Search

Extensive research has been conducted on biomimetic interfaces mimicking the complex and diverse microenvironment of cell membranes to gain insights into bioactive compound interactions and membrane biophysics modulation. The present study proposes an innovative approach that combines five prospective label‐free methodologies (derivative spectroscopy, synchrotron small‐ and wide‐angle X‐Ray scattering, attenuated total reflection–Fourier‐transform infrared spectroscopy, quartz‐crystal microbalance with dissipation, and surface plasmon resonance) to showcase their synergistic capabilities and complementarity in investigating drug–membrane interactions. This multitechnique approach combines the real‐time monitoring of the adsorption process under continuous flow conditions with the steady‐state perspective of this process. As a proof of concept, the interaction of three bioactive compounds (caffeine, testosterone, and diclofenac) with two biomimetic membrane interfaces (multistacked lipid bilayers and supported lipid bilayers) mimicking the more ordered lipid transient phases, with and without cholesterol (lo and so), that are responsible for a variety of membrane‐associated biological activities, is investigated. The biophysical effects of the bioactives are discussed using complementary data from real‐time and steady‐state experiments, including membrane adsorption and distribution, predicted location, and induced changes in order and fluidity, encompassing bilayer thickness, hydration, and area per lipid molecule. [ABSTRACT FROM AUTHOR]

During the last three decades, numerous investigations have been conducted on polyoxidovanadates to treat several illnesses and inhibit enzymes. Numerous decavanadate compounds have been proposed as potential therapies for Diabetes mellitus, Cancer, and Alzheimer’s disease. Only six relevant functional proteins interacting with decavanadate, V10, have been deposited in the PDB. These are acid phosphatase, tyrosine kinase, two ecto-nucleoside triphosphate diphosphohydrolases (NTPDases), the human transient receptor potential cation channel (TRPM4), and the human cell cycle protein CksHs1. The interaction sites in these proteins mainly consist of Arginine and Lysine, side chains binding to the decavanadate anion. To get further knowledge regarding non-covalent interactions of decavanadate in protein environments, guanidinium and spermidinium decavanadates were synthesized, crystallized, and subjected to analysis utilizing various techniques, including FTIR, Raman, 51V-NMR, TGA, and X-ray diffraction. The DFT calculations were employed to calculate the interaction energy between the decavanadate anion and the organic counterions. Furthermore, the Quantum Theory of Atoms in Molecules (QTAIM) and Non-covalent Interaction-Reduced Density Gradient (NCI-RDG) analyses were conducted to understand the non-covalent interactions present in these adducts. Decavanadate can engage in electrostatic forces, van der Waals, and hydrogen bond interactions with guanidinium and spermidinium, as shown by their respective interaction energies. Both compounds were highly stabilized by strong hydrogen bond interactions N−H···O and weak non-covalent interactions C−H···O. In addition, the interactions between guanidinium and spermidinium cations and decavanadate anion form several stable rings. This study provides new information on non-covalent intermolecular interactions between decavanadate and small biomimetic models of arginine and lysine lateral chains in protein environments.

Using nanoparticles (NPs) in drug delivery has exhibited promising therapeutic potential in various cancer types. Nevertheless, several challenges must be addressed, including the formation of the protein corona, reduced targeting efficiency and specificity, potential immune responses, and issues related to NP penetration and distribution within 3-dimensional tissues. To tackle these challenges, we have successfully integrated iron oxide nanoparticles into neuroblastoma-derived extracellular vesicles (EVs) using the parental labeling method. We first developed a tissue-engineered (TE) neuroblastoma model, confirming the viability and proliferation of neuroblastoma cells for at least 12 days, supporting its utility for EV isolation. Importantly, EVs from long-term cultures exhibited no differences compared to short-term cultures. Concurrently, we designed Rhodamine (Rh) and Polyacrylic acid (PAA)-functionalized magnetite nanoparticles (Fe3O4@PAA-Rh) with high crystallinity, purity, and superparamagnetic properties (average size: 9.2 ± 2.5 nm). We then investigated the internalization of Fe3O4@PAA-Rh nanoparticles within neuroblastoma cells within the TE model. Maximum accumulation was observed overnight while ensuring robust cell viability. However, nanoparticle internalization was low. Taking advantage of the enhanced glucose metabolism exhibited by cancer cells, glucose (Glc)-functionalized nanoparticles (Fe3O4@PAA-Rh-Glc) were synthesized, showing superior cell uptake within the 3D model without inducing toxicity. These glucose-modified nanoparticles were selected for parental labeling of the TE models, showing effective NP encapsulation into EVs. Our research introduces innovative approaches to advance NP delivery, by partially addressing the challenges associated with 3D systems, optimizing internalization, and enhancing NP stability and specificity through EV-based carriers. Also, our findings hold the promise of more precise and effective cancer therapies while minimizing potential side effects. [ABSTRACT FROM AUTHOR]

Hydrogen peroxide is a versatile reductant that under the right conditions can react to form dioxygen in an electrochemical reaction. This reaction has a low carbon footprint and applications are being sought for batteries. In this work a computational study is presented on a recently reported nonheme iron(II) complex where we study mechanistic pathways leading to dioxygen formation from H2O2. The work shows that upon reduction of the iron(III)‐hydroperoxo species it rapidly leads through heterolytic cleavage of the dioxygen bond to form iron(IV)‐oxo(hydroxo). The dimerization reaction of two iron(IV)‐oxo(hydroxo) complexes then leads to formation of the dioxygen bond rapidly with small barriers. Dissociation of the dimer expels dioxygen in an exothermic reaction. An alternative mechanism through the formation of a μ‐1,2‐peroxo‐μ‐1,1‐hydroperoxodiiron(II) intermediate was also tested but found to be highly endergonic. These studies highlight the electrochemical feasibilities of nonheme iron(III)‐hydroperoxo complexes. [ABSTRACT FROM AUTHOR]

High‐valent metal‐oxo species play critical roles in enzymatic catalysis yet their properties are still poorly understood. In this work we report a combined experimental and computational study into biomimetic iron(IV)‐oxo and iron(III)‐oxo complexes with tight second‐coordination sphere environments that restrict substrate access. The work shows that the second‐coordination sphere slows the hydrogen atom abstraction step from toluene dramatically and the kinetics is zeroth order in substrate. However, the iron(II)‐hydroxo that is formed has a low reduction potential and hence cannot do OH rebound favorably. The tolyl radical in solution then reacts further with alternative reaction partners. By contrast, the iron(IV)‐oxo species reacts predominantly through OH rebound to form alcohol products. Our studies show that the oxidation state of the metal influences reactivities and selectivities with substrate dramatically and that enzymes will likely need an iron(IV) center to catalyze C−H hydroxylation reactions. [ABSTRACT FROM AUTHOR]

High‐valent iron(IV)‐oxo intermediates are versatile oxidants in the biotransformation of various substrates by metalloenzymes and catalyze essential reactions for human health as well as in the biodegradation of toxic organic pollutants in the environment. Herein, we report a biomimetic system that efficiently reacts with halophenols through defluorination reactions and characterize various short‐lived intermediates along the reaction mechanism. We study the reactivity pattern of a nonheme iron(IV)‐oxo species with a series of trihalophenols (X=F, Cl, Br). A combined experimental and computational study reveals that the oxidative dehalogenation of 2,4,6‐trifluorophenol is initiated with an H‐atom abstraction from the phenolic group by the iron(IV)‐oxo species resulting in the formation of a phenolate radical and an iron(III)‐hydroxo species. This iron(III)‐hydroxo species forms an adduct with the oxidized substrate with λmax at 558 nm which subsequently decays to give quinones as products. [ABSTRACT FROM AUTHOR]

High‐valent metal‐oxo species are typical catalytic cycle intermediates in mono‐oxygenases and dioxygenases and commonly react through oxygen atom transfer to substrates. In this work we study a biomimetic model complex with a 1,1'‐bis((3,5‐dimethylpyridin‐2‐yl)methyl)‐2,2'‐bipiperidine ligand system bound to a manganese(IV)‐oxo(hydroxo) species and study its formation from manganese(II)‐hydroxo and H2O2 as well as its reaction with (S)‐1‐phenylisochromane through dehydrogenative α‐oxygenation. The work utilizes density functional theory methods to explore its catalytic cycle and its reactivity patterns. We show that the manganese(IV)‐oxo(hydroxo) species is an active oxidant and preferentially the oxo group abstracts a hydrogen atom from substrate with barriers well lower in energy than those found for hydrogen atom abstraction by the hydroxo group. Interestingly, the rate‐determining step is the OH rebound rather than the hydrogen atom abstraction, which would imply they would have limited kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium. [ABSTRACT FROM AUTHOR]

Hypohalites are commonly generated in biological systems, mostly with functions related to defense and immune system response. These hypohalites can bind to metal centers and are known for their strong oxidizing properties that play crucial roles in various biological processes. Herein, we report the synthesis, characterization and reactivity of novel biomimetic Ru(III)-hypochlorite complexes and focus the work on the electronic effects associated with the incorporation of methyl groups in a pentadentate ligand framework in an asymmetric fashion. The intermediates are stable at room temperature and were characterized by mass spectrometry, UV-vis absorption, resonance Raman and EPR spectroscopy. We show for the first time that the resultant ruthenium-hypochlorite adducts function as an electrophilic oxidant and efficiently catalyze hydrogen atom abstraction reactions from phenol and oxygen atom transfer reactions with dimethylsulfide., (© 2025 Wiley-VCH GmbH.)

Manman Sun,1 Ke Huang,1 Xueshi Luo,2,3 Hong Li1 1Department of Materials Science and Engineering, College of Chemistry and Materials Science, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 2The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong, People’s Republic of China; 3Department of Chemistry, College of Chemistry and Materials Science, Jinan University, Guangzhou, Guangdong, People’s Republic of ChinaCorrespondence: Xueshi Luo; Hong Li Tel +86 020 85223062Fax +86 020 85223271Email 1254914942@qq.com; tlihong@jnu.edu.cnPurpose: Bone metastasis is one of the common causes of death relative to breast cancer. However, the evolvement of bone niche in cancer progression remains poorly understood. A three-dimensional (3D) engineered bone matrix was developed as an effective biomimetic model to explore the mechanism relative to bone cancer metastasis.Methods: In the study, a 3D engineered bone matrix was developed via cell biomineralization templated by a biomimetic collagen template. The process of bone metastasis relative to breast cancer was investigated by co-culturing breast cancer MDA-MB-231-GFP cells with pre-osteogenic MC3T3-E1 cells on the 3D bone matrix.Results: A typical bone matrix was obtained, where mineralized collagen fibers were packed into the bundle to form a 3D engineered bone matrix. As the cancer cells were invading along the way vertical to the alignment of mineralized collagen fiber, the bone matrix gradually became thinner, accompanied with the erosion of Col I and the loss of calcium and phosphorus. As a result, the disassembled structure of mineralized collagen fiber was observed, which may be attributed to osteolytic bone metastasis.Conclusion: An engineered 3D bone-like matrix was successfully prepared via cell mineralization, which can act as a model for bone metastasis process. The study revealed mineralized collagen fiber disassembled at nanoscale relative to breast cancer cells.Keywords: biomimetic models, breast cancer, MDA-MB-231-GFP cells, bone metastasis

To develop the structural and functional modeling chemistry of [NiFe]-H2ases, we have carried out a study regarding the synthesis, structural characterization and reactivity of a new series of [NiFe]-H2ase model complexes. Thus, treatment of diphosphine dppb-chelated Ni complex (dppb)NiCl2 (dppb = 1,2-(Ph2P)2C6H4) with (dppv)Fe(CO)2(pdt) (dppv = 1,2-(Ph2P)2C2H2, pdt = 1,3-propanedithiolate) and NaBF4 gave dicarbonyl complex [(dppb)Ni(pdt)Fe(CO)2(dppv)](BF4)2 ([A](BF4)2). Further treatment of [A](BF4)2 with Me3NO and Bu4NCN or KSCN afforded t-cyanido and t-isothiocyanato complexes [(dppb)Ni(pdt)Fe(CO)(t-R)(dppv)]BF4 ([1]BF4, R = CN; [2]BF4, R = NCS), respectively. While azadiphosphine MeN(CH2PPh2)2-chelated t-hydride complex [MeN(CH2PPh2)2Ni(pdt)Fe(CO)(t-H)(dppv)]BF4 ([3]BF4) was prepared by treatment of dicarbonyl complex [MeN(CH2PPh2)2Ni(pdt)Fe(CO)2(dppv)](BF4)2 ([B](BF4)2) with Me3NO and 1.5 MPa of H2, treatment of dicarbonyl complex [B](BF4)2 with Me3NO (without H2) in pyridine resulted in formation of a novel monocarbonyl complex [MeN(CH2PPh2)2Ni(SCHCH2CH2S)Fe(CO)(dppv)]BF4 ([4]BF4) via the unexpected sp3 C-H bond activation reaction. Furthermore, azadiphosphine PhN(CH2PPh2)2-chelated µ-mercapto complex [PhN(CH2PPh2)2Ni(pdt)Fe(CO)(µ-SH)(dppv)]BF4 ([5]BF4) was prepared by treatment of dicarbonyl complex [PhN(CH2PPh2)2Ni(pdt)Fe(CO)2(dppv)](BF4)2 ([C](BF4)2) with Me3NO and H2S gas, whereas treatment of azadiphosphine Ph2CHN(CH2PPh2)2-chelated dicarbonyl complex [Ph2CHN(CH2PPh2)2Ni(pdt)Fe(CO)2(dppe)](BF4)2 ([D](BF4)2, dppe = 1,2-(Ph2P)2C2H4) with Me3NO⋅2H2O gave rise to µ-hydroxo complex [Ph2CHN(CH2PPh2)2Ni(pdt)Fe(CO)(µ-OH)(dppe)]BF4 ([6]BF4). All the possible pathways for formation of the new model complexes are briefly discussed, and their structures were fully characterized by various spectroscopic techniques and for six of them by X-ray crystallography. [ABSTRACT FROM AUTHOR]

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]

Eduarda Fernandes,1,2 Sofia Benfeito,3 Fernando Cagide,3 Hugo Gonçalves,4 Sigrid Bernstorff,5 Jana B Nieder,2 M Elisabete CD Real Oliveira,1 Fernanda Borges,3 Marlene Lúcio1,6 1Departamento de Física da Universidade do Minho, CF-UM-UP, Centro de Física das Universidades do Minho e Porto, Campus de Gualtar, Braga, 4710-057, Portugal; 2 Ultrafast Bio- and Nanophotonics Group, INL – International Iberian Nanotechnology Laboratory, Braga, Portugal; 3CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal; 4Paralab, SA, Valbom, 4420-392, Portugal; 5Elettra-Sincrotrone Trieste S. C.p.A.,, Basovizza, Trieste, I-34149, Italy; 6CBMA, Centro de Biologia Molecular e Ambiental, Departamento de Biologia, Universidade do Minho, Campus de Gualtar, Braga 4710-057, PortugalCorrespondence: Marlene LúcioUniversidade do Minho, Campus de Gualtar, Braga 4710-057, PortugalEmail mlucio@fisica.uminho.ptFernanda BorgesCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalEmail fborges@fc.up.ptPurpose: AntiOxCIN3 is a novel mitochondriotropic antioxidant developed to minimize the effects of oxidative stress on neurodegenerative diseases. Prior to an investment in pre-clinical in vivo studies, it is important to apply in silico and biophysical cell-free in vitro studies to predict AntiOxCIN3 biodistribution profile, respecting the need to preserve animal health in accordance with the EU principles (Directive 2010/63/EU). Accordingly, we propose an innovative toolbox of biophysical studies and mimetic models of biological interfaces, such as nanosystems with different compositions mimicking distinct membrane barriers and human serum albumin (HSA).Methods: Intestinal and cell membrane permeation of AntiOxCIN3 was predicted using derivative spectrophotometry. AntiOxCIN3 –HSA binding was evaluated by intrinsic fluorescence quenching, synchronous fluorescence, and dynamic/electrophoretic light scattering. Steady-state and time-resolved fluorescence quenching was used to predict AntiOxCIN3-membrane orientation. Fluorescence anisotropy, synchrotron small- and wide-angle X-ray scattering were used to predict lipid membrane biophysical impairment caused by AntiOxCIN3 distribution.Results and Discussion: We found that AntiOxCIN3 has the potential to permeate the gastrointestinal tract. However, its biodistribution and elimination from the body might be affected by its affinity to HSA (> 90%) and by its steady-state volume of distribution (VDSS=1.89± 0.48 L∙Kg− 1). AntiOxCIN3 is expected to locate parallel to the membrane phospholipids, causing a bilayer stiffness effect. AntiOxCIN3 is also predicted to permeate through blood-brain barrier and reach its therapeutic target – the brain.Conclusion: Drug interactions with biological interfaces may be evaluated using membrane model systems and serum proteins. This knowledge is important for the characterization of drug partitioning, positioning and orientation of drugs in membranes, their effect on membrane biophysical properties and the study of serum protein binding. The analysis of these interactions makes it possible to collect valuable knowledge on the transport, distribution, accumulation and, eventually, therapeutic impact of drugs which may aid the drug development process.Keywords: biomimetic models, biophysical profiling, drug–membrane interaction, blood–brain barrier permeability, drug distribution, small and wide-angle X-ray diffraction

The cytochrome P450 enzymes are important enzymes in the liver that trigger drug metabolism reactions. In biotechnology and biomimetic chemistry, synthetic models of the active species of P450 have been developed and designed and often react differently. Here, we investigate a biomimetic P450 model complex with phthalocyanine equatorial ligand rather than heme or porphyrin and with and without four tert-butyl substituents to the periphery of the ligand. Density functional theory studies on the electronic properties of the active species of the system, namely the iron(IV)-oxo with equatorial ligand cation radical species and its reactivity in oxygen atom transfer were studied. The work shows that a phthalocyanine equatorial ligand rather than porphyrin leads to a dramatic effect on the orbital energy levels of the iron(IV)-oxo species and creates a species with close-lying doublet and quartet spin states with two unpaired electrons in π*xz and π*yz for the Fe−O interaction coupled to a ligand radical in an a1u-type orbital. The latter contrasts P450 Compound I that has the a1u orbital doubly occupied and a singly occupied a2u orbital instead, As a consequence, our biomimetic model gives a reduced redox potential as compared to a system with a porphyrin-based radical and makes it a weaker oxidant. Nevertheless, the iron(IV)-oxo cation radical species with phthalocyanine ligand is shown to react with para-X-substituted thioanisole (X = CH3, Cl, CN, H, NO2, OCH3) substrates with small oxygen atom transfer barriers that align with the σ-Hammett parameter. The reactions are concerted with a single barrier leading to sulfoxide products. Synopsis: A series of density functional theory studies are presented on the electronic properties of a phthalocyanine ligated iron(IV)-oxo cation radical species and its reactivity with para-substituted thioanisole substrates. The studies show that despite the fact the reactant is electronically different from cytochrome P450 Compound I, it should react with sulfides in a concerted synchronous manner efficiently. [ABSTRACT FROM AUTHOR]

On the basis of biomimetic, phylometabolic, and thermodynamic analysis of modern CO2 assimilation pathways, a paleophenotypic reconstruction of ancient autotrophic metabolism systems was carried out. As a chemical basis for CO2 fixation paleometabolism, metabolic networks capable of self-reproduction and evolution are considered, and the reversibility of the transformation reactions of its intermediates is the most important factor in self-development of this network. The substances of the C–H–O system, paragenetically associated with hydrocarbons, create a phase space, which is a set of universal intermediates of the autotrophic paleometabolism chemical network. The concept of two strategies for the origin and development of autotrophic carbon fixation paleometabolism in the oxidized (CO2) and reduced (CH4) redox regimes of degassing of the ancient Earth is proposed. It was shown that P, T, and the redox conditions of hydrothermal systems of the early Archean were favorable for the development of primary methanotrophic metabolism. [ABSTRACT FROM AUTHOR]

Cardiovascular disease remains the number one cause of mortality and morbidity worldwide and includes atherosclerosis, which presents as a deadly and chronic inflammatory disease. The initial pathological factor in atherosclerosis is a dysfunctional endothelium (Dys-En), which results in enhanced permeability of the endothelium and enhanced expression of adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1), among others. Nanomedicines represent a growing arsenal of novel therapeutics aimed at treating atherosclerosis; however, nanoparticle (NP) interactions as a function of their biophysiochemical properties with the Dys-En are not currently well understood. In this study, we investigated targeted NP biophysicochemical properties for maximal VCAM-1 binding and permeability across several Dys-En models that we established using cardiovascular inflammatory mediators. We found that NP size governs permeability and binding, regardless of the type and density of VCAM-1 peptide ligand used. Our results suggest that the design of NPs in the range of 30–60 nm can highly increase permeability and binding across the Dys-En. These findings confirm the importance of in vitro models of Dys-En as a preliminary screening and predictive tool for atherosclerosis NP targeting. [ABSTRACT FROM AUTHOR]

Uranium is widely spread in the environment due to its natural and anthropogenic occurrences, hence the importance of understanding its impact on human health. The skeleton is the main site of long-term accumulation of this actinide. However, interactions of this metal with biological processes involving the mineralized extracellular matrix and bone cells are still poorly understood. To get a better insight into these interactions, we developed new biomimetic bone matrices containing low doses of natural uranium (up to 0.85 µg of uranium per cm2). These models were characterized by spectroscopic and microscopic approaches before being used as a support for the culture and differentiation of pre-osteoclastic cells. In doing so, we demonstrate that uranium can exert opposite effects on osteoclast resorption depending on its concentration in the bone microenvironment. Our results also provide evidence for the first time that resorption contributes to the remobilization of bone matrix-bound uranium. In agreement with this, we identified, by HRTEM, uranium phosphate internalized in vesicles of resorbing osteoclasts. Thanks to the biomimetic matrices we developed, this study highlights the complex mutual effects between osteoclasts and uranium. This demonstrates the relevance of these 3D models to further study the cellular mechanisms at play in response to uranium storage in bone tissue, and thus better understand the impact of environmental exposure to uranium on human bone health. [ABSTRACT FROM AUTHOR]

Cleavage and formation of the O-O bond in dioxygen is among the most important metal-dependent processes in Nature. The former process has been mimicked structurally and functionaly with a number of biomimetic iron complexes. The reverse process, namely the dioxygen bond formation, however, appears unfavorable with iron. Over the years many attempts have been made to oxidize water on a mononuclear iron center through reactions with peroxide. In this work we present a computational study focused on the mechanism of dioxygen formation on two mononuclear non-heme iron(IV)-oxo species upon addition of peracid (m-chloroperbenzoic acid, mCPBA). A range of test reactions and sequences are analyzed with thermochemical cycles with respect to the thermodynamic and kinetic feasibility of product formation. The work shows that iron-borne O-O bond formation through peracid attack at FeIVO indeed is feasible through two competing pathways. These are initiated by homolytic inner-sphere splitting of the RC(O)OO-H and the RC(O)O-OH bond in the peracid, respectively. [ABSTRACT FROM AUTHOR]

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood–brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug’s location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS = 5.75 ± 0.932 L·Kg−1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

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]

Methane hydroxylation by metal-oxo oxidants is one of the Holy Grails in biomimetic and biotechnological chemistry. The only enzymes known to perform this reaction in Nature are iron-containing soluble methane monooxygenase and copper-containing particulate methane monooxygenase. Furthermore, few biomimetic iron-containing oxidants have been designed that can hydroxylate methane efficiently. Recent studies reported that μ-nitrido-bridged diiron(IV)-oxo porphyrin and phthalocyanine complexes hydroxylate methane to methanol efficiently. To find out whether the reaction rates are enhanced by replacing iron by ruthenium, we performed a detailed computational study. Our work shows that the μ-nitrido-bridged diruthenium(IV)-oxo reacts with methane via hydrogen atom abstraction barriers that are considerably lower in energy (by about 5 kcal mol‒1) as compared to the analogous diiron(IV)-oxo complex. An analysis of the electronic structure implicates similar spin and charge distributions for the diiron(IV)-oxo and diruthenium(IV)-oxo complexes, but the strength of the O‒H bond formed during the reaction is much stronger for the latter. As such a larger hydrogen atom abstraction driving force for the Ru complex than for the Fe complex is found, which should result in higher reactivity in the oxidation of methane. [ABSTRACT FROM AUTHOR]

Mononuclear nonheme MnIII‐peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side‐on MnIII‐peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C−H by C−D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy. [ABSTRACT FROM AUTHOR]

Iron is an essential element in nonheme enzymes that plays a crucial role in many vital oxidative transformations and metabolic reactions in the human body. Many of those reactions are regio‐ and stereospecific and it is believed that the selectivity is guided by second‐coordination sphere effects in the protein. Here, results are shown of a few engineered biomimetic ligand frameworks based on the N4Py (N,N‐bis(2‐pyridylmethyl)‐N‐bis(2‐pyridyl)methylamine) scaffold and the second‐coordination sphere effects are studied. For the first time, selective substitutions in the ligand framework have been shown to tune the catalytic properties of the iron(IV)‐oxo complexes by regulating the steric and electronic factors. In particular, a better positioning of the oxidant and substrate in the rate‐determining transition state lowers the reaction barriers. Therefore, an optimum balance between steric and electronic factors mediates the ideal positioning of oxidant and substrate in the rate‐determining transition state that affects the reactivity of high‐valent reaction intermediates. It takes two: A combined spectroscopy and computational study on engineered iron(IV)‐oxo complexes identified a second‐coordination sphere effect that enables better positioning of the iron(IV)‐oxo and higher reactivity. [ABSTRACT FROM AUTHOR]

Chronic liver disease is characterized by progressive hepatic fibrosis leading to the formation of cirrhosis irrespective of the etiology with no effective treatment currently available. Liver stiffness (LS) is currently the best clinical predictor of this fibrosis progression irrespective of the etiology. LS and hepatocytes-nonparenchymal cells (NPC) interactions are two variables known to be important in regulating hepatic function during liver fibrosis, but little is known about the interplay of these cues. Here, we use polydimethyl siloxane (PDMS) based substrates with tunable mechanical properties to study how cell–cell interaction and stiffness regulates hepatocytes function. Specifically, primary rat hepatocytes were cocultured with NIH-3T3 fibroblasts on soft (2 kPa) and stiff substrates that recreates physiologic (2 kPa) and cirrhotic liver stiffness (55 kPa). Urea synthesis by primary hepatocytes depended on the presence of fibroblast and was independent of the substrate stiffness. However, albumin synthesis and Cytochrome P450 enzyme activity increased in hepatocytes on soft substrates and when in coculture with a fibroblast. Western blot analysis of hepatic markers, E-cadherin, confirmed that hepatocytes on soft substrates in coculture promoted better maintenance of the hepatic phenotype. These findings indicate the role of stiffness in regulating the hepatocytes interactions with NPCs necessary for maintenance of hepatocytes function.

Current in vitro practices must overcome important challenges to compare favorably with human studies. The limited applicability of conventional in vitro assays and strategies can be explained by the fact that standard approaches do not enable recapitulation of the complexity of human tissues and physiological functions. To address this challenge, novel bioengineering tools, techniques and technologies are rapidly emerging to advance current fundamental knowledge and innovate in vitro practices. For example, organs-on-a-chip have recently appeared as a small-scale solution to overcome the transability, financial and ethical concerns associated with animal studies in drug discovery and development. In parallel, biomimetic interfaces are increasingly recapitulating 3D structures with tissue-like dynamic properties to allow in-depth investigation of disease mechanisms. This review aims at highlighting current bioengineering approaches poised to address the shortcomings of conventional in vitro research practices towards the generation of more effective solutions for improving human health.

We report on the preparation and characterization of two new air‐stable mononuclear molybdenum(VI) complexes, termed MoVIO2(OPNO)2 (1) and MoVIO2(SPNO)2 (2). The potential of these complexes to act as functional mimics of molybdoenzymes from the DMSO reductase family was investigated. Initial catalytic studies suggest that 2 (but not 1) catalyzes the reduction of a sulfoxide into the thioether derivative. Studying the catalytic intermediates by UV/Vis spectroscopy, NMR spectroscopy, and DFT indicates that the active species (SPNO)2OMoV–O–MoVO(SPNO)2 (4), a dinuclear molybdenum(V) dimer with one µ‐oxo bridge, is formed upon successive reduction of the (SPNO)– ligands and the molybdenum(VI) ion. [ABSTRACT FROM AUTHOR]

Salen ligands are ubiquitous in inorganic chemistry with utility in applications ranging from materials to catalysis. Additionally, salen ligands have the potential for redox-activity due to energetically accessible molecular orbitals. This review will focus on elucidation of the electronic structure in oxidized metal–salen complexes. Due to the highly modular synthesis of these ligands, we present a comprehensive examination of structural factors that play a role in determining the overall electronic structure upon one-electron oxidation. Experimental and theoretical techniques used in the study of oxidized metal-salen complexes are presented, as well as the basics for the interpretation of such techniques. While the emphasis of the review is on complexes of the first-row transition metals, we briefly discuss second- and third-row transition metal–salen complexes, as well as salen-type ligand derivatives. [ABSTRACT FROM AUTHOR]

This paper illustrates the outcomes of a density functional theory investigation aimed at unraveling mechanistic aspects of the 5′-outer ring deiodination process of thyroxine (T4) assisted by the sterically protected organoselenol compound BpqSeH. BpqSeH, which was previously synthesized and tested for its deiodinase activity, is able to afford the active hormone 3,5,3′-tetraiodothyronine (T3) by selective outer-ring deiodination of T4, and to protect the SeH moiety inside the nano-sized molecular cavity from further reactivity, allowing its isolation and characterization. Calculations were also performed including an imidazole ring that, mimicking a His residue in the active site of the original enzyme, plays an crucial role in deprotonating the selenol moiety. Both the suggested enol/keto tautomerization and the previously proven formation of an intermediate whose main characteristic is the presence of a Se⋯I⋯C halogen bond, were examined along the pathway leading to 5′-outer ring deiodination. The calculated potential energy surface showed that neither the pathway encompassing enol/keto tautomerism nor the formation of a halogen bond paving the way to C-I bond breaking and chalcogen-I bond forming is viable. The exergonic formation of the final selenenyl iodide product confirms the stabilization effect of the molecular cavity. [ABSTRACT FROM AUTHOR]

Gentisate-1,2-dioxygenase (GDO), a nonheme iron enzyme in the cupin superfamily, catalyzes the cleavage of the aromatic-ring of 2,5-dihydroxybenzoic acid (gentisic acid) to form maleylpyruvic acid in the microbial aerobic degradation of aromatic compounds. To develop a functional model of GDO, we have isolated a nonheme iron(II) complex, [(TpPh2)FeII(DHN-H)] (TpPh2=hydrotris(3,5-diphenylpyrazole-1-yl)borate, DHN-H=1,4-dihydroxy-2-naphthoate). In the reaction with O2, the biomimetic complex oxidatively cleaves the aromatic ring of the coordinated substrate with the incorporation of both the oxygen atoms from molecular oxygen into the cleavage product. The presence of para-hydroxy group on the substrate plays a crucial role in directing the aromatic-ring cleaving reaction. [ABSTRACT FROM AUTHOR]

Metal-peroxo intermediates are key species in the catalytic cycles of nonheme metalloenzymes, but their chemical properties and reactivity patterns are still poorly understood. The synthesis and characterization of a manganese(III)-peroxo complex with a pentadentate bispidine ligand system and its reactivity with aldehydes was studied. Manganese(III)-peroxo can react through hydrogen-atom abstraction reactions instead of the commonly proposed nucleophilic addition reaction. Evidence of the mechanism comes from experiments which identify a primary kinetic isotope effect of 5.4 for the deformylation reaction. Computational modeling supports the established mechanism and identifies the origin of the reactivity preference of hydrogen-atom abstraction over nucleophilic addition. [ABSTRACT FROM AUTHOR]

Iron(III)-hydroperoxo complexes are found in various nonheme iron enzymes as catalytic cycle intermediates; however, little is known on their catalytic properties. The recent work of Banse and co-workers on a biomimetic nonheme iron(III)-hydroperoxo complex provided evidence of its involvement in reactivity with arenes. This contrasts the behavior of heme iron(III)-hydroperoxo complexes that are known to be sluggish oxidants. To gain insight into the reaction mechanism of the biomimetic iron(III)-hydroperoxo complex with arenes, we performed a computational (density functional theory) study. The calculations show that iron(III)-hydroperoxo reacts with substrates via low free energies of activation that should be accessible at room temperature. Moreover, a dominant ketone reaction product is observed as primary products rather than the thermodynamically more stable phenols. These product distributions are analyzed and the calculations show that charge interaction between the iron(III)-hydroxo group and the substrate in the intermediate state pushes the transferring proton to the meta-carbon atom of the substrate and guides the selectivity of ketone formation. These studies show that the relative ratio of ketone versus phenol as primary products can be affected by external interactions of the oxidant with the substrate. Moreover, iron(III)-hydroperoxo complexes are shown to selectively give ketone products, whereas iron(IV)-oxo complexes will react with arenes to form phenols instead. [ABSTRACT FROM AUTHOR]

This work presents a comparative study of the interaction of three porphyrins: the cationic meso-tetra(4- N, N, N-trimethylanilinium) porphine tetrachloride (T973); the anionic meso-tetra(4-carboxyphenyl) porphine (T790); and the neutral meso-tetra( p-hydroxyphenyl) porphine (T679) with model membranes, at two different pH values. The models for the biological membrane used were micelles of hexadecylphosphocholine and large unilamellar liposomes of egg yolk phosphatidylcholine. The liposome-buffer partition coefficients ( K) were determined by derivative spectrophotometry at two different pH values (7.4 and 5.8), in order to mimic plasma and tumor tissue conditions, respectively. Different types of partition were observed for different molecules, systems and pH values. Theoretical mathematical models, which accounted for the stoichiometry of the interaction, were used to fit the experimental data and determine the value of K. The values of K obtained are important in the choosing of a promising light-sensitizing agent to be used in photodynamic therapy for cancer treatment, since this parameter governs the distribution of the drug in the organism and the amount of drug that can be found on the site of irradiation. [ABSTRACT FROM AUTHOR]

Catechol intradiol dioxygenation is a unique reaction catalyzed by iron-dependent enzymes and non-heme iron(III) complexes. The mechanism by which these systems activate dioxygen in this important metabolic process remains controversial. Using a combination of kinetic measurements and computational modelling of multiple iron(III) catecholato complexes, we have elucidated the catechol cleavage mechanism and show that oxygen binds the iron center by partial dissociation of the substrate from the iron complex. The iron(III) superoxide complex that is formed subsequently attacks the carbon atom of the substrate by a rate-determining CO bond formation step. [ABSTRACT FROM AUTHOR]

Abstract: The catalytic oxidation of chlorhexidine (CHX, a strong microbicidal agent) mediated by ironporphyrins has been investigated by using hydrogen peroxide, mCPBA, tBuOOH, or NaOCl as oxidant. All of these oxygen donors yielded p-chloroaniline (pCA) as the main product. The higher pCA yields amounted to 71% in the following conditions: catalyst/oxidant/substrate molar ratio of 1:150:50, aqueous medium, FeTMPyP as catalyst. The medium pH also had a strong effect on the pCA yields; in physiological pH, formation of this product was specially favored in the presence of the catalysts, with yields 58% higher than those achieved in control reactions. This provided strong evidence that CHX is metabolized to pCA upon ingestion. [Copyright &y& Elsevier]

Abstract: Carbamazepine (CBZ), which is one of the most commonly prescribed antiepileptic drugs and also used in the treatment of trigeminal neuralgia and psychiatric disorders, is metabolized primarily by the cytochromes P450. A homologous series of β-brominated porphyrins derived from 5,10,15,20-tetrakis(4-carbomethoxyphenyl)porphyrinatomanganese(III) chloride, i.e., Mn(III)(Br x TCMPP)Cl (x =0, 2, 4, 6, and 8), was investigated as cytochrome P450 models for CBZ oxidation in CH2Cl2 by iodosylbenzene, iodobenzene diacetate, tert-butyl hydroperoxide, meta-chloroperoxybenzoic acid, and hydrogen peroxide. Unlike previous studies on metalloporphyrin-based CBZ oxidation, which yielded CBZ epoxide (CBZ-EP) as the sole product, the Mn(III)(Br x TCMPP)Cl systems catalyzed both the oxidation of CBZ to CBZ-EP and the formation of the respective vicinal diol, CBZ-DiOH. The influence of β-bromination of the macrocycle and the choice of the oxidant on the catalytic properties of the Mn(III)(Br x TCMPP)Cl (x =0, 2, 4, 6, and 8) series were examined. Some partially β-brominated Mn-porphyrins surpass the corresponding octabrominated analogue in efficiency and selectivity, but the extent by which the β-bromination affects the catalytic activity depends on the choice of oxidant. The selectivity for CBZ oxidation to yield the respective epoxide reached 100% or ∼94% by using tert-butyl hydroperoxide or hydrogen peroxide as oxygen donors, respectively. [Copyright &y& Elsevier]

A structural and functional model of bacterial nitric oxide reductase (NOR) has been designed by introducing two glutamates (Glu) and three histidines (His) in sperm whale myoglobin. X-ray structural data indicate that the three His and one Glu (V68E) residues bind iron, mimicking the putative FeB site in NOR, while the second Glu (1107E) interacts with a water molecule and forms a hydrogen bonding network in the designed protein. Unlike the first Glu (V68E), which lowered the heme reduction potential by ∼110 mV, the second Glu has little effect on the heme potential, suggesting that the negatively charged Glu has a different role in redox tuning. More importantly, introducing the second Glu resulted in a ∼100% increase in NOR activity, suggesting the importance of a hydrogen bonding network in facilitating proton delivery during NOR reactivity. In addition, EPR and X-ray structural studies indicate that the designed protein binds iron, copper, or zinc in the Fe6 site, each with different effects on the structures and NOR activities, suggesting that both redox activity and an intermediate five-coordinate heme-NO species are important for high NOR activity. The designed protein offers an excellent model for NOR and demonstrates the power of using designed proteins as a simpler and more well-defined system to address important chemical and biological issues. [ABSTRACT FROM AUTHOR]

Abstract: Primidone (PRM) oxidation by various oxidants such as iodosylbenzene (PhIO), tert-butyl hydroperoxide 70wt.% (t-BOOH), 3-chloroperoxybenzoic acid (m-CPBA) and hydrogen peroxide 30wt.%, mediated by either a salen complex or metalloporphyrins, was investigated. The catalytic systems led to phenylethylmalondiamide (PEMA) and phenobarbital (FENO), the same metabolites obtained in vivo with P450 enzymes, although three other products were also detected. Product formation was highly dependent on the oxidant, co-catalyst (imidazole), pH and dioxygen. These biomimetic chemical models have potential application in the synthesis of drug metabolites, which should provide samples for pharmacological tests. They can also be employed in studies that pursue the elucidation of in vivo drug metabolism. [Copyright &y& Elsevier]

Abstract: The flexibility of the coordination sphere in the diiron organometallic is likely an important design component in nature''s electrocatalyst for proton reduction or H2 oxidation, i.e, the active site of [FeFe]hydrogenase. A series of complexes, (μ-SCH2CRR′CH2S)[Fe(CO)3][Fe(CO)2L] with steric bulk incorporated into the μ-S-to-S linker was synthesized and the compounds were analyzed by infrared spectroscopy and cyclic voltammetry [(R/R′=Me/Me, Et/Et, Bu/Et), (L=CO, PPh3, IMes (1,3-bis(2,4,6-trimethylphenyl)-imidazol-2-ylidene), and IMe (1,3-dimethylimidazole-2-ylidene))]. While added steric bulk at the bridgehead carbon of the μ-SCH2CR2CH2S produced little change in the ground state structures (X-ray diffraction) and electronic character for the (μ-SRS)[Fe(CO)3]2 complexes, monosubstitution of a CO with L produced distortions consistent with steric interference of the μ-SRS with nearby ligands as compared to the similar (μ-pdt)[Fe(CO)3][Fe(CO)2L] (pdt=S(CH2)3S). Variable temperature NMR studies have shown that the activation barrier for CO site exchange on the sterically bulky complexes decreases in a manner predicted by theory [J.W. Tye, M.B. Hall, M.Y. Darensbourg, Inorg. Chem. 45 (2006) 1552]. [Copyright &y& Elsevier]

Abstract: In the present contribution, a density functional theory (DFT) investigation is described regarding a recently synthesized Fe6S6 complex – see C. Tard, X. Liu, S.K. Ibrahim, M. Bruschi, L. De Gioia, S.C. Davies, X. Yang, L.-S. Wang, G. Sawers, C.J. Pickett, Nature 433 (2005) 610 – that is structurally and functionally related to the [FeFe]-hydrogenases active site (the so-called H-cluster, which includes a binuclear subsite directly involved in catalysis and an Fe4S4 cubane). The analysis of relative stabilities and atomic charges of different isomers evidenced that the structural and redox properties of the synthetic assembly are significantly different from those of the enzyme active site. A comparison between the hexanuclear cluster and simpler synthetic diiron models is also described; the results of such a comparison indicated that the cubane moiety can favour the stabilization of the cluster in a structure closely resembling the H-cluster geometry when the synthetic Fe6S6 complex is in its dianionic state. However, the opposite effect is observed when the synthetic cluster is in its monoanionic form. [Copyright &y& Elsevier]

Abstract: The water oxidising enzyme, photosystem II, performs one of the most important reactions for life on Earth. Today, in the context of finding renewable sources of energy as alternatives for fossil fuels, the four-electron oxidation of water using light energy stands as one of the most challenging reactions for scientists to understand and reproduce. Mastering this reaction is considered to be a key step towards the use of water and sunlight to produce renewable hydrogen. It is therefore not only timely but also urgent to understand the mechanism of this enzyme so that this understanding can be used to design artificial catalysts. A chemical catalyst that shares the property of the enzyme in its ability to oxidize water with a low overpotential, could greatly improve the efficiency of water electrolysis and photolysis. Here we briefly describe aspects of the enzyme focusing on the essential cofactors involved in the light driven oxidation of water and provide an overview of the work done to produce a biomimetic photocatalyst for water oxidation. The development of such a device can be conceptualized as the association of two chemical modules, a photoactive unit and a catalytic unit. The candidate of choice for the photoactive unit, at least on a proof-of-principle basis, is [Ru(bpy)3]2+. This is due to its robustness, its synthetic flexibility and its unique photophysical properties. The elusive manganese catalyst acting as the catalytic site is dealt with in the previous chapters of this issue. In this review we discuss the different challenges that must be met to develop a synthetic system for water photolysis. These include (1) efficient light absorption by a sensitizer, (2) development of a stable charge separating device, (3) vectorial electron flow to/from, (3a) a donor site that must be capable to accumulate charges for consequent catalytic reactions, and (3b) an acceptor system that allows a multi-electron process. [Copyright &y& Elsevier]

Abstract: In this work, we investigated carbamazepine (CBZ) oxidation by 3-chloroperoxybenzoic acid (m-CPBA), tert-butyl hydroperoxide 70wt.% (t-BuOOH) or hydrogen peroxide 30wt.%, mediated by a salen complex in homogeneous medium or encapsulated in a polymeric matrix based on poly(dimethylsiloxane) (PDMS). The formation of carbamazepine 10,11-epoxide (CBZ-EP) is highly dependent on the oxidant, pH, solvent and co-catalyst. CBZ oxidation by m-CPBA, t-BuOOH and H2O2 is more efficient at low pH values, although the pH influence is small in the case of m-CPBA and t-BuOOH, in the entire pH range. This shows that the presence of substituents linked to the −OOH group of m-CPBA and t-BuOOH affects the catalytic activity of the studied system significantly. The encapsulated Jacobsen catalyst proved to be an efficient catalyst for carbamazepine oxidation by the oxidants t-BuOOH and m-CPBA. However, the hybrid polymeric membrane acted as a barrier against the oxidant H2O2, preventing it from reaching the bulk of the membrane, making substrate oxidation impossible in this case. [Copyright &y& Elsevier]

The biomimetic catalytic oxidation of 3,5-di-tert-butylcatechol by the dicopper(II) complex of the ligand a,a'-bis{bis[1-(1'-methyl-2'-benzimidazolyl)methyl]amino}-m-xylene in the presence of dioxygen has been investigated as a function of temperature and pH in a mixed aqueous/organic solvent. The catalytic cycle occurs in two steps, the first step being faster than the second step. In the first step, one molecule of catechol is oxidized by the dicopper(II) complex, and the copper(II) centers are reduced. From the pH dependence, it is deduced that the active species of the process is the monohydroxo form of the dinuclear complex. In the second step, the second molecule of catechol is oxidized by the dicopper(I)-dioxygen complex formed upon oxygenation of the reduced complex. In both cases, catechol oxidation is an inner-sphere electron transfer process involving binding of the catechol to the active species. The binary catechol-dicopper(II) complex formed in the first step could be characterized at very low temperature (-90 °C), where substrate oxidation is blocked. On the contrary, the ternary complex of dicopper(I)-O2-catechol relevant to the second step does not accumulate in solution and could not be characterized, even at low temperature. The investigation of the biphasic kinetics of the catalytic reaction over a range of temperatures allowed the thermodynamic (?H° and ?S°) and activation parameters (?H? and ?S?) connected with the key steps of the catecholase process to be obtained. [ABSTRACT FROM AUTHOR]

Copper(II) chelates of composition CuL2 were synthesized based on 4-aminomethylene derivatives of 5-thiopyrazoles (LH). The complexes were studied by UV, IR, ESR, and EXAFS spectroscopy, magnetochemistry, and X-ray diffraction analysis. The coordination polyhedra in the complexes are pseudotetrahedra or octahedra of the types CuN2S2 or CuN4S2, respectively, which are distorted due to the Jahn—Teller effect. The UV and ESR spectra of copper chelates with a six-coordinate metallocycle formed by the N and S atoms of the azomethine ligand and the nitrogen atom of the quinoline substituent (R) of the C=N−R fragment are most similar to the spectra observed for metals involved in the active centers of natural metalloenzymes (“blue” copper proteins). [ABSTRACT FROM AUTHOR]