an electron stored in the reductive ligand and a proton at the proximal phenol moiety are transferred to the Mn center in a concerted way. By virtue of this mechanism, complex 1 exhibited a low overpotential comparable to that of natural enzyme in electrochemical hydrogen production using phenol as a proton source. [ABSTRACT FROM AUTHOR]

α‐glucosidase inhibitors are potential antihyperglycemic agents. Seventeen chalcones derivatives (1–17) were synthesized by reactions of diversely substituted aldehydes with various ketones. The structures of compounds were characterized by using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS) and carbon, hydrogen, nitrogen (CHN) analysis. These synthetic molecules were tested for α‐glucosidase inhibitory activity. Acarbose was used as a standard drug and positive control in this study which exhibited an IC50 of 2.91±0.02 μM. Of seventeen, nine molecules 1‐3, 5, 6, 8, and 11‐13 displayed significant inhibition with IC50 values 1.19±0.19 to 15.79±0.99 μM. Compound 6 {(E)‐3‐(3,5‐dichloro‐2‐hydroxyphenyl)‐1‐(p‐tolyl)prop‐2‐en‐1‐one} with hydroxy and chloro substitutions was found to be the most active compound and a novel compound of this library with IC50=1.19±0.19 μM. Active molecules were subjected to in silico study to determine binding interactions with target site of α‐glucosidase. [ABSTRACT FROM AUTHOR]

The epigenetic marker 5‐methyl‐2′‐deoxycytidine (5mdC) is the most prevalent modification to DNA. It is removed inter alia via an active demethylation pathway: oxidation by Ten‐Eleven Translocation 5‐methyl cytosine dioxygenase (TET) and subsequent removal via base excision repair or direct demodification. Recently, we have shown that the synthetic iron(IV)‐oxo complex [FeIV(O)(Py5Me2H)]2+ (1) can serve as a biomimetic model for TET by oxidizing the nucleobase 5‐methyl cytosine (5mC) to its natural metabolites. In this work, we demonstrate that nucleosides and even short oligonucleotide strands can also serve as substrates, using a range of HPLC and MS techniques. We found that the 5‐position of 5mC is oxidized preferably by 1, with side reactions occurring only at the strand ends of the used oligonucleotides. A detailed study of the reactivity of 1 towards nucleosides confirms our results; that oxidation of the anomeric center (1′) is the most common side reaction. [ABSTRACT FROM AUTHOR]

Naturally‐occurring B12‐dependent enzymes catalyze various molecular transformations that are of particular interest from the viewpoint of biological chemistry as well as synthetic organic chemistry. Inspired by the unique property of the B12‐dependent enzymes, various catalytic reactions have been developed using its model complex. Among the B12 model complexes, heptamethyl cobyrinate, synthesized from natural vitamin B12, is highly soluble in various organic solvents and a redox active cobalt complex with an excellent catalysis in electroorganic synthesis. The electrochemical dechlorination of pollutant organic chlorides, such as DDT, was effectively catalyzed by the B12 complex. Modification of the electrode surface by the sol‐gel method to immobilize the B12 complex was also developed. The B12 modified electrodes were effective for the dehalogenation of organic halides with high turnover numbers based on the immobilized B12 complex. Electrolysis of an organic halide catalyzed by the B12 complex provided dechlorinated products under anaerobic conditions, while the electrolysis under aerobic conditions afforded oxygen incorporated products, such as an ester and amide along with dechlorination. Benzotrichloride was transformed into ethylbenzoate or N,N‐diethylbenzamide in the presence of ethanol or diethylamine, respectively. This amide formation was further expanded to a unique paired electrolysis. Electrochemical reductions of an alkene and alkyne were also catalyzed by the B12 complex. A cobalt‐hydrogen complex should be formed as a bioinspired intermediate. Using the B12 complex, light‐assisted electrosynthesis was also developed to save the applied energy. [ABSTRACT FROM AUTHOR]

In this contribution, the unique and unprecedented stereochemical phenomenon of an aldoxime dehydratase‐catalyzed enantioselective dehydration of racemic E‐ and Z‐aldoximes with selective formation of both enantiomeric forms of a chiral nitrile is rationalized by means of molecular modelling, comprising in silico mutations and docking studies. This theoretical investigation gave detailed insight into why with the same enzyme the use of racemic E‐ and Z‐aldoximes leads to opposite forms of the chiral nitrile. The calculated mutants with a larger or smaller cavity in the active site were then prepared and used in biotransformations, showing the theoretically predicted decrease and increase of the enantioselectivities in these nitrile syntheses. This validated model also enabled the rational design of mutants with a smaller cavity, which gave superior enantioselectivities compared to the known wild‐type enzyme, with excellent E‐values of up to E>200 when the mutant OxdRE‐Leu145Phe was utilized. [ABSTRACT FROM AUTHOR]

Nonheme iron dioxygenases catalyze vital reactions for biosystems including the biosynthesis of antibiotics. One such enzyme, namely the hygromycin biosynthesis enzyme (HygX), performs an oxidative ring‐closure reaction to form an ortho−ester product, which is a relevant reaction step for drug synthesis and biotechnology. To understand the selective reaction mechanism of oxidative ring‐closure to form ortho−ester products in HygX, we investigated its catalytic reaction mechanism leading to various products. Large active site cluster models were set‐up and various pathways for substrate activation have been calculated. The work identifies a high‐valent iron(IV)‐oxo species in the quintet spin state as the active oxidant that selectively abstracts a proton of an alcohol group of the substrate, which is followed by a hydrogen atom abstraction from a tertiary C−H group and rapid electron transfer. The latter‐formed biradical intermediate rearranges to form the desaturated ring‐closed product. The calculations show that an active site Lys residue donates positive charge to the metal−oxo group and guides the reaction to a chemoselective desaturation pathway. [ABSTRACT FROM AUTHOR]

A key part of the optimization of small molecules in pharmaceutical inhibitor development is to vary the molecular design to enhance complementarity of chemical features of the compound with the positioning of amino acids in the active site of a target enzyme. Typically this involves iterations of synthesis, to modify the compound, and biophysical assay, to assess the outcomes. Selective targeting of the anti-cancer carbonic anhydrase isoform XII (CA XII), this process is challenging because the overall fold is very similar across the twelve CA isoforms. To enhance drug development for CA XII we used a reverse engineering approach where mutation of the key six amino acids in the active site of human CA XII into the CA II isoform was performed to provide a protein chimera (chCA XII) which is amenable to structure-based compound optimization. Through determination of structural detail and affinity measurement of the interaction with over 60 compounds we observed that the compounds that bound CA XII more strongly than CA II, switched their preference and bound more strongly to the engineered chimera, chCA XII, based on CA II, but containing the 6 key amino acids from CA XII, behaved as CA XII in its compound recognition profile. The structures of the compounds in the chimeric active site also resembled those determined for complexes with CA XII, hence validating this protein engineering approach in the development of new inhibitors. [ABSTRACT FROM AUTHOR]

We present the synthesis and coordination chemistry of a bulky, tripodal N,N,O ligand, ImPh2NNOtBu (L), designed to model the 2‐His‐1‐carboxylate facial triad (2H1C) by means of two imidazole groups and an anionic 2,4‐di‐tert‐butyl‐subtituted phenolate. Reacting K‐L with MCl2 (M = Fe, Zn) affords the isostructural, tetrahedral non‐heme complexes [Fe(L)(Cl)] (1) and [Zn(L)(Cl)] (2) in high yield. The tridentate N,N,O ligand coordination observed in their X‐ray crystal structures remains intact and well‐defined in MeCN and CH2Cl2 solution. Reacting 2 with NaSPh affords a tetrahedral zinc thiolate complex, [Zn(L)(SPh)] (4), that is relevant to isopenicillin N synthase (IPNS) biomimicry. Cyclic voltammetry studies demonstrate the ligand's redox non‐innocence, where phenolate oxidation is the first electrochemical response observed in K‐L, 2 and 4. However, the first electrochemical oxidation in 1 is iron‐centred, the assignment of which is supported by DFT calculations. Overall, ImPh2NNOtBu provides access to well‐defined mononuclear, monoligated, N,N,O‐bound metal complexes, enabling more accurate structural modelling of the 2H1C to be achieved. [ABSTRACT FROM AUTHOR]

S=2 oxoiron(IV) species act as reactive intermediates in the catalytic cycle of nonheme iron oxygenases. The few available synthetic S=2 FeIV=O complexes known to date are often limited to trigonal bipyramidal and very rarely to octahedral geometries. Herein we describe the generation and characterization of an S=2 pseudotetrahedral FeIV=O complex 2 supported by the sterically demanding 1,4,7‐tri‐tert‐butyl‐1,4,7‐triazacyclononane ligand. Complex 2 is a very potent oxidant in hydrogen atom abstraction (HAA) reactions with large non‐classical deuterium kinetic isotope effects, suggesting hydrogen tunneling contributions. For sterically encumbered substrates, direct HAA is impeded and an alternative oxidative asynchronous proton‐coupled electron transfer mechanism prevails, which is unique within the nonheme oxoiron community. The high reactivity and the similar spectroscopic parameters make 2 one of the best electronic and functional models for a biological oxoiron(IV) intermediate of taurine dioxygenase (TauD‐J). [ABSTRACT FROM AUTHOR]

High‐valent metal‐oxo species are key intermediates for the oxygen atom transfer step in the catalytic cycles of many metalloenzymes. While the redox‐active metal centers of such enzymes are typically supported by anionic amino acid side chains or porphyrin rings, peptide backbones might function as strong electron‐donating ligands to stabilize high oxidation states. To test the feasibility of this idea in synthetic settings, we have prepared a nickel(II) complex of new amido multidentate ligand. The mononuclear nickel complex of this N5 ligand catalyzes epoxidation reactions of a wide range of olefins by using mCPBA as a terminal oxidant. Notably, a remarkably high catalytic efficiency and selectivity were observed for terminal olefin substrates. We found that protonation of the secondary coordination sphere serves as the entry point to the catalytic cycle, in which high‐valent nickel species is subsequently formed to carry out oxo‐transfer reactions. A conceptually parallel process might allow metalloenzymes to control the catalytic cycle in the primary coordination sphere by using proton switch in the secondary coordination sphere. [ABSTRACT FROM AUTHOR]

The design of biomimetic models of metalloenzymes needs to take into account many factors and is therefore a challenging task. We propose in this work an original strategy to control the second coordination sphere of a metal centre and its distal environment. A biomimetic complex, reproducing the first coordination sphere, is encapsulated in a self‐assembled hydrogen‐bonded capsule. The cationic complex is co‐encapsulated with its counter‐anion or with solvent molecules. The capsule is dynamic, allowing a fast in/out exchange of the co‐encapsulated species. It also provides both a hydrogen‐bonding site in the second coordination sphere and a source of proton as it can be deprotonated in the presence of the complex, providing a globally neutral host‐guest assembly. This simple and broad scope strategy is unprecedented in biomimetic studies. The approach appears to be a very promising method for the stabilisation of reactive species and for the study of their reactivity. [ABSTRACT FROM AUTHOR]

Three new hetero‐metallic copper(II)‐manganese(II) complexes, [(CuL)2Mn3(C6H5CO2)6] (1), [(CuL)2Mn(CH3CO2)2] (2), and {[(CuL)2Mn(C6H5CH2CO2)2] ⋅ 2CH3CN} (3), have been synthesized using [CuL] as "metalloligand" (where H2L=N,N′‐bis(2‐hydroxynaphthyl‐methylidene)‐1,3‐propanediamine). Single‐crystal structural analyses show an almost linear penta‐nuclear structure for complex 1 where a square planar [CuL] unit is connected to each of the two terminal MnII ions of a linear, centrosymmetric [Mn3(benzoate)6] unit through the double phenoxido bridges. Both complexes 2 and 3 possess a linear tri‐nuclear structure where two terminal square‐pyramidal [CuL] units are bonded to the central MnII ion through double phenoxido oxygen atoms along with a syn‐syn bridging acetate (for 2)/phenyl acetate (for 3). All three complexes exhibit catecholase, and phenoxazinone synthase‐like activities under aerial conditions. For catecholase like activity, the turnover numbers (kcat) are 595, 40, and 205 h−1 whereas, for phenoxazinone synthase like activity, the turnover numbers are 25, 4, and 11 h−1 for complexes 1–3, respectively. The mechanism of both catalytic oxidase activities is proposed on the basis of mass spectral evidences. Variable‐temperature (2–300 K) dc molar magnetic susceptibility measurements of 1 reveal antiferromagnetic interactions between the Cu−Mn centres (J1=−29.3 cm−1), and also between the Mn−Mn centres of the [Mn3(benzoate)6] unit (J2=−0.68 cm−1). On increasing the magnetic field at 2 K, its ground spin state changes from S=3/2 to S=5/2 at 4 T, attributable to the low value of J2 which makes the excited spin states close in energy with the ground spin state. Complexes 2 and 3 show antiferromagnetic coupling interactions between the Cu−Mn pairs with J values of −9.51, and −5.32 cm−1, respectively. [ABSTRACT FROM AUTHOR]

Cytochrome P450 (CYP450) enzymes play important roles in maintaining human health and their reaction rates are dependent on the first electron transfer from the reduction partner. Interestingly, experimental work has shown that this step is highly influenced by the addition of metal ions. To understand the effect of external perturbations on the CYP450 first reduction step, we have performed a computational study with model complexes in the presence of metal and organic ions, solvent molecules, and an electric field. The results show that these medium‐range interactions affect the driving force as well as electron‐transfer rates dramatically. Based on the location, distance, and direction of the ions/electric field, the catalytic reaction rates are enhanced or impaired. Calculations on a large crystal structure with bonded alkali metal ions indicated inhibition patterns of the ions. Therefore, we predict that the active forms of the natural CYP450 isozymes will not have more than one alkali metal ion bound in the second‐coordination sphere. As such, this study provides an insight into the activity of CYP450 enzymes and the effects of ions and electric field perturbations on their activity. [ABSTRACT FROM AUTHOR]

The design of biomimetic model complexes for the cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO) is reported, where the 3‐His coordination of the iron ion is simulated by three pyrazole donors of a trispyrazolyl borate ligand (Tp) and protected cysteine and cysteamine represent substrate ligands. It is found that the replacement of phenyl groups—attached at the 3‐positions of the pyrazole units in a previous model—by mesityl residues has massive consequences, as the latter arrange to a more spacious reaction pocket. Thus, the reaction with O2 proceeds much faster and afterwards the first structural characterization of an iron(II) η2‐O,O‐sulfinate product became possible. If one of the three Tp‐mesityl groups is placed in the 5‐position, an even larger reaction pocket results, which leads to yet faster rates and accumulation of a reaction intermediate at low temperatures, as shown by UV/Vis and Mössbauer spectroscopy. After comparison with the results of investigations on the cobalt analogues this intermediate is tentatively assigned to an iron(III) superoxide species. [ABSTRACT FROM AUTHOR]

Enzyme‐powered micro‐ and nanomotors are tiny devices inspired by nature that utilize enzyme‐triggered chemical conversion to release energy stored in the chemical bonds of a substrate (fuel) to actuate it into active motion. Compared with conventional chemical micro‐/nanomotors, these devices are particularly attractive because they self‐propel by utilizing biocompatible fuels, such as glucose, urea, glycerides, and peptides. They have been designed with functional material constituents to efficiently perform tasks related to active targeting, drug delivery and release, biosensing, water remediation, and environmental monitoring. Because only a small number of enzymes have been exploited as bioengines to date, a new generation of multifunctional, enzyme‐powered nanorobots will emerge in the near future to selectively search for and utilize water contaminants or disease‐related metabolites as fuels. This Minireview highlights recent progress in enzyme‐powered micro‐ and nanomachines. [ABSTRACT FROM AUTHOR]

To develop the synthetic methodology for [Fe]‐H2ase models, a new type of the Hantzsch ester moiety‐containing [Fe]‐H2ase models (1–7) has been synthesized on the basis of preparing a series of new 2,6‐disubstituted pyridine precursors (L1–L10). Thus, the iodo models [2‐COCH2‐6‐(HEH)C5H3N]Fe(CO)2I (1), {2‐COCH2‐6‐[C6H4(HEH)]C5H3N}Fe(CO)2I (2), and {2‐COCH2‐6‐[Me(HEH)]C5H3N}Fe(CO)2I (3) could be prepared by reactions of precursors 2‐TsOCH2‐6‐(HEH)C5H3N (L2), 2‐TsOCH2‐6‐[C6H4(HEH)]C5H3N (L6), and 2‐TsOCH2‐6‐[Me(HEH)]C5H3N (L10) with Na2Fe(CO)4 followed by treatment of the resulting Fe(0) intermediates M1, M2 and M3 with iodine, respectively. In addition, further treatment of model 1 with AgOTf followed by reaction of the resulting Fe(II) intermediate M4 with MeCN gave the MeCN‐coordinated model {[2‐COCH2‐6‐(HEH)C5H3N]Fe(CO)2(MeCN)}(OTf) (4), whereas reaction of precursor L2 with Na2Fe(CO)4 followed by treatment of intermediate M1 with dimers (RCO2)2 afforded benzoato models [2‐COCH2‐6‐(HEH)C5H3N]Fe(CO)2(O2CR) (5, R = 4‐ClC6H4; 6, 2,6‐F2C6H3; 7, 2‐F3CC6H4). All the new precursors L1–L10 and models 1–7 were characterized by various spectroscopic methods and for some of them by X‐ray crystallography. [ABSTRACT FROM AUTHOR]

Despite CYP102A1 (P450BM3) representing one of the most extensively researched metalloenzymes, crystallisation of its haem domain upon modification can be a challenge. Crystal structures are indispensable for the efficient structure‐based design of P450BM3 as a biocatalyst. The abietane diterpenoid derivative N‐abietoyl‐l‐tryptophan (AbiATrp) is an outstanding crystallisation accelerator for the wild‐type P450BM3 haem domain, with visible crystals forming within 2 hours and diffracting to a near‐atomic resolution of 1.22 Å. Using these crystals as seeds in a cross‐microseeding approach, an assortment of P450BM3 haem domain crystal structures, containing previously uncrystallisable decoy molecules and diverse artificial metalloporphyrins binding various ligand molecules, as well as heavily tagged haem‐domain variants, could be determined. Some of the structures reported herein could be used as models of different stages of the P450BM3 catalytic cycle. [ABSTRACT FROM AUTHOR]

The tungsten(IV) complex (Et4N)2[W(O)(mnt)2] (1; mnt = maleonitriledithiolate) was proposed (Sarkar et al., J. Am. Chem. Soc. 1997, 119, 4315) to be a functional analogue of the active center of the enzyme acetylene hydratase from Pelobacter acetylenicus, which hydrates acetylene (ethyne; 2) to acetaldehyde (ethanal; 3). In the absence of a satisfactory mechanistic proposal for the hydration reaction, we considered the possibility of a metal–vinylidene type activation mode, as it is well established for ruthenium-based alkyne hydration catalysts with anti-Markovnikov regioselectivity. To validate the hypothesis, the regioselectivity of tungsten-catalyzed alkyne hydration of a terminal, higher alkyne had to be determined. However, complex 1 was not a competent catalyst for the hydration of 1-octyne under the conditions tested. Furthermore, we could not observe the earlier reported hydration activity of complex 1 towards acetylene. A critical assessment of, and a possible explanation for the earlier reported results are offered. The title question is answered with "no".

Reaction of Cu(ClO4)2⋅6 H2O with a tripodal 2N2O ligand, H2Me2NL, having a p‐(dimethylamino)phenol moiety, in CH2Cl2/MeOH (1:1 v/v) under basic conditions under an inert gas atmosphere gave [Cu(Me2NL)(H2O)] (1). The same reaction carried out under aerobic conditions gave [Cu(Me2NL)(MeOH)]ClO4 (2), which could be obtained also from the isolated complex 1 by reaction with O2 in CH2Cl2/MeOH. The X‐ray crystal structures of 1 and 2 revealed similar square‐pyramidal structures, but 2 showed the (dimethylamino)phenoxyl radical features. Complex 1 exhibits characteristic CuII EPR signals of the dx2-y2 ground state in CH2Cl2/MeOH at 77 K, whereas 2 is EPR‐silent. The EPR and X‐ray absorption fine structure (XAFS) results suggest that 2 is assigned to the CuII–(dimethylamino)phenoxyl radical. However, complex 1 showed different features in the absence of MeOH. The EPR spectrum of the CH2Cl2 solution of 1 exhibits distortion from the dx2-y2 ground state and a temperature‐dependent equilibrium between the CuII–(dimethylamino)phenolate and the CuI–(dimethylamino)phenoxyl radical. From these results, CuII–phenoxyl radical complex 2 is concluded to be formed by the reaction of 1 with O2 via the CuI–phenoxyl radical species. [ABSTRACT FROM AUTHOR]

In the pursuit of carbon‐free fuels, hydrogen can be considered as an apt energy carrier. The design of molecular electrocatalysts for hydrogen production is important for the development of renewable energy sources that are abundant, inexpensive, and environmentally benign. Over the last 20 years, a large number of electrocatalysts have been developed, and considerable efforts have been directed toward the design of earth‐abundant, first‐row transition‐metal complexes capable of promoting electrocatalytic hydrogen evolution reaction (HER). In this context, numerical approaches have emerged as powerful tools to study the catalytic performances of these complexes. This review covers some of the most significant theoretical mechanistic studies of biomimetic and bioinspired homogeneous HER catalysts. The approaches employed to study the free energy landscapes are discussed and methods used to obtain accurate estimates of relevant observables required to study the HER are presented. Furthermore, the structural and electronic parameters that govern the reactivity, and are necessary to achieve efficient hydrogen production, are discussed in view of future research directions. [ABSTRACT FROM AUTHOR]

The biodegradation of compounds with C−F bonds is challenging due to the fact that these bonds are stronger than the C−H bond in methane. In this work, results on the unprecedented reactivity of a biomimetic model complex that contains an N‐bridged diiron‐phthalocyanine are presented; this model complex is shown to react with perfluorinated arenes under addition of H2O2 effectively. To get mechanistic insight into this unusual reactivity, detailed density functional theory calculations on the mechanism of C6F6 activation by an iron(IV)‐oxo active species of the N‐bridged diiron phthalocyanine system were performed. Our studies show that the reaction proceeds through a rate‐determining electrophilic C−O addition reaction followed by a 1,2‐fluoride shift to give the ketone product, which can further rearrange to the phenol. A thermochemical analysis shows that the weakest C−F bond is the aliphatic C−F bond in the ketone intermediate. The oxidative defluorination of perfluoroaromatics is demonstrated to proceed through a completely different mechanism compared to that of aromatic C−H hydroxylation by iron(IV)‐oxo intermediates such as cytochrome P450 Compound I. [ABSTRACT FROM AUTHOR]

Two bioinspired hydroxo‐bridged diferric complexes 6 and 7 with N4‐donor ligands of the PDP type (PDP=N,N′‐bis(pyridin‐2‐ylmethyl)‐2,2′‐bipyrrolidine), differing by substituents at the pyridine rings (4‐NMe2 in 7 vs. 3,5‐Me2‐4‐OMe in 6), efficiently catalyze the enantioselective alkene epoxidation with H2O2 and peracetic acid in the presence of a carboxylic acid additive (up to 99 catalyst turnover numbers, TON, toward epoxide, up to 94 % ee). Catalyst systems based on complex 7 display the high‐spin perferryl intermediate 7 aAA (S=3/2, g1, g2=3.69, g3=1.96), whereas catalyst systems based on complex 6 exhibit the low‐spin perferryl intermediate 6 aAA (S=1/2, g1=2.07, g2=2.01, g3=1.96). The S=3/2 and the S=1/2 intermediates directly react with cyclohexene and cyclohexane at low temperatures (−40 °C and −85 °C, respectively). The catalyst systems, exhibiting less reactive intermediate 7 aAA, demonstrate higher enantioselectivity (% ee) in the epoxidation of chalcone. The origin of the unprecedented high‐spin state of the perferryl intermediate is discussed. [ABSTRACT FROM AUTHOR]

Two nickel complexes supported by tridentate NS2 ligands, [Ni2(κ‐N,S,S,S′‐NPh{CH2(MeC6H2R′)S}2)2] (1; R′=3,5‐(CF3)2C6H3) and [Ni2(κ‐N,S,S,S′‐NiBu{CH2C6H4S}2)2] (2), were prepared as bioinspired models of the active site of [NiFe] hydrogenases. The solid‐state structure of 1 reveals that the [Ni2(μ‐ArS)2] core is bent, with the planes of the nickel centers at a hinge angle of 81.3(5)°, whereas 2 shows a coplanar arrangement between both nickel(II) ions in the dimeric structure. Complex 1 electrocatalyzes proton reduction from CF3COOH at −1.93 (overpotential of 1.04 V, with icat/ip≈21.8) and −1.47 V (overpotential of 580 mV, with icat/ip≈5.9) versus the ferrocene/ferrocenium redox couple. The electrochemical behavior of 1 relative to that of 2 may be related to the bent [Ni2(μ‐ArS)2] core, which allows proximity of the two Ni⋅⋅⋅Ni centers at 2.730(8) Å; thus possibly favoring H+ reduction. In contrast, the planar [Ni2(μ‐ArS)2] core of 2 results in a Ni⋅⋅⋅Ni distance of 3.364(4) Å and is unstable in the presence of acid. [ABSTRACT FROM AUTHOR]

At the redox‐active center of thioredoxin reductase (TrxR), a selenenyl sulfide (Se−S) bond is formed between Cys497 and Sec498, which is activated into the thiolselenolate state ([SH,Se−]) by reacting with a nearby dithiol motif ([SHCys59,SHCys64]) present in the other subunit. This process is achieved through two reversible steps: an attack of a cysteinyl thiol of Cys59 at the Se atom of the Se−S bond and a subsequent attack of a remaining thiol at the S atom of the generated mixed Se−S intermediate. However, it is not clear how the kinetically unfavorable second step progresses smoothly in the catalytic cycle. A model study that used synthetic selenenyl sulfides, which mimic the active site structure of human TrxR comprising Cys497, Sec498, and His472, suggested that His472 can play a key role by forming a hydrogen bond with the Se atom of the mixed Se−S intermediate to facilitate the second step. In addition, the selenenyl sulfides exhibited a defensive ability against H2O2‐induced oxidative stress in cultured cells, which suggests the possibility for medicinal applications to control the redox balance in cells. [ABSTRACT FROM AUTHOR]

Myoglobin reconstituted with Ni tetradehydrocorrin was investigated as a model of F430‐containing methyl‐coenzyme M reductase, which catalyzes anaerobic methane generation. The NiII tetradehydrocorrin complex has a NiII/NiI redox potential of −0.34 V vs. SHE and EPR spectroscopy indicates the formation of a NiI species upon reduction by dithionite. This redox potential is approximately 0.31 V more positive than that of F430. The NiI tetradehydrocorrin moiety is bound to the apo‐form of myoglobin to yield the reconstituted protein. Methane gas is generated in the reaction of the model with methyl iodide in the presence of the reconstituted protein under reductive conditions, whereas the NiI complex itself does not produce methane gas. This is the first example of a protein‐based functional model of F430‐containing methyl‐coenzyme M reductase. [ABSTRACT FROM AUTHOR]

Ten‐eleven‐translocation (TET) methyl cytosine dioxygenases play a key role in epigenetics by oxidizing the epigenetic marker 5‐methyl cytosine (5mC) to 5‐hydroxymethyl cytosine (5hmC), 5‐formyl cytosine (5fC), and 5‐carboxy cytosine (5cC). Although much of the metabolism of 5mC has been studied closely, certain aspects—such as discrepancies among the observed catalytic activity of TET enzymes and calculated bond dissociation energies of the different cytosine substrates—remain elusive. Here, it is reported that the DNA base 5mC is oxidized to 5hmC, 5fC, and 5cC by a biomimetic iron(IV)‐oxo complex, reminiscent of the activity of TET enzymes. Studies show that 5hmC is preferentially turned over compared with 5mC and 5fC and that this is in line with the calculated bond dissociation energies. The optimized syntheses of d3‐5mC and d2‐5hmC are also reported and in the reaction with the biomimetic iron(IV)‐oxo complex these deuterated substrates showed large kinetic isotope effects, confirming the hydrogen abstraction as the rate‐limiting step. Taken together, these results shed light on the intrinsic reactivity of the C−H bonds of epigenetic markers and the contribution of the second coordination sphere in TET enzymes. [ABSTRACT FROM AUTHOR]

A self‐assembled Fe4L6 cage complex internally decorated with acid functions is capable of accelerating the thioetherification of activated alcohols, ethers and amines by up to 1000‐fold. No product inhibition is seen, and effective supramolecular catalysis can occur with as little as 5 % cage. The substrates are bound in the host with up to micromolar affinities, whereas the products show binding that is an order of magnitude weaker. Most importantly, the cage host alters the molecularity of the reaction: whereas the reaction catalyzed by simple acids is a unimolecular, SN1‐type substitution process, the rate of the host‐mediated process is dependent on the concentration of nucleophile. The molecularity of the cage‐catalyzed reaction is substrate‐dependent, and can be up to bimolecular. In addition, the catalysis can be prevented by a large excess of nucleophile, where substrate inhibition dominates, and the use of tritylated anilines as substrates causes a negative feedback loop, whereby the liberated product destroys the catalyst and stops the reaction. [ABSTRACT FROM AUTHOR]

Several copper(I) and copper(II) complexes supported by hemilabile bis(pyrazolylmethyl)amine (pzma) ligands are synthesized and structurally characterized. The copper(I) complexes with hexafluoridophosphate or perchlorate anions are employed as catalysts for the tyrosinase‐like oxygenation of 2,4‐di‐tert‐butylphenol (DTBP‐H). Their activities are comparable to that of [Cu(MeCN)2PMP]PF6 (PMP= pyrazolylmethylpyridine) investigated earlier. In contrast to the copper(I) pzma complexes, their congeners supported by non‐hemilabile bis(pyrazolylethyl)amine (pzea) ligands are found to be catalytically inactive. [ABSTRACT FROM AUTHOR]

Abstract The direct aldol reaction between a protected dihydroxyacetone derivative and 4-nitrobenzaldehyde catalyzed by chiral Zn2+ complexes of 1-(n -carboxylalkyl)-7-aminoacyl-1,4,7,10-tetraazacyclododecane is reported. New Zn2+ complexes containing l -histidine and carboxylalkyl chains that mimic a class II aldolase, carboxypeptidase A and a serine protease were designed and synthesized. Syn -aldol products were mainly formed by an aldol reaction of acetonide-protected dihydroxyacetone with benzaldehydes and other benzaldehydes in N -methylpyrrolidone (NMP)/alcohol (MeOH, EtOH or 2-PrOH) in good yields with a high degree of diastereo- and enantioselectivity (56%∼quant., 57∼>99% ee). Mechanistic aspect based on ESI-HRMS, elemental analysis and pH titrations of model ligands is also discussed. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

[Display omitted] • The first functional model of α -ketoglutarate dependent halogenases in a catalytic process. • Direct Mn-catalyzed C(sp3)−H azidation using H 2 O 2 as oxidant and TMSN 3 as azide source. • The C(sp3)−H activation and subsequent C(sp3)−N bond formation are enantioselective. • Preferential N 3 vs. OH rebound is determined by the catalyst's ligand topology. α -Ketoglutarate dependent nonheme halogenases catalyze regioselective functionalization of aliphatic C H bonds via H abstraction by the ferryl site of the [X − FeIV = O] intermediate, followed by radical rebound to an adjacent halogen ligand X at the same Fe center. Herein we report biomimetic nonheme Mn complexes, possessing two labile cis - α coordination sites and capable of catalyzing the enantioselective azidation of C(sp3)−H groups. Proper ligand environment of the active sites imposes steric constraints on HO − Mn rebound, thus accounting for preferential C-radical rebound to the adjacent N 3 − Mn ligand. Such mechanism of selectivity control is analogous to that operating in the prototypical α -ketoglutarate-dependent nonheme iron halogenases. [ABSTRACT FROM AUTHOR]

Circadian rhythm (CR) dysregulation negatively impacts health and contributes to mental disorders. The role of melatonin, a hormone intricately linked to CR, is still a subject of active study. The enzyme arylalkylamine N-acetyltransferase (AANAT) is responsible for melatonin synthesis, and it is a potential target for disorders that involve abnormally high melatonin levels, such as seasonal affective disorder (SAD). Current AANAT inhibitors suffer from poor cell permeability, selectivity, and/or potency. To address the latter, we have employed an X-ray crystal-based model to guide the modification of a previously described AANAT inhibitor, containing a rhodanine-indolinone core. We made various structural modifications to the core structure, including testing the importance of a carboxylic acid group thought to bind in the CoA site, and we evaluated these changes using MD simulations in conjunction with enzymatic assay data. Additionally, we tested three AANAT inhibitors in a zebrafish locomotion model to determine their effects in vivo. Key discoveries were that potency could be modestly improved by replacing a 5-carbon alkyl chain with rings and that the central rhodanine ring could be replaced by other heterocycles and maintain potency., (© 2023 Wiley-VCH GmbH.)

Catalytic H2 oxidation has been dissected by means of DFT into the key steps common to the Fe2 unit of both the [FeFe]‐hydrogenase cofactor and selected biomimics. The aim was to elucidate the molecular details underlying the very different performances of the two systems. We found that the better enzyme performance is based on a single iron atom that is maintained electron‐poor, favoring H2 binding, although embedded within a highly electron‐rich cofactor, ensuring a facile oxidation of the Fe2–H2 adduct. This is due to 1) CN− coordinating to both iron atoms, due to their amphipathic Lewis acid/base properties, and 2) the 4Fe4S subunit further withdrawing electrons from the Fe2 core. Preserving a moderate electron deficiency at a single iron also helps the cofactor preserve hydride affinity, which favors H2 cleavage. Such valuable characteristics allow the biocatalyst to turnover close to equilibrium conditions. All previous biomimicry has shown, in contrast, the impossibility to properly balance the two apparently contrasting aforementioned requisites, although evident progress has been made by the H2‐ase community. Disclosure of the differences identified could inspire the design of novel biomimics, for instance, reconsidering the use of CN− in the catalyst architecture. Indeed, in the presence of bases normally employed in oxidative catalysis, undesired stable protonation at coordinated CN−, which affects the opposite process (proton reduction), could be overcome. Nature versus biomimicry: Dissecting H2 oxidation by the [FeFe]‐H2ase core in comparison with a series of Fe2S2 models has revealed that CN− ligands and the 4Fe4S subunit are the key to the higher catalytic performance of the enzyme compared with the synthetic compounds. Indeed, cyanides and cubane provide a single electron‐poor iron (which assists H2 binding) embedded within an electron‐rich environment, which in turn ensures a facile subsequent oxidation. [ABSTRACT FROM AUTHOR]