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Two alkylated verdazyl radicals (AlkVZs) were investigated as active compounds for photoinitiated controlled MCF-7 cell death. Observed results unambiguously showed that AlkVZ could be a potential structural moiety for the design of a novel family of photodynamic therapy agents. The main advantage of the proposed substances is an oxygen-independent generation of active radicals, which play a pivotal role in the treatment of oxygen-deficient tumors.

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Current chemotherapies suffer low specificity and sometimes drug resistance. Neutrophil elastase activity in cancer is associated with poor prognosis and metastasis settlement. More generally, tumors harbor various and persistent protease activities unseen in healthy tissues. In an attempt to be more specific, we designed prodrugs that are activatable by neutrophil elastase. Upon activation, these alkoxyamine-based drugs release cytotoxic alkyl radicals that act randomly to prevent drug resistance. As a result, U87 glioblastoma cells displayed high level caspase 3/7 activation during the first hour of exposure in the presence of human neutrophil elastase and the prodrug in vitro. The apoptosis process and cell death occurred between 24 and 48 h after exposure with a half lethal concentration of 150 μM. These prodrugs are versatile and easy to synthetize and can be adapted to many enzymes.

The nature of plasmon interaction with organic molecules is a subject of fierce discussion about thermal and non-thermal effects. Despite the abundance of physical methods for evaluating the plasmonic effects, chemical insight has not been reported yet. In this contribution, we propose a chemical insight into the plasmon effect on reaction kinetics using alkoxyamines as an organic probe through their homolysis, leading to the generation of nitroxide radicals. Alkoxyamines (TEMPO- and SG1-substituted) with well-studied homolysis behavior are covalently attached to spherical Au nanoparticles. We evaluate the kinetic parameters of homolysis of alkoxyamines attached on a plasmon-active surface under heating and irradiation at a wavelength of plasmon resonance. The estimation of kinetic parameters from experiments with different probes (Au–TEMPO, Au–SG1, Au–SG1–TEMPO) allows revealing the apparent differences associated with the non-thermal contribution of plasmon activation. Moreover, our findings underline the dependency of kinetic parameters on the structure of organic molecules, which highlights the necessity to consider the nature of organic transformations and molecular structure in plasmon catalysis., Kinetic study of alkoxyamine homolysis revealed the impact of non-thermal effects in plasmon-assisted reactions.

In 1986, Rizzardo et al. discovered the nitroxide-mediated polymerization which relies on the reversibility of homolysis of the C-ON bond of alkoxyamine R1R2NOR3, a unique property of these molecules. This discovery has generated a tremendous endeavor in the field of polymer chemistry. Alkoxyamines have been used as initiators/controllers for nitroxide-mediated polymerization. Moreover, photoexcitable alkoxyamines that dissociate under light at different wavelengths have also been developed for polymer chemistry. Over the past few years, alkoxyamines have started to be used in materials sciences. In many cases (e.g., self-healing polymers), the development of smart materials requires the use of smart building blocks, that is, molecules or systems whose properties and/or structures change upon external stimuli. Alkoxyamines exhibit a unique property: reversible homolysis (i.e., homolysis of the C-ON bond into alkyl R3• and nitroxyl R1R2NO• radicals and reformation via the coupling of these two species). Until now, this property has been controlled only by changes in temperatures or by light irradiation. Chemical and/or biochemical control of the homolysis event would open new gates for the application of these molecules in different fields such as biology and medicine. Thus, the concept of smart alkoxyamines is discussed and exemplified via the activation of alkoxyamines using chemical or/and biochemical changes amplifying the polar, steric, and stabilization effects. In situ activation is also discussed. It is shown that (i) increasing the electron-withdrawing properties of the alkyl fragment weakens the C-ON bond and thus favors homolysis but is opposite for the nitroxyl fragment; (ii) increasing the steric hindrance on the nonactive site affords dramatic conformation changes which weaken the C-ON bond; and (iii) increasing the stabilization of the released alkyl radical weakens the C-ON bond. Solvent effects and intramolecular hydrogen bonding are also discussed. Reactions used to highlight our purpose are either reversible or nonreversible and used under conditions that are as mild as possible (temperatures below 40 °C and atmospheric pressure). For example, a several (thousands of millions of) millions of orders of magnitude enhancement of the homolysis rate constant is observed upon enzymatic hydrolysis at 37 °C, meaning that a shift from a stable alkoxyamine (t1/2 = 42 000 milleniums) to a highly labile alkoxyamine (tmax = 1500 s for 35% conversion) is achieved. Applications of this concept are discussed for safe NMP initiators and for theranostic agents.

Polyunsaturated fatty acids like linolenic acid or arachidonic acid upon enzymatic hydroxylation (lipoxygenases) can lead to corresponding hydroperoxides. Their dehydration gave rise to vinyl allene oxides, which cyclized into cyclopentenones, precursors of jasmonic acid or prostanoids. The jasmonates, representing signal molecules involved in plant stress responses, in the defense against pathogens as well as in development.

International audience; Cost-effective and portable MRI systems operating at Earth-field would be helpful in poorly accessible areas or in developing nations. Furthermore Earth-field MRI can provide new contrasts opening the way to the observation of pathologies at the biochemical level. However low-field MRI suffers from a dramatic lack in detection sensitivity even worsened for molecular imaging purposes where biochemical specificity requires detection of dilute compounds. In a preliminary spectroscopic approach, it is proposed here to detect protease-driven hydrolysis of a nitroxide probe thanks to electron-nucleus Overhauser enhancement in a home-made double resonance system in Earth-field. The combination of the Overhauser effect and the specific enzymatic modification of the probe provides a smart contrast reporting the enzymatic activity. The nitroxide probe is a six-line nitroxide which lines are shifted according to its substrate/product state, which requires quantum mechanical calculations to predict EPR line frequencies and Overhauser enhancements at Earth field. The NMR system is equipped with a 13-mT prepolarization coil, a 153-MHz EPR coil and a 2-kHz NMR coil. Either prepolarized NMR or DNP-NMR without prepolarization provide NMR spectra within 3 min. The frequency dependence of Overhauser enhancement was in agreement with theoretical calculations. Protease-mediated catalysis of the nitroxide probe could only be measured through the Overhauser effect with 5 min time resolution. Future developments shall open the way for the design of new low-field DNP-MRI systems.

Alkoxyamines, which are connected with a phenol moiety by a (substituted) methylene bridge undergo homolytic cleavage upon chemical oxidation or a photo-induced hydrogen transfer. This selectively triggered reaction yields a nitroxide radical. In the presence of an excess of lead dioxide as the oxidant in tert-butylbenzene as solvent, spontaneous, instantaneous and almost quantitative generations of nitroxides from various alkoxyamines are observed at room temperature, which support activation energies for the cleavage lower than 100 kJ mol−1. The rate and the amount of released nitroxide depend on the amount of “catalyst” and the structure of alkoxyamines.

The excitation of localized plasmon resonance on nanoparticles followed by the interaction with organic molecules leads to new pathways of chemical reactions. Although a number of physical factors (temperature, illumination regime, type of nanoparticles, etc.) are affecting this process, the role of the chemical factors is underestimated. Challenging this assumption, here we studied the kinetic of plasmon-induced homolysis of five alkoxyamines (AAs) with different chemical and electronic structures using electron paramagnetic resonance (EPR). The kinetic data revealed the dependence of plasmonic homolysis rate constant (kd) with the HOMO energy of AAs, which cannot be described by the kinetic parameters derived from thermal homolysis experiments. The observed trend in kd allowed to suggest the key role of intramolecular excitation mechanism supported by the TDFDT calculations, additional spectroscopic characterization, and control experiments. Our work sheds light on the role of the electronic structure of organic molecules in plasmonic chemistry.

The excitation of localized plasmon resonance on nanoparticles followed by the interaction with organic molecules leads to new pathways of chemical reactions. Although a number of physical factors (temperature, illumination regime, type of nanoparticles, etc.) are affecting this process, the role of the chemical factors is underestimated. Challenging this assumption, here we studied the kinetic of plasmon-induced homolysis of five alkoxyamines (AAs) with different chemical and electronic structures using electron paramagnetic resonance (EPR). The kinetic data revealed the dependence of plasmonic homolysis rate constant (kd) with the HOMO energy of AAs, which cannot be described by the kinetic parameters derived from thermal homolysis experiments. The observed trend in kd allowed to suggest the key role of intramolecular excitation mechanism supported by the TDFDT calculations, additional spectroscopic characterization, and control experiments. Our work sheds light on the role of the electronic structure of organic molecules in plasmonic chemistry.

International audience; Photodynamic therapy (PDT) is a promising technique to treat different kinds of disease especially cancer. PDT requires three elements: molecular oxygen, a photoactivatable molecule called the photosensitizer (PS), and appropriate light. Under illumination, the PSs generate, in the presence of oxygen, the formation of reactive oxygen species including singlet oxygen, toxic, which then destroys the surrounding tissues. Even if PDT is used with success to treat actinic keratosis or prostate cancer for example, PDT suffers from two major drawbacks: the lack of selectivity of most of the PSs currently used clinically as well as the need for oxygen to be effective. To remedy the lack of selectivity, targeting the tumor neovessels is a promising approach to destroy the vascularization and cause asphyxia of the tumor. KDKPPR peptide affinity for the neuropilin-1 (NRP-1) receptor overexpressed on endothelial cells has already been proven. To compensate for the lack of oxygen, we focused on photoactivatable alkoxyamines (Alks), molecules capable of generating toxic radicals by light activation. In this article, we describe the synthesis of a multifunctional platform combining three units: a PS for an oxygen-dependent PDT, a peptide to target tumor neovessels, and an Alk for an oxygen-independent activity. The synthesis of the compound was successfully carried out, and the study of its photophysical properties showed that the PS retained its capacity to form singlet oxygen and the affinity tests confirmed the affinity of the compound for NRP-1. Thanks to the electron paramagnetic resonance spectroscopy, a technique of choice for radical investigation, the radicals generated by the illumination of the Alk could be detected. The proof of concept was thus successfully established.

Frataxin is a highly conserved protein whose deficiency results in the neurodegenerative disease Friederich’s ataxia. Frataxin’s actual physiological function has been debated for a long time without reaching a general agreement; however, it is commonly accepted that the protein is involved in the biosynthetic iron-sulphur cluster (ISC) machinery, and several authors have pointed out that it also participates in iron homeostasis. In this work, we use site-directed spin labeling coupled to electron paramagnetic resonance (SDSL EPR) to add new information on the effects of ferric and ferrous iron binding on the properties of human frataxin in vitro. Using SDSL EPR and relating the results to fluorescence experiments commonly performed to study iron binding to FXN, we produced evidence that ferric iron causes reversible aggregation without preferred interfaces in a concentration-dependent fashion, starting at relatively low concentrations (micromolar range), whereas ferrous iron binds without inducing aggregation. Moreover, our experiments show that the ferrous binding does not lead to changes of protein conformation. The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions.

The on-demand generation of stable organic radicals from the precursors can be considered as an essential challenge for the plethora of applications in various fields of science. In this contribution, we prepared a range of N-(methyl)benzyl derivatives of 6-oxoverdazyl via atom transfer radical addition from moderate to high yields and studied their thermal- and photo-initiated homolysis. The kinetics of homolysis was measured, and the dissociating rate constant kd, activation energy Ea and frequency factor A were estimated. Variation of the substituent at the C3-position of the verdazyl ring was successfully applied for fine-tuning the homolysis rate: the value of kd was higher for alkylverdazyls with electron-withdrawing groups, e.g., the para nitro group afforded a 6-fold increase in kd. In contrast to thermal homolysis, the rate of photoinduced decomposition depends on both the extinction coefficient and the value of activation energy. Thus, nitro-containing alkylated verdazyls show the highest homolysis rate in both types of initiations. The achieved results afford a novel opportunity in the controlled generation of verdazyls and further application of these compounds in medicine and chemical industry.

International audience; The potential of alkoxyamines as theranostic agents has been recently promoted by our groups. The success of such an approach relies on the switch upon enzymatic triggering between highly stable precursor alkoxyamines and activated alkoxyamines exhibiting fast homolysis of the CON bond. Hence, at 37°C in water, benzyl 2-(2,2,6,6-tetramethylpiperidin-N-oxy)-3-ethoxy-3-acetoxypropanoate and benzyl 2-ditert-butylaminoxy-3-ethoxy-3-acetoxy propanoate afford t max of 2000 s (35% conversion) and 500 s (60% conversion), respectively, for the CON bond homolysis in the presence of Subtilisin A whereas t 1/2 of ca. 42 thousand millenniums and 330 years are expected accordingly to E a values in n-propanol. These results nicely highlight the on/off switch, provided that an enzymatic activity controls the CON bond homolysis. † Electronic supplementary information (ESI) available: Experimental procedures, analysis data, kinetics, LFER analysis and XRD data are reported as ESI. CCDC 1989155. For ESI and crystallographic data in CIF or other electronic format see

Nitroxide-mediated polymerization is now a mature technique, at 35 years of age. During this time, several variants have been developed: electron spin capture polymerization (ESCP), photoNMP (NMP2), chemically initiated NMP (CI-NMP), spin label NMP (SL-NMP), and plasmon-initiated NMP (PI-NMP). This mini-review is devoted to the features and applications of these variants.

WOS:000472219400057; A plasmon as a stimulus opens up new opportunities for selective and regulated "from-surface" polymerization and functionalization of surfaces. Here, the first example of plasmon-assisted nitroxide-mediated polymerization (NMP) of stimuli-responsive block copolymers poly(N-isopropylacrylamide)-co-4-vinylboronic acid is reported. The growth of a polymer film at room temperature was achieved via plasmon-induced homolysis of alkoxyamines covalently attached to the surface of plasmon-active gold gratings at room temperature. Control of temperature, finite-difference time-domain method simulation of plasmon intensity distribution shift during polymerization, electron paramagnetic resonance experiments and other assays provide strong support for the plasmon-initiated mechanism of NMP. We demonstrated not only the control of the resulting polymer thickness but also the preparation of a surface-enhanced Raman spectroscopy chip for the detection of glycoproteins as a powerful example of plasmon-assisted NMP potential.

Effect of alkoxyamines on normal and tumor cells was studied in vitro and in vivo. In vitro experiments showed that alkoxyamines produce a dose-dependent toxic effect on cells of human breast tumor MCF7 line. Transplantation of Krebs-2 ascites carcinoma cells preincubated with alkoxyamines to mice did not induce tumor growth. An opposite effect was observed in normal mouse cells: functional activity of peritoneal macrophages increased. The possibility of using alkoxyamines as theranostic agents is discussed.

Malaria and schistosomiasis are major infectious causes of morbidity and mortality in the tropical and sub-tropical areas. Due to the widespread drug resistance of the parasites, the availability of new efficient and affordable drugs for these endemic pathologies is now a critical public health issue. In this study, we report the design, the synthesis and the preliminary biological evaluation of a series of alkoxyamine derivatives as potential drugs against Plasmodium and Schistosoma parasites. The compounds (RS/SR)-2F, (RR/SS)-2F, and 8F, having IC50 values in nanomolar range against drug-resistant P. falciparum strains, but also five other alkoxyamines, inducing the death of all adult worms of S. mansoni in only 1 h, can be considered as interesting chemical starting points of the series for improvement of the activity, and further structure activity, relationship studies. Moreover, investigation of the mode of action and the rate constants kd for C-ON bond homolysis of new alkoxyamines is reported, showing a possible alkyl radical mediated biological activity. A theoretical chemistry study allowed us to design new structures of alkoxyamines in order to improve the selectivity index of these drugs.

International audience; With the increasing use of γ-irradiated containers made of multilayer poly-meric flexible films for food and biopharmaceutical applications, the possible migration of degradation products of the polymers and their additives is becoming a topic of concern. This article aims at highly reliably identifying the degradation products generated after gamma irradiation and their origin to later on assess their potential harmfulness in single-use containers. In this study, GC-MS is used to identify by-products created by γ-irradiation of primary and secondary antioxidants usually present in polyolefin-based biotechnological single-use materials and to confirm identification relevancy based on the literature survey or standard when available. Degradation pathways are proposed to account for the formation of by-products identified during the study and to list intermediates and other by-products present in too small amounts to be detected and identified accurately in all extractable studies.

WOS:000430904400002; Recently, we reported on the activation of the C-ON bond homolysis in alkoxyamines R1R2NOR3 using the coordination of the alkyl fragment R-3 with metal cations Cu(II) and Zn(II). Here, we report the selective coordination of the diethylphosphoryl group carried by the nitroxyl fragment by the oxophilic metal cation Tb(III). Coordination on the nitroxyl fragment afford a slight 2-fold decrease in the C-ON bond homolysis rate constant kd. (C) 2018 Elsevier B.V. All rights reserved.

Alkoxyamine 1 is selectively hydrolyzed by chymotrypsin and substilisin A into alkoxyamine 2H+ for which C–ON bond homolysis occurred with a 4-fold increase in rate constants compared to 1 while non-specific proteases had no effect. This highlights the triggering effect of enzymes. This is a proof of concept for a theranostic approach for treating solid tumors using enzyme-activated alkoxyamines releasing a cytotoxic alkyl radical and a stable nitroxide as a contrast agent for Overhauser-enhanced MRI.

WOS:000481879400050; International audience; Because the C-ON bond homolysis rate constant k(d) is an essential parameter of alkoxyamine reactivity, it is especially important to tune k(d) without a major alteration of the structure of the molecule. Recently, several approaches have become known, e.g., protonation of functional groups and formation of metal complexes. In this paper, coordination reactions of [Zn(hfac)(2)(H2O)(2)] with a series of new SG1-based alkoxyamines affording complexes with different structures are presented. The k(d) values of the complexed forms of the alkoxyamines were compared to those of free and protonated ones to reveal the contribution of the electron-withdrawing property and structure stabilization. Together with previously published data, this work provides clues to the design of alkoxyamines that can be effectively activated upon coordination with metal ions. Furthermore, our results provide insight into the mechanism underlying the influence of complexation on the reactivity of alkoxyamines. This led us to describe different types of coordination: intramolecular in nitroxyl fragment, intramolecular in alkyl fragment, intramolecular between alkyl and nitroxyl fragment, and intermolecular one. All of them exhibit different trends which are dramatically altered by changes in conformation.

International audience; As the well known protonated cyclopropanes' present calculations confirm the existence of acetylated cyclopropanes, we describe the structure of edge- and corner-acetylated cyclopropanes rising from the energetically favored addition of acetyl cation to cyclopropanes. Some of those explain the few available experimental results concerning the acetylation reaction of cyclopropanes. Structures have been calculated at the B3LYP/6-311++G(3df,3pd) and MP2/6-311++G(3df,3pd) levels of theory in ideal gas and in dichloromethane as solvent. Transition state geometries in ideal gas and in dichloromethane as solvent were confirmed by intrinsic reaction coordinate (IRC) calculations. (C) 2016 Elsevier Ltd. All rights reserved.

Frataxin is a highly conserved protein whose deficiency results in the neurodegenerative disease Friederich&rsquo, s ataxia. Frataxin&rsquo, s actual physiological function has been debated for a long time without reaching a general agreement, however, it is commonly accepted that the protein is involved in the biosynthetic iron-sulphur cluster (ISC) machinery, and several authors have pointed out that it also participates in iron homeostasis. In this work, we use site-directed spin labeling coupled to electron paramagnetic resonance (SDSL EPR) to add new information on the effects of ferric and ferrous iron binding on the properties of human frataxin in vitro. Using SDSL EPR and relating the results to fluorescence experiments commonly performed to study iron binding to FXN, we produced evidence that ferric iron causes reversible aggregation without preferred interfaces in a concentration-dependent fashion, starting at relatively low concentrations (micromolar range), whereas ferrous iron binds without inducing aggregation. Moreover, our experiments show that the ferrous binding does not lead to changes of protein conformation. The data reported in this study reveal that the currently reported binding stoichiometries should be taken with caution. The use of a spin label resistant to reduction, as well as the comparison of the binding effect of Fe2+ in wild type and in the pathological D122Y variant of frataxin, allowed us to characterize the Fe2+ binding properties of different protein sites and highlight the effect of the D122Y substitution on the surrounding residues. We suggest that both Fe2+ and Fe3+ might play a relevant role in the context of the proposed FXN physiological functions.

After quantum calculations of the absolute free energies G of twenty homooligopeptides (X)n, we have studied the variations of G(X)n as a function of the repeating amino acids n and observed that these values are correlated by, (a) an excellent linear relationship G ( X ) n = A n - 47978.6 ± 7 (kcal mol−1) (TPSS-TPSS/6.311++G(dp)); (b) the difference of the weighted absolute free energies between two oligoamino acids (X)n and (Y)n — G ( X ) n / n - G ( Y ) n / n — is a constant irrespective of n and is due to the difference of the absolute free energies of the side chains. Consequently, from the Gn values of oligoglycines, a determination of the absolute free energies of an oligoamino acid (X)n is obtained with a good accuracy; (c) the corresponding increments G ( X ) n / n - G ( X ) ( n - 1 ) / ( n - 1 ) are equaled and lead to a single power law irrespective of X: G n / n - G ( n - 1 ) / ( n - 1 ) = 83904 / n 2.172 (kcal mol−1) or a linear relationship: G n / n - ( G ( n - 1 ) / ( n - 1 ) = 47986.63 / n ( n - 1 ) - 0.176 (kcal mol−1). These unprecedented observations are again observed for homooligodipeptides, homooligotripeptides, unnatural ω-aminoacids and, partially, for some hydrocarbons.

MEDLINE:30813542; Because alkoxyamines are employed in a number of important applications, such as nitroxide-mediated polymerization, radical chemistry, redox chemistry, and catalysis, research into their reactivity is especially important. Typically, the rate of alkoxyamine homolysis is strongly dependent on temperature. Nonetheless, thermal regulation of such reactions is not always optimal. This review describes various ways to reversibly change the rate of C⁻ON bond homolysis of alkoxyamines at constant temperature. The major methods influencing C⁻ON bond homolysis without alteration of temperature are protonation of functional groups in an alkoxyamine, formation of metal⁻alkoxyamine complexes, and chemical transformation of alkoxyamines. Depending on the structure of an alkoxyamine, these approaches can have a significant effect on the homolysis rate constant, by a factor of up to 30, and can shorten the half-lifetime from days to seconds. These methods open new prospects for the application of alkoxyamines in biology and increase the safety of (and control over) the nitroxide-mediated polymerization method.

WOS:000465176600001; Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Activation of the homolysis was conducted by protonation and/or methylation. These new molecules displayed cytotoxic activities towards human glioblastoma cell lines, including the U251-MG cells that are highly resistant to the conventional chemotherapeutic agent Temozolomide. We further showed that the biological activities of the alkoxyamines were not only related to their half-life times of homolysis. We lastly identified the alkoxyamine ( RS/SR)-4a, with both a high antitumour activity and favourable logD(7.4) and pK(a) values, which make it a robust candidate for blood-brain barrier penetrating therapeutics against brain neoplasia.

WOS:000459836600013; After quantum calculations of absolute free energies of polyatomic sulfur derivatives or hydrocarbon oligomer compounds, we have studied the variations of G(n) as a function of the number of repeating units n (sulfur atoms or hydrocarbon units, G(n) = 2 to about 60), and observed that these values can be correlated by (a) a nearly perfect linear relationship, Gn = An + B (A and B, constants), with a high accuracy which enables an extrapolation for higher values of n, and (b) a power law:, delta G = G(n)/n - G((n-1)) /(n-1) = C/n(d) (C and d, constants). From comparison of variations of the C-C bond lengths, we show that the conjugation of trans-polyenes (up to C60H62) is more important than for polyynes (up to C60H2).

International audience; While optical methods are not efficient enough for the easy, fast, and efficient detection of enzymatic activity in turbid media, the properties of the electron paramagnetic resonance (EPR) technique make it suitable for use in such media. Nitroxides which exhibit a change in their EPR hyperfine coupling constants upon enzymatic activity and are selective to lipases were developed under the name of shifting-nitroxides. Several fatty acids, exhibiting saturated and unsaturated chains of various lengths, were coupled with the shifting-nitroxide via an enol ester link and tested against several lipases. As the solubility of fatty acids is low in HEPES buffer, experiments were performed in turbid aqueous solution. Almost all labeled fatty acids were hydrolyzed by Candida rugosa lipase, and more selectivity is observed with Porcine Pancreas lipase type II. No activity was observed for lipase AK Amano 20, Candida antartica lipase B, and Mucor miehei lipase.

International audience; The metal complexation reactions of bis(hexafluoroacetylacetonato)copper(II)(Cu(hfac)(2)) with alkoxyamines (diethyl(2,2-dimethyl-1-(tert-butyl-(1-(pyridine-4-yl)ethoxy)amino)propyl)phosphonate and diethyl (2,2-dimethyl-1-(tert-butyl-(1-(pyridine-2-yl)ethoxy)amino)propyl)phosphonate) were studied. According to X-ray analysis, the molecular and crystal structures of 1:1 complexes depend on the configuration of the free alkoxyamines, that is dimeric (RSSR) and chain-polymeric (RR/SS) structures for para-pyridyl-substituted alkoxyamines, and cyclic unimeric (RS/SR) structure for ortho-pyridyl derivative. The complex (2:1 ratio Cu(hfac)(2)/alkoxyamine) for ortho-pyridyl-substituted alkoxyamine is not resolved. Upon warming, ortho complexes decomposed into free alkoxyamines and only a weak activation was observed. Upon warming, para complexes decomposed into their corresponding unimers, and then, a 21-fold increase in the rate constant of the C-ON bond homolysis was observed compared to the corresponding free alkoxyamines. Tuning of the homolysis rate constant of the C-ON bond via addition of pyridine is also reported.

International audience; In two recent articles (Org. Biomol. Chem., 2015 and 2016), we showed that changes in the phosphorus hyperfine coupling constant a(P) at position beta in beta-phosphorylated nitroxides can be dramatic. Such changes were applied to the titration of water in organic solvents and conversely of organic solvents in water. One of the molecules tested was a non-cyclic nitroxide meaning that a thorough investigation of the solvent effect on the EPR hyperfine coupling constant is timely due. In this article, we show that the aP of persistent non-cyclic beta-phosphorylated nitroxides decrease with the normalized polarity Reichardt's constant ENT. The Koppel-Palm and Kalmet-Abboud-Taft relationships were applied to gain deeper insight into the effects influencing a(N) and a(P): polarity/polarizability, hydrogen bond donor properties, and the structuredness of the cybotactic region.

WOS:000432826800003; Preparation of materials by nitroxide-mediated polymerization (NMP) is well known nowadays. To increase the possible usefulness of NMP for the production of hybrid materials or polymer-decorated complexes, coordination-initiated NMP (CI-NMP) was developed and investigated here. CI-NMP was exemplified using the instantaneous and spontaneous reaction of alkoxyamines carrying a pyridyl moiety on the alkyl group and the Zn(hfac)(2) (hfac: hexafluoroacetylacetonate) complex as a metal centre. NMP of styrene and n-butyl acrylate was carried out with either previously or in situ-prepared complexes. Both approaches afforded NMP of the same quality. The positive influence of metal centre coordination is highlighted by efficient NMP at 90 degrees C.

WOS:000447480900004; Various aspects of the structure, the reactivity in organic synthesis, in the atmosphere, in environment, in biology of ozone are described. Emphasis is placed on the relation with singlet oxygen and dihydrotrioxide. (C) 2018 Elsevier Ltd. All rights reserved.

WOS:000434089500009; International audience; A nitroxide carrying a peptide specific to the binding pocket of the serine proteases chymotrypsin and cathepsin G is prepared. This peptide is attached as an enol ester to the nitroxide. Upon enzymatic hydrolysis of the peptide, the enol ester moiety is transformed into a ketone moiety. This transformation affords a difference of 5G in phosphorus hyperfine coupling constant between the electronic paramagnetic resonance (EPR) signals of each nitroxide. This property is used to monitor the enzymatic activity of chymotrypsin and cathepsin G by EPR. Michaelis constants were determined and match those reported for conventional optical probes.

WOS:000445759000010; International audience; Pulmonary inflammatory diseases are a major burden worldwide. They have in common an influx of neutrophils. Neutrophils secrete unchecked proteases at inflammation sites consequently leading to a protease/inhibitor imbalance. Among these proteases, neutrophil elastase is responsible for the degradation of the lung structure via elastin fragmentation. Therefore, monitoring the protease/inhibitor status in lungs non-invasively would be an important diagnostic tool. Herein we present the synthesis of a MeO-Suc-(Ala)(2)-Pro-Val-nitroxide, a line-shifting elastase activity probe suitable for Electron Paramagnetic Resonance spectroscopy (EPR) and Overhauser-enhanced Magnetic Resonance Imaging (OMRI). It is a fast and sensitive neutrophil elastase substrate with K-m = 15 +/- 2.9 mu M, k(cat)/K-m = 930,000 s(-1) M-1 and K-m = 25 +/- 5.4 mu M, k(cat)/K-m = 640,000 s(-1) M-1 for the R and S isomers, respectively. These properties are suitable to detect accurately concen trations of neutrophil elastase as low as 1 nM. The substrate was assessed with broncho-alveolar lavages samples derived from a mouse model of Pseudomonas pneumonia. Using EPR spectroscopy we observed a clear-cut difference between wild type animals and animals deficient in neutrophil elastase or deprived of neutrophil Elastase, Cathepsin G and Proteinase 3 or non-infected animals. These results provide new preclinical ex vivo and in vivo diagnostic methods. They can lead to clinical methods to promote in time lung protection.

International audience; The design of new R1R2NOR3 alkoxyamines for various applications relies on the accurate prediction of two kinetic parameters, the C-ON bond homolysis rate constant (k(d)) and its re-formation rate constant (k(c)). Relationships to describe the steric and polar effects of the R1R2NO fragment ruling k(d) have been developed. For all cyclic nitroxyl fragments, the steric effect is described as the sum of the bulkiness of the R-1 and R-2 groups (i.e., normal steric effect), while for the noncyclic nitroxyl fragment (except for one case), a leveled steric effect is assumed. In this work, we show that the normal steric effect also applies to noncyclic nitroxyl fragments and that for one case an enhanced steric effect is also observed, i.e., experimental k(d) \\textgreater 5-fold larger than the predicted value.

International audience; Sulfur is one of the most necessary biogenic elements in nature that must be assimilated by all organisms; it is an essential macronutrient for living organisms and has multiple roles in plant development. The oxidation of elemental sulfur is a complex process involving the contact of cells with sulfur particles, the oxidation of sulfur to sulfite, and the oxidation of sulfite to sulfate. To provide hypothesis concerning the most probable processes in the early states, we determined, by quantum-chemical calculations, the energies of some allotropic forms containing up to 32-40 sulfur atoms and energetics of their reactions with triplet dioxygen. The most probable reactions occurred with methylpolysulfane anions with an electron transfer to give the superoxide anion radical (and thiyls radicals) and especially the formation of peroxydic polysulfane anions. Calculations confirmed that the triplet diradical is more stable than the singlet one for acyclic polysulfide chains. (C) 2017 Elsevier Ltd. All rights reserved.

International audience; Solvent effects in beta-phosphorylated nitroxides show that nitrogen and phosphorus hyperfine coupling constants a(N) and a(p), increase and decrease with increasing polarity, polarizity, and Hydrogen Bond Donor effects of solvents, respectively. In a series of articles, it was shown that the driving interaction controlling the change in a(p) is the maximization of the N+center dot O-center dot center dot center dot center dot center dot center dot P+-O- dipole - dipole interaction. In this work, we show that the steric strain in Spiro beta-phosphotylated nitroxides affords the opposite trend for a(p) that is, a(p) increases with increasing solvent properties features. (C) 2017 Elsevier Ltd. All rights reserved.