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Cyclam-picolinate chelators were functionalized

[Abstract] The limited use of palladium-103 and -109 radionuclides for molecular radiotherapy is surely due to the lack of appropriate ligands capable of fulfilling all criteria required for application in nuclear medicine. Furthermore, the thermodynamic properties of these complexes in solution remain difficult to establish. The challenge is compounded when considering that radiolabeling of compounds for translation to clinical trials requires fast complexation. Thus, the coordination of Pd(II) and 103/109Pd-nuclides is a huge challenge in terms of molecular design and physicochemical characterization. Herein, we report a comprehensive study highlighting TE1PA, a monopicolinate cyclam – already established in nuclear imaging with 64Cu-PET (positron emission tomography) imaging tracers – as a highly relevant chelator for natural Pd and subsequently 109Pd-nuclide. The structural, thermodynamic, kinetic and radiolabeling studies of Pd(II) with TE1PA, as well as the comparison of this complex with three structurally related derivatives, support palladium-TE1PA radiopharmaceuticals as leading candidates for targeted nuclear medicine. R.T. and N.L.B. acknowledge the Ministère de l′Enseignement Supérieur et de la Recherche and the Centre National de la Recherche Scientifique. J.P. is grateful to the Ligue contre le Cancer, the MAC-group (UBO) and the University of Cape Town for her PhD fellowship; C.H.S.D thanks the Technology Innovation Agency (TIA) seed fund implemented through the South African Nuclear Energy Corporation for financial support. C.P.-I. thanks Centro de Supercomputación de Galicia for providing access to computing facilities. L.M.P.L was financially supported by Project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular), funded by FEDER funds through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI) and by national funds through FCT - Fundação para a Ciência e a Tecnologia

Agriculture is changing to rely on agroecological practices that take into account biodiversity, and the ecological processes occurring in soils. The use of agricultural biostimulants has emerged as a valid alternative to chemicals to indirectly sustain plant growth and productivity. Certain BS have been shown to select and stimulate plant beneficial soil microorganisms. However, there is a lack of knowledge on the effects and way of action of the biostimulants operating on soil functioning as well as on the extent and dynamic of these effects. In this study we aimed to decipher the way of action of a seaweed and amino-acids based biostimulant intended to be applied on soil crop residues to increase their microbial mineralization and the further release of nutrients. By setting-up a two-phase experiment (soil plant-growing and soil incubation), our objectives were to (1) determine the effects of the soil biostimulant over time on the active soil bacteria and fungi and the consequences on the organic carbon mineralization in bare soils, and (2) assess the biostimulant effects on soil microorganisms relatively to plant legacy effects in planted soils. We demonstrated that the soil biostimulant had a delayed effect on the active soil microorganisms and activated both plant growth promoting bacteria and saprophytes microorganisms at the medium-term of 49 days. However, the changes in the abundances of active microbial decomposers were not associated to a higher mineralization rate of organic carbon derived from soil and/or litter. The present study assessed the biostimulant beneficial effect on active soil microbial communities as similar as or even higher than the legacy effects of either A. thaliana or T. aestivum plants. We specifically showed that the biostimulant increased the active fungal richness to a higher extent than observed in soils that previously grew the two plants tested.

Following the successful synthesis of a C-functionalized version of the TE1PA ligand, a monopicolinate cyclam, we looked to demonstrate its in vivo properties versus DOTA and NOTA, after conjugation on the 9E7.4 rat antibody, an IgG2a against CD138 murine, which has relevant properties for multiple myeloma targeting. For each ligand, different conjugation approaches had been considered to select the most appropriate for the comparative study. The p-SCN-Bn-TE1PA, NHS-DOTA, and p-SCN-Bn-NOTA were finally chosen for conjugation and radiolabeling tests. For in vivo comparison, we used a model of subcutaneous grafted mice with 5T33 tumor cells. In vitro tests and immuno-PET study highlighted 64Cu-9E7.4-p-SCN-Bn-NOTA as the least attractive. Further competitive biodistribution and hepatic metabolic studies at 2, 24, and 48 h post-injection (100 μg radiolabeled with 10 MBq of 64Cu) were then performed with the 64Cu-9E7.4-p-SCN-Bn-TE1PA and 64Cu-9E7.4-NHS-DOTA. Results show a better in vivo resistance of 64Cu-9E7.4-p-SCN-Bn-TE1PA to transchelation compared to 64Cu-9E7.4-NHS-DOTA, especially at later times. This was confirmed with 64Cu-9E7.4-p-SCN-Bn-NOTA at 48 h PI. 64Cu-9E7.4-p-SCN-Bn-TE1PA also demonstrated an excellent hepatic clearance. 64Cu-9E7.4-p-SCN-Bn-TE1PA displayed an overall superiority compared to 64Cu-9E7.4-NHS-DOTA and 64Cu-9E7.4-p-SCN-Bn-NOTA in terms of in vivo stability, reinforcing the usefulness of the p-SCN-Bn-TE1PA ligand for 64Cu immuno-PET imaging.

International audience

Herein we present the preparation of two novel cyclam-based macrocycles (

Herein we present the preparation of two novel cyclam-based macrocycles (te1pyp and cb-te1pyp), bearing phosphonate-appended pyridine side-arms for the coordination of copper(II) ions in the context of 64Cu PET imaging. The two ligands have been prepared through conventional protection-alkylation sequences on cyclam, and their coordination properties have been thoroughly investigated. The corresponding copper complexes have been fully characterized in the solid-state (X-Ray diffraction analysis) and in solution (EPR and UV-Vis spectroscopies). Potentiometric studies, combined with spectrometry, have also allowed us to determine their thermodynamic stability constants, confirming their high affinity for copper(II) cations. The kinetic inertness of the complexes has also been verified by acid-assisted dissociation experiments, enabling their use in 64Cu-PET imaging in mice for the first time. Indeed, the two ligands could be quantitatively radiolabeled under mild conditions, and the resulting 64Cu complexes have demonstrated excellent stability in serum. PET imaging demon-strated a set of features emerging from the combination of picolinates and phosphonate units: high stability in vivo, fast clear-ance from the body via renal elimination, and most interestingly, very low fixation in the liver. The latter is in contrast with what was observed for monopicolinate cyclam (te1pa), that had a non-negligible accumulation in the liver, owing probably to its different charge and lipophillicity. These results thus pave the way for the use of such phosphonated pyridine chelators for in vivo 64Cu-PET imaging.

International audience; Herein we present the preparation of two novel cyclam-based macrocycles (te1pyp and cb-te1pyp), bearing phosphonate-appended pyridine side arms for the coordination of copper(II) ions in the context of 64Cu PET imaging. The two ligands have been prepared through conventional protection–alkylation sequences on cyclam, and their coordination properties have been thoroughly investigated. The corresponding copper complexes have been fully characterized in the solid state (X-ray diffraction analysis) and in solution (EPR and UV–vis spectroscopies). Potentiometric studies combined with spectrometry have also allowed us to determine their thermodynamic stability constants, confirming their high affinity for copper(II) cations. The kinetic inertness of the complexes has been verified by acid-assisted dissociation experiments, enabling their use in 64Cu-PET imaging in mice for the first time. Indeed, the two ligands could be quantitatively radiolabeled under mild conditions, and the resulting 64Cu complexes have demonstrated excellent stability in serum. PET imaging demonstrated a set of features emerging from the combination of picolinates and phosphonate units: high stability in vivo, fast clearance from the body via renal elimination, and most interestingly, very low fixation in the liver. This is in contrast with what was observed for monopicolinate cyclam (te1pa), which had a non-negligible accumulation in the liver, owing probably to its different charge and lipophilicity. These results thus pave the way for the use of such phosphonated pyridine chelators for in vivo64Cu-PET imaging.

International audience; Temperature inducible phenotypic plasticity is a major player in plant responses to climate warming. Functional responses and their role in determining thermal plasticity of plants remain poorly understood. Our objective was to compare trait responses of six populations of Ludwigia peploides resulting from seed from Oceanic climate and from Mediterranean climate after an exposure at three temperatures (16, 24, and 30°C). A comparative analysis showed that at 30°C, the six populations of L. peploides shared different morphological responses, whereas a common pattern of morphological responses was found for the six populations at 16°C. At 16°C, the growth was very low suggesting a stress. At 30°C, the three Mediterranean populations of L. peploides accumulated ≈ sevenfold more total biomass than the populations from Oceanic region. Despite drawing similar response pattern to temperature, the populations showed several different metabolic responses. The thermal plastic responses to the highest temperature differed according to the origin of the populations. The Mediterranean populations of L. peploides could be better adapted to rising temperature. These abilities could allow them to take advantage from climate warming if the temperature is not warming up to temperature above a critical threshold.

An improved glucose-chelator-albumin bioconjugate (GluCAB) derivative, GluCAB-2

In the aim to design small molecules capable of binding in vivo to albumin to form bioconjugates, a second generation GluCAB derivative(Glucose-Chelator-Albumin Bioconjugate) has been synthesized and studied for in vivo 64Cu-PET/CT imaging in breast cancer mice models together with its first-generation analogue. This series of radioligands - also capable of complexing therapeutic isotopes and therefore classified as theranostic agents - are working on the principle of tumor targeting through the Enhanced Permeability and Retention (EPR) effect as well as glucose metabolism.

Plant litter decomposition is an essential ecosystem function in temperate streams. Both riparian vegetation and decomposer communities are major determinants of the decomposition efficiency and the interactions occurring within litter mixtures. However, the extent to which such litter mixture interactions are affected by combined shifts in litter traits and decomposer community is not well understood. We used leaf litter from 10 European tree species in order to study litter decomposition and litter mixture effects occurring in two-species litter mixtures in a temperate forested stream of northwestern France. The study distinguished between (1) decomposition involving microorganisms alone or together with invertebrates, and (2) decomposition involving litter mixtures of similar or dissimilar nutrient content. Increasing mean litter nutrient concentration favored both microbial activity and litter decomposition rate. Surprisingly, the highest litter mixture effects occurred in mixtures containing two nutrient-rich litters and occurred mainly in macroinvertebrate presence. Both the “mass ratio hypothesis,” expressed as the community-weighted mean traits (TraitCWM), and the “niche complementarity hypothesis,” expressed as the functional dissimilarity of litter traits (TraitFD), contributed to explain litter mixture effects. However, TraitCWM was found to be a better predictor than TraitFD. Finally, when evaluating the individual contributions of litter nutrients, calcium and magnesium appeared as important drivers of litter mixture effects. Our findings suggest that the mass ratio hypothesis overrules the niche complementarity hypothesis as a driver of litter diversity effects. Our study highlights the key importance of macroinvertebrates and of leaf nutrients, such as Ca and Mg, which are often neglected in decomposition studies in streams.

Amyloid-β (Aβ) aggregation and metal ion dyshomeostasis are found to be pathological features upon the progress of Alzheimer's disease (AD). In addition, Aβ and metal ions are reported to interact with each other forming metal–Aβ complexes, which can affect the aggregation of Aβ and cause oxidative stress via the production of reactive oxygen species (ROS). To disrupt metal coordination to Aβ and control the reactivities of metal–Aβ, metal chelating agents have been tested. Herein, a series of azamacrocyclic compounds with different properties of Cu(II) and Zn(II) binding and Aβ interaction were rationally selected under criteria based on structural and functional variations on the backbone of Cyclam. The series contains Cyclam, its N-methylated and cross-bridged (N-methylated or not) analogs, as well as their C-appended hydroxyethyl derivatives, and some of them have been newly synthesized. The reactivities of the cyclam derivatives towards the aggregation of metal–Aβ and the generation of ROS mediated by metal–Aβ were evaluated. Their modulative reactivities towards metal–Aβ could be achieved by generating a ternary complex with metal–Aβ and chelating the metal ion from metal–Aβ. Moreover, the toxicity induced by metal–Aβ in living cells was alleviated by the cyclam derivatives capable of regulating metal–Aβ aggregation and metal–Aβ-triggered ROS formation. Overall, our studies illustrate new examples of azamacrocyclic metal chelators that alter the interactions between metal ions and Aβ and subsequently modify the reactivities of metal–Aβ, with an indication of how the slight structure–property difference can influence such effects of small molecules.

Following the successful synthesis of a

International audience; Production of biogas through anaerobic digestion of organic wastes should play an important role in sustainable development of energy supply, and the environmental effects of digestates have to be assessed. We investigated the effect of anaerobic digestion of pig slurry (PS) on the molecular quality of the digestate produced. The consequences of digested (DPS) and undigested PS use as organic soil fertilizer on soil microbial and biochemical properties and C-gas emissions (CO2 and volatile organic compounds) were studied during a two-month incubation. PS and DPS differed in the amount of volatile organic compounds (VOCs) emitted, in their organic C and lignin contents but not in their active microbial composition. Application of both types of slurry to the soil immediately increased the content of soil dissolved organic carbon (DOC) compared to the control soil. The application of DPS induced few changes in the biochemical composition of soil organic matter compared to its raw material (PS) that increased the amount of phenolic compounds. After 60 days, both amended and control soils contained similar amounts of DOC, amended soils presenting a more diverse biochemical composition of their soil organic matter. Application of both slurries to soil triggered a succession of different active microbial communities, which could be attributed to the introduction of new microorganisms and the input of new labile organic carbon. Changes in fungal communities were stronger than those of bacteria and archaea; however, only slight differences were observed between the slurries. Different fluxes and emission dynamics of five VOCs (methanol, acetone, DMS, 2-pentanone and phenol) were observed during the incubation time following application of PS or DPS to soil while no differences in CO2 emissions were observed. The present study calls for long-term field studies with VOC analyses as a promising tool to differentiate organic fertilization practices.

In view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C-functionalization of TE1PA on one carbon atom in the β-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N-functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h.

International audience; In view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C-functionalization of TE1PA on one carbon atom in the β-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N-functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h.

International audience

International audience; A versatile and efficient bisaminal template approach for the synthesis of cyclam and [13]aneN4 (homocyclen) bifunctional chelating agents (BCAs) bearing a hydroxyethyl function as a C-appended group is presented. The synthesis is rapid (two steps/one week) and does not require fastidious protection–deprotection steps or chromatographic purification. Another reactional route and alternative work-up give access to their oxo-cyclam and oxo-homocyclen analogues. The procedure consists of the cyclization of the preorganized tetraamine 1,4,8,11-tetraazaundecane, in its cis-butanedione-bisaminal form, with an α,β-unsaturated lactone to provide the tetracyclic oxo-intermediate whose bisaminal bridge can be easily removed and/or its amide function reduced under mild conditions. Furthermore, the synthetic route was successfully applied to the synthesis of teta and trita BCAs analogues starting from the linear tetraamine 1,4,7,10-tetraazadecane. Additionally, the appended alcohol functions of various cyclam and homocyclen based ligands were converted into their ethylamine functions following a very convenient procedure. Finally, preliminary analytical and complexation studies highlight that the supplementary hydroxyethyl C-appended chain has only a low impact on the acid–base behaviour and copper(II) or zinc(II) coordination properties of the macrocycle.

International audience; We investigated whether perennial soil organic amendments of pig slurry (PS) and methanized pig slurry (MPS) affect active bacterial communities and change the diversity and the C-flux of Volatile Organic Compounds (VOCs) emitted by soils compared to control plots without any fertilization (C). The long term effects of the fertilization history of the amendments and the short term impact of the organic inputs were both investigated by measuring VOCs emissions using a Proton Transfer Reaction-Mass Spectrometer (PTR-MS) and by analyzing active bacterial diversity by MiSeq Illumina sequencing just before and up to 64 days following the inputs. Soil VOCs emissions (diversity and fluxes) naturally varied with temperature and rainfall variations, irrespective of manure inputs. No effect of the 5-yr fertilization history was observed on bacterial communities' composition and on soil VOCs emissions. However, both manure inputs (PS and MPS) were associated with an inoculation of gamma-Proteobacteria (Pseudomonas sp. and/or Marinospirinum sp.) to the soil on top of which PS inputs activated native soil Bacillus sp. (Firmicutes). VOCs spectra was mainly dominated by methanol and acetonitrile, the acetonitrile emissions not depending on the organic practices. C-VOCs fluxes from the soil to the atmosphere varied from 12 to 76 mu g of C-VOCs h(-1) m(-2) in the control plots. Pig slurry and methanized pig slurry differentially impacted soil VOCs emissions: PS inputs doubled the C-VOC fluxes due to high emission of methanol while MPS inputs reduced VOCs fluxes even less than the control unamended plots, which is of great interest in the context of mitigating greenhouse gases in agriculture. Our results suggest that soil fluxes could, under certain conditions, not be marginal compared to plant fluxes and be potentially driven by new land-uses in agriculture.

International audience; The acid–base and copper(II) coordination properties of three previously described cyclam derivatives are reported. Potentiometry, mass spectrometry, UV-vis absorption spectroscopy, electrochemistry and theoretical calculations were combined to investigate the protonation and binding properties of Bn-cyclam-EtOH (L1), oxo-cyclam-EtOH (L2) and oxo-Bn-cyclam-EtOH (L3). These three cyclams are C-functionalized by a hydroxyethyl pendant arm and display either one N-benzyl group and/or an amide replacing one macrocyclic secondary amine. The N-benzylic substitution has a significant effect of lowering the basicity of the corresponding protonation sites, while the presence of the amide function lowers the first protonation constants of the ligands. Regardless of the system considered, ESI mass spectrometry showed that only monocupric chelates are formed. Compared to the literature data, the stability constants measured by potentiometry (pCu L1 = 14.67; pCu L2 = 16.95; pCu L3 = 15.28) showed that: (i) the C-appended group has a negligible influence on Cu2+ complexation, (ii) N-benzylation decreases the cupric complex stability, and (iii) the “oxo” function significantly increases the stability of the Cu2+ complex. Furthermore, UV-vis absorption versus pH measurements are in excellent agreement with the potentiometric titrations and show an equal involvement of the four nitrogen atoms in L1 and the strong binding properties of L2 and L3 related to the deprotonation of the carboxamide. The electrochemistry parameters determined by cyclic voltammetry showed the predominance of the [CuL1]2+, [CuL2-H]+ and [CuL3-H]+ species but also the irreversibility of the three Cu2+/Cu+ systems. Finally, density functional theory (DFT) and multiconfigurational CASSCF/NEVPT2 calculations confirmed that the protonation of the cupric complexes occurs at the oxygen atom of the amide group of the “oxo” ligands, which is in agreement with the experimental data.

International audience; A giant-size polyamine macrocycle L, composed of four 1,4,8,11-tetraazacyclotetradecane (cyclam) units linked by 1,3-dimethylenbenzyl spacers, strongly interacts in aqueous solution with four pH indicators (bromocresol purple (H2BCP), phenol red (H2PR), phenolphthalein (H2PP) and fluorescein (H2F)) in their anionic forms. Besides 1 : 1 complexes, L also forms assemblies with an unusual 1 : 2 receptor to dye stoichiometry, thanks to its large dimensions, which allow for the simultaneous interaction of the receptor protonated forms with two anionic dyes. The formation of the assemblies markedly affects the pKa values of the phenol groups of the dyes, which change colour upon complexation in well-defined pH ranges. This property can be effectively exploited for optical detection of anions. The L-H2BCP 1 : 2 assembly is able to selectively detect the triphosphate anion at slightly acidic pH values, thanks to the release, upon triphosphate coordination, of the dye from the ensemble, with a consequent colour change of the solution from purple-violet (complexed BCP2− dye) to yellow (free BCP2−). No effect is caused by other inorganic anions. The L-H2BCP 1 : 2 assembly represents a rare case of an optical chemosensor for the triphosphate anion.

International audience; Synthesis and characterization of three new polyamine receptors, composed of a cyclam unit (cyclam=1,4,8,11-tetraazacyclotetradecane) linked by a 2,6-dimethylpyridinyl spacer to the linear polyamines 1,4,8,11-tetraazaundecane (), 1,4,7-triazaheptane (), and to a quaternary ammonium group (L3 py+), are reported. All receptors form highly charged polyammonium cations at neutral pH, suitable for anion recognition studies. ATP recognition was analyzed by using potentiometric, calorimetric, 1H and 31P NMR measurements in aqueous solution. All receptors form 1:1 adducts with ATP in aqueous solution, stabilized by charge–charge and hydrogen-bonding interactions between their ammonium groups and the anionic triphosphate chain of ATP. The binding ability of the three receptors for ATP increases in the order of L3 py+<

International audience; The host–guest binding interaction involving two bis-linear tetraamines, namely 1,3-xylenylbis-1,4,8,11-tetraazaundecane (L1) and 2,6-dimethylpyridinylbis-1,4,8,11-tetraazaundecane (L2), with triphosphate and ATP anions is reported. These polyamines, obtained by linking two linear tetraamines with an aromatic spacer, are able to form in aqueous solution and around neutral p[H], very stable complexes with the targeted anionic substrates by means of electrostatic interactions such as hydrogen bonds. This study, investigated by potentiometric and NMR measurements in solution, clearly highlights the different coordination schemes exhibited by these anions according to their inorganic or organic nature; particularly, concerning ATP, the role of the aromatic linker in the complexation, through π-stacking interactions with the adenine part, is evidenced.

International audience; The host–guest binding interaction between two symmetrical octaazaligands containing a para-xylenyl spacer and triphosphate anion is reported. The ligands studied here are the para-xylenylbiscyclam (AMD3100) and its linear analogue the para-xylenylbis-1,4,8,11-tetraazaundecane, obtained by linking the two corresponding cyclic or open-chain tetraamines. The purpose of this study is to evaluate the effect of these two different architectures on the factors governing the recognition of the triphosphate anion. The results clearly indicate that compared to its biscyclam analogue, the linear octaamine presents a better triphosphate recognition in the whole p[H] range. On the one hand, the capacity of the octaamine to form easily polyprotonated species constitutes the driving force favouring the formation of ternary species, and, on the other hand, the adaptability of this receptor in organizing hydrogen bonds represents also a benefit for the binding of triphosphate substrate. The polyprotonated ligand is sufficiently flexible to wrap itself round the anion in a way to achieve an optimal fit for the best host–guest recognition.

International audience; A new easy‐to‐run route to cyclen, homocyclen, and cyclam is proposed, based on the cyclization with dibromo‐ or ditosyloxy‐derivatives of bisaminal intermediates obtained by condensation of the appropriate linear tetraamine with cyclohexanedione. In the cyclization step, the use of cesium carbonate instead of potassium carbonate as proton trapper caused a remarkable increase of yields

On reaction with Group 6 metal carbonyls M(CO)6, vic type bis-aminals L, issued from the condensation of an α-dicarbonyl compound on a linear tetraamine, give rise to mononuclear cis-M(CO)4L complexes.

A mixture of bis-aminal isomers was obtained from aqueous glyoxal-triethylenetetraamine condensation. The irreversible isomerization of the species was observed and a new synthesis of cyclen proposed.

Cyclen, cyclam and homocyclen have been synthesized from the corresponding butanedione-protected linear tetramines. The cyclization step is followed by a facile deprotection of the rigidifying moiety.

Bisaminals of linear tetraamines were selectively N-monofunctionalised with acrylonitrile in a Michael-type addition giving rise, after reduction, to three open-chain dissymmetrical pentaamines, bearing a new aminopropyl group on one terminal nitrogen atom.

International audience; We describe an easy synthesis of original C-functionalized cyclam derivatives based on the efficient bisaminal template method. In the perspective of developing bifunctional chelating agents (BCAs), this new synthetic strategy offers the possibility of introducing various coupling functions on one carbon atom in the β-N position of the macrocycle, leaving the four nitrogen atoms available for the introduction of pendant coordinating arms. The methodology is based on a keystone C-functionalized oxo-cyclam bisaminal intermediate that is obtained by cyclization of a preorganized tetraamine using various methyl acrylate analogues. These compounds constitute valuable precursors for selective preparation of mono- and di-N-protected C-functionalized cyclams and C-functionalized cyclams, cross-bridged cyclams, and oxo-cyclam derivatives. This approach was successfully adapted to the synthesis of three BCAs with great interest especially for biomedical applications: TETA, TE2A, and CB-TE2A. The structures of different intermediates and Cu(II) complexes of C-functionalized cyclam derivatives were confirmed using single-crystal X-ray diffraction, while reactivity of the key intermediates was rationalized by the analysis of the electrostatic potentials calculated at the TPSSh/6-311G(d,p) level.

International audience; The synthesis of a new linear bis-tetraamine ligand L1, based on two 1,4,8,11-tetraazaundecane units grafted at the 2 and 6 positions of a pyridinyl linker substituted by an anthracenyl fluorophore in the para position, is described and anion complexation studies of L1 with anionic substrates are reported. The protonation pattern and the study of the binding properties of L1 in an aqueous medium with two anionic substrates, the nucleotide adenosine triphosphate (ATP) and the herbicide glyphosate (N-(phosphonomethyl)glycine, PMG), were investigated by means of potentiometry, NMR spectroscopy and absorption and emission spectroscopic techniques. To decipher the impact of the chromophoric linker on the complexation process and to highlight its optical properties, a comparison is established with its previously reported analog L2 devoid of the anthracenyl group. The results unambiguously show that the protonation and complexation properties are preserved despite the presence of the bulky linker, allowing for the use of L1 as a fluorescent sensor for ATP and PMG.

The Mannich reaction from fatty phosphites followed by quaternarisation of the resulting aminophosphonates led to new cationic phosphonolipids which showed promising DNA transfection properties.

On reaction with Group 6 metal carbonyl [M(CO)6] (MCr, Mo or W), linear tri- and tetraamines act as bi- or tri-dentate ligands giving rise to complexes [LM(CO)4], [LM(CO)42] or [LM(CO)3] depending on the chain length and the metal M.

International audience; Binding of Zn(II) by the ditopic ligands L1py, L2py and L1para, composed of a cyclam unit linked to the linear polyamines 1,4,8,11-tetraazaundecane (L1py and L2para) and 1,4,7-triazaheptane (L2py) via a 2,6-dimethylpyridinyl (L1py and L2py) or a 1,4-dimethylbenzyl spacer (L2para), has been analyzed by means of potentiometric and 1H and 13C NMR measurements. All ligands form stable mononuclear Zn(II) complexes in a wide pH range, featuring the metal ion bound to the macrocyclic unit. The open-chain polyamine unit can easily bind several protons in aqueous solution affording protonated metal complexes at neutral and acidic pH values. These complexes behave as bifunctional receptors for the anionic substrates N-(phosphonomethyl)glycine (glyphosate or PMG) and ATP. Potentiometric, 1H and 31P NMR measurements show that the Zn(II) complex with L1py is the better receptor for both substrates, thanks to the simultaneous presence of a pyridine linker functionalized at its 2,6 positions and of a flexible linear tetraamine chain. In fact, these structural features allow a stronger interaction of PMG and ATP with both the protonated tetraamine moiety and the Zn(II)–cyclam core.

International audience; This paper reports a study of the interaction between a ditopic cyclic–open-chain polyazaligand L1py and the herbicide glyphosate [N-(phosphonomethyl)glycine or PMG] by potentiometric titrations as well as calorimetry and NMR measurements. This nonsymmetrical ligand is composed of a cyclam unit (1,4,8,11-tetraazacyclotetradecane) and the linear tetraamine 1,4,8,11-tetraazaundecane linked by a 2,6-dimethylpyridine spacer. This ligand forms stable adducts with PMG. For comparison, two analogous symmetrical ditopic ligands, a bis-macrocycle L4py and a bis-tetraamine L5py, and two related anions, iminodiacetic acid (IDA) and iminobis(methylphosphonic acid) (IDP), were also investigated. The results unambiguously show that L1py selectively binds PMG, especially around neutral pH, whereas L4py and L5py exhibit a weaker affinity for this substrate. Calorimetic and 1H NMR measurements showed that the host–guest adducts are mainly stabilized by charge–charge interactions and hydrogen bonds involving the ammonium function of PMG and the nonprotonated nitrogen atom of the pyridine linker.

International audience; The ‘triazine’ methodology for the synthesis of functionalized bipyridine ligands proved to be a convenient method for the preparation of luminescent Eu(III) complexes. The approach allows flexible construction of chromophore and coordination sphere with control of photophysical properties. Europium(III) complexes [Eu1]–[Eu5] prepared in this way exhibit intense long-life metal-centered luminescence in aqueous media. The aromatic substituent in the position 5 of bipyridine has a significant influence on luminescence parameters and is used to introduce functionality for bioconjugation. The complexes [Eu4] and [Eu5] bearing primary amine groups are ready-to-go luminescent ‘tags’ for peptide labeling.

Dissymmetric ω, ω′-N-dialkylated linear tetraamines have been obtained after the successive reactions of two aldehydes and subsequent reduction and removal of the M(CO) 3 protection.

The synthesis and the effect of phosphite–phosphonate ligands in rhodium-catalyzed hydroformylation of styrene are described. Activity and selectivity of the catalyst are improved, at low temperature, by increasing bulkiness of both phosphite and phosphonate moieties.

Several phosphonates with two fatty chains and different polar heads were synthesized and evaluated for their potential to transfer DNA into epithelial (COS-7) and hematopoietic (K562) cell lines, and compared to commercially available references. In both cases, ammonium-phosphonates were particularly efficient.

International audience; The synthesis of a new linear-cyclic ditopic polyazaligand with a xylenyl linker 1 is described. The sequence is based on the stoichiometric reaction of a dissymmetrical biselectrophilic reagent, p-(chloromethyl)benzyl-p-toluenesulfonate, with phosphorylcyclam to give rise to an original intermediate possessing a p-chloroxylenyl pendant arm. The subsequent reaction of this compound with glyoxal-protected linear tetraamine, followed by deprotection steps, leads to the desired ditopic ligand with a good overall yield

International audience; A new route to triethylenetetraamine selective mono-N-alkylation on secondary nitrogen atom using simultaneously bisaminal and diamide protections is presented and applied to the synthesis of poly-linear aza-ligands.

International audience; An easy‐to‐run route to a new ditopic ligand possessing linear and cyclic tetraaza subunits is described. In the first step, the reaction consists in the preparation of a triprotected cyclam bearing a 3‐bromopropyl pendant side chain. A subsequent reaction with a bisaminal protected linear tetraamine gives, after deprotection, the desired ditopic ligand.