Determination of triazine herbicides and their metabolites in the marine environment

[Resumen:] En este trabajo se han validado dos métodos para la determinación de nueve triazinas y ocho productos de degradación en agua de mar y sedimentos marinos. Los metódos se basan en la extracción en fase sólida (agua de mar) y la extracción mediante dispersión de la matriz en fase sólida (sedimentos), seguida de análisis por cromatografía de líquidos con detección con espectrometría de masas/masas (LC-MS/MS). La linearidad de las curvas de calibrado proporcionó R2>0.99 para todos los compuestos en ambas matrices. Los LOQs oscilaron entre 0.05 y 0.45μg/L para agua de mar y entre 0.23 y 4.26 μg/kg en sedimentos. La repetibilidad y reproducibilidad fueron menores de 1.41 % para todos los compuestos y las recuperaciones se encuentran en el rango de 87.5-99.4 % y de 60.9-99.7 % para agua de mar y sedimento respectivamente.[Resumo:] Neste traballo validáronse dous métodos para a determinación de nove triazinas e oito produtos de degradación en auga de mar e sedimentos mariños. Os métodos baséanse na extracción en fase sólida (auga de mar) e na extracción mediante dispersión da matriz en fase sólida (sedimentos), seguida de análise por cromatografía de líquidos con detección con espectrometría de masas/masas (LC-MS/MS). A linearidade das curvas de calibrado proporcionou R2>0.99 para todos os compostos en ambas matrices. Os LOQs oscilaron entre 0.05 e 0.45 μg/L para auga de mar e entre 0.23 e 4.26 μg/kg en sedimentos. A repetibilidade e reproducibilidade foron menores de 1.41 % para todos os compostos e as recuperacións atópanse no rango de 87.5-99.4 % e de 60.9-99.7 % para auga de mar e sedimento respectivamente.[Abstract:] In this work, two methods for the determination of nine triazines and eight degradation products in seawater and marine sediments were validated. The analytical methods are based on solid phase extraction (seawater) and extraction by matrix solid phase dispersion (sediments), followed by analysis by liquid chromatography with mass/mass spectrometry detection (LC-MS/MS). Linearity of calibration curves provide R2>0.99 for all the compounds in both matrices. LOQs oscillate between 0.05 and 0.45 μg/L for seawater and between 0.23 and 4.26 μg/kg in sediments. Repeatability and reproducibility were below 1.41% for all compounds and recoveries ranged from 87.5-99.4 % and 60.9-99.7 % for seawater and sediment respectively.Traballo fin de grao (UDC.CIE). Química. Curso 2015/201

Thermodynamic Stability of Mn(II) Complexes with Aminocarboxylate Ligands Analyzed Using Structural Descriptors

[Abstract] We present a quantitative analysis of the thermodynamic stabilities of Mn(II) complexes, defined by the equilibrium constants (log KMnL values) and the values of pMn obtained as −log[Mn]free for total metal and ligand concentrations of 1 and 10 μM, respectively. We used structural descriptors to analyze the contributions to complex stability of different structural motifs in a quantitative way. The experimental log KMnL and pMn values can be predicted to a good accuracy by adding the contributions of the different motifs present in the ligand structure. This allowed for the identification of features that provide larger contributions to complex stability, which will be very helpful for the design of efficient chelators for Mn(II) complexation. This issue is particularly important to develop Mn(II) complexes for medical applications, for instance, as magnetic resonance imaging (MRI) contrast agents. The analysis performed here also indicates that coordination number eight is more common for Mn(II) than is generally assumed, with the highest log KMnL values generally observed for hepta- and octadentate ligands. The X-ray crystal structure of [Mn2(DOTA)(H2O)2], in which eight-coordinate [Mn(DOTA)]2– units are bridged by six-coordinate exocyclic Mn(II) ions, is also reported.C.P.-I. and D.E.-G. (PID2019-104626GB-I00) and A.R.-R. (Grant PID2019-108352RJ-I00) thank Ministerio de Ciencia e Innovación and Xunta de Galicia (Grant ED431B 2020/52) for generous financial support. R.U.-V. thanks the Xunta de Galicia (Grant ED481A-2018/314) for funding her Ph.D. contract. L.V is indebted to CACTI (Universidade de Vigo) for X-Ray measurements. P.C. acknowledges funding from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK121789)Xunta de Galicia; ED431B 2020/52Xunta de Galicia; ED481A-2018/314Estados Unidos de América. National Institute of Diabetes and Digestive and Kidney Diseases; R01DK12178

A Pentadentate Member of the Picolinate Family for Mn(ɪɪ) Complexation and an Amphiphilic Derivative

[Abstract] We report a pentadentate ligand containing a 2,2′-azanediyldiacetic acid moiety functionalized with a picolinate group at the nitrogen atom (H3paada), as well as a lipophylic derivative functionalized with a dodecyloxy group at position 4 of the pyridyl ring (H3C12Opaada). The protonation constants of the paada3− ligand and the stability constant of the Mn(II) complex were determined using a combination of potentiometric and spectrophotometric titrations (25 °C, 0.15 M NaCl). A detailed relaxometric characterisation was accomplished by recording 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O chemical shifts and relaxation rates. These studies provide detailed information on the microscopic parameters that control their efficiency as relaxation agents in vitro. For the sake of completeness and to facilitate comparison, we also characterised the related [Mn(nta)]− complex (nta = nitrilotriacetate). Both the [Mn(paada)]− and [Mn(nta)]− complexes turned out to contain two inner-sphere water molecules in aqueous solution. The exchange rate of these coordinated water molecules was slower in [Mn(paada)]− (k298ex = 90 × 107 s−1) than in [Mn(nta)]− (k298ex = 280 × 107 s−1). The complexes were also characterised using both DFT (TPSSh/def2–TZVP) and ab initio CAS(5,5) calculations. The lipophylic [Mn(C12Opaada)]− complex forms micelles in solution characterised by a critical micellar concentration (cmc) of 0.31 ± 0.01 mM. This complex also forms a rather strong adduct with Bovine Serum Albumin (BSA) with an association constant of 5.5 × 104 M−1 at 25 °C. The enthalpy and entropy changes obtained for the formation of the adduct indicate that the binding event is driven by hydrophobic interactions.Authors R. P.-P., I. B., E. I., C. P.-I. and D. E.-G. thank Ministerio de Economía y Competitividad (CTQ2016-76756-P) and Xunta de Galicia (ED431B 2017/59 and ED431D 2017/01) for generous financial support and Centro de Supercomputación of Galicia (CESGA) for providing the computer facilities. R. P.-P. thanks Ministerio de Economía y Competitividad for a PhD FPI grant (BES-2014-068399) and a fellowship for a short term stay in Alessandria (EEBB-I-18-13075). R. U.-V. thanks Xunta de Galicia for a PhD grant (ED481A-2018/314). M.B. and F.C. are grateful to Università del Piemonte Orientale for financial support (Ricerca locale 2016). This work was carried out within the framework of the COST CA15209 Action “European Network on NMR Relaxometry”Xunta de Galicia; ED431B 2017/59Xunta de Galicia; ED431D 2017/01Xunta de Galicia; ED481A-2018/31

Understanding the Effect of the Electron Spin Relaxation on the Relaxivities of Mn(II) Complexes with Triazacyclononane Derivatives

[Abstract] Investigating the relaxation of water ¹H nuclei induced by paramagnetic Mn(II) complexes is important to understand the mechanisms that control the efficiency of contrast agents used in diagnostic magnetic resonance imaging (MRI). Herein, a series of potentially hexadentate triazacyclononane (TACN) derivatives containing different pendant arms were designed to explore the relaxation of the electron spin in the corresponding Mn(II) complexes by using a combination of ¹H NMR relaxometry and theoretical calculations. These ligands include 1,4,7-triazacyclononane-1,4,7-triacetic acid (H₃NOTA) and three derivatives in which an acetate group is replaced by sulfonamide (H₃NOƨASAm), amide (H₂NOƨAM), or pyridyl (H₂NOƨAPy) pendants. The analogue of H₃NOTA containing three propionate pendant arms (H₃NOTPrA) was also investigated. The X-ray structure of the derivative containing two acetate groups and a sulfonamide pendant arm [Mn(NOƨASAm)]⁻ evidenced six-coordination of the ligand to the metal ion, with the coordination polyhedron being close to a trigonal prism. The relaxivities of all complexes at 20 MHz and 25 °C (1.1–1.3 mM⁻¹ s⁻¹) are typical of systems that lack water molecules coordinated to the metal ion. The nuclear magnetic relaxation profiles evidence significant differences in the relaxivities of the complexes at low fields (<1 MHz), which are associated with different spin relaxation rates. The zero field splitting (ZFS) parameters calculated by using DFT and CASSCF methods show that electronic relaxation is relatively insensitive to the nature of the donor atoms. However, the twist angle of the two tripodal faces that delineate the coordination polyhedron, defined by the N atoms of the TACN unit (lower face) and the donor atoms of the pendant arms (upper face), has an important effect in the ZFS parameters. A twist angle close to the ideal value for an octahedral coordination (60°), such as that in [Mn(NOTPrA)]⁻, leads to a small ZFS energy, whereas this value increases as the coordination polyhedron approaches to a trigonal prism.C.P.-I., D.E.-G., and A.R.-R. thank Ministerio de Ciencia e Innovación (Grants CTQ2016-76756-P and PID2019-108352RJ-I00) and Xunta de Galicia (Grants ED431B 2017/59 and ED431D 2017/01) for generous financial support. R.U.-V. thanks Xunta de Galicia (Grant ED481A-2018/314) for funding her PhD contractXunta de Galicia; ED431B 2017/59Xunta de Galicia; ED431D 2017/01Xunta de Galicia; ED481A-2018/31

On the Dissociation Pathways of Copper Complexes Relevant as Pet Imaging Agents

[Abstract] Several bifunctional chelators have been synthesized in the last years for the development of new 64Cu-based PET agents for in vivo imaging. When designing a metal-based PET probe, it is important to achieve high stability and kinetic inertness once the radioisotope is coordinated. Different competitive assays are commonly used to evaluate the possible dissociation mechanisms that may induce Cu(II) release in the body. Among them, acid-assisted dissociation tests or transchelation challenges employing EDTA or SOD are frequently used to evaluate both solution thermodynamics and the kinetic behavior of potential metal-based systems. Despite of this, the Cu(II)/Cu(I) bioreduction pathway that could be promoted by the presence of bioreductants still remains little explored. To fill this gap we present here a detailed spectroscopic study of the kinetic behavior of different macrocyclic Cu(II) complexes. The complexes investigated include the cross-bridge cyclam derivative [Cu(CB-TE1A)]+, whose structure was determined using single-crystal X-ray diffraction. The acid-assisted dissociation mechanism was investigated using HClO4 and HCl to analyse the effect of the counterion on the rate constants. The complexes were selected so that the effects of complex charge and coordination polyhedron could be assessed. Cyclic voltammetry experiments were conducted to investigate whether the reduction to Cu(I) falls within the window of common bioreducing agents. The most striking behavior concerns the [Cu(NO2Th)]2+ complex, a 1,4,7-triazacyclononane derivative containing two methylthiazolyl pendant arms. This complex is extremely inert with respect to dissociation following the acid-catalyzed mechanism, but dissociates rather quickly in the presence of a bioreductant like ascorbic acid.The authors thank Ministerio de Ciencia e Innovación (PID2019-104626GB-I00) and Xunta de Galicia (ED431B 2020/52) for generous financial support. R.U.-V. thanks Xunta de Galicia (Grant ED481A-2018/314) for funding her PhD contract. V. P. and R. T. acknowledge the Ministère de l'Enseignement Supérieur et de la Recherche and the Centre National de la Recherche Scientifique. L.V. thanks CACTI (Universidade de Vigo) for X-ray measurementsXunta de Galicia; ED431B 2020/52Xunta de Galicia; ED481A-2018/31

Mn2+ complexes containing sulfonamide groups with pH-responsive relaxivity

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (H3DPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H3NO2ASAm). These ligands were designed to provide pH-dependent relaxivity response upon complexation with Mn2+ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn2+ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonation of the sulfonamide groups of the ligands are characterized by protonation constants of logKiH = 10.36 and 10.59 for DPASAm3 and HNO2ASAm2 , respectively. These values decrease dramatically to logKiH = 6.43 and 5.42 in the presence of Mn2+ due to the coordination of the negatively charged sulfonamide groups to the metal ion. The higher logKiH value in [Mn(DPASAm)] is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)] is six-coordinated. The X ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N at-om, the N atom of the sulfonamide group and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)] complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (< 7.0). However, protonation of the sulfonamide group in [Mn(DPASAm)] falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r1p = 3.8 mM 1 s 1 at pH 9.0 to r1p = 8.9 mM 1 s 1 at pH 4.0 (10 MHz, 25 ºC).Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Xunta de Galicia | Ref. ED481A-2018/314Universitá degli Studi del Piemonte OrientaleMinisterio de Ciencia, Innovación y Universidades | Ref. BEAGAL18/0014

New contrast agents alternative to those based on gadolinium

Programa Oficial de Doutoramento en Química Ambiental e Fundamental. 5031V01[Abstract] The main objective of this doctoral thesis is the development of new systems based on transition metal ions with both high thermodynamic stability and kinetic inertness, that may be used in Magnetic Resonance lmaging (MRI) as an alternative to commercial gadolinium-based contrast agents. As a first approximation, a detailed literature revision of the stability constants of Gd3+ and Mn2+ complexes has been carried out, allowing the development of empirical expressions capable of predicting the stability constants of the complexes, as well as the corresponding pM value at pH = 7.4. Next, new Mn+2 metal complexes based on acyclic systems (rigidified H4PDTA analogues) or a macrocyclic one (triazacyclononane platform, TACN) have been prepared and fully characterized. Finally, an in vitro study of their ability to act as contrast agents supported by computational studies (DFT and CASSCF /NEVPT2) have also been performed. These studies have made it possible to obtain structural information about their behavior in solution, as well as a better understanding at the molecular level, on the mechanisms that modulate their response as contrast agents in MRI.[Resumen] El objetivo principal de la presente tesis doctoral es el desarrollo de nuevos sistemas basados en metales de transición que posean una estabilidad termodinámica e inercia química elevadas, y que puedan ser utilizados en Imagen por Resonancia Magnética (IRM) como una alternativa a los agentes de contraste comerciales existentes basados en gadolinio. Con este fin, se ha realizado una revisión bibliográfica de las constantes de estabilidad de los complejos de Gd3+ y Mn2+que ha permitido el desarrollo de expresiones empíricas capaces de predecir las constantes de estabilidad de los complejos de ambos iones, así como el valor de pM a pH = 7,4. En base a estos resultados, se han diseñado, sintetizado, caracterizado y estudiado las propiedades fisicoquímicas de nuevos complejos metálicos de Mn+2 basados en sistemas acíclicos (análogos rígidos de H4PDTA) y macrocíclicos (derivados de la plataforma triazaciclononano, TACN). Por último, se ha realizado un análisis detallado in vitro de la capacidad de estos sistemas para actuar como agentes de contraste apoyado en estudios computacionales (DFT y CASSCF/NEVPT2). Estos estudios han permitido obtener información estructural y del comportamiento en disolución de los sistemas preparados, así como información a nivel molecular sobre los mecanismos por los que darían respuesta en IRM.[Resumo] O obxectivo principal da presente tese de doutoramento é o desenvolvemento de novos sistemas baseados en metais de transición que posúan unha estabilidade termodinámica e inercia química elevadas, e que poidan ser empregados en lmaxe por Resonancia Magnética (IRM) como unha alternativa aos axentes de contraste comerciais existentes baseados en gadolinio. Con este fin, realizouse unha revisión bibliográfica das constantes de estabilidade dos complexos de Gd3+ e Mn2+ que permitiu o desenvolvemento de expresións empíricas capaces de predicir as constantes de estabilidade dos complexos de ámbolos dous ións, así como o valor de pM a pH = 7,4. En base a estes resultados, levouse a cabo o deseño, síntese, caracterización e estudo das propiedades fisicoquímicas de novos complexos metálicos de Mn2+ baseados en sistemas acíclicos (análogos ríxidos de H4PDTA) e macrocíclicos (derivados da plataforma triazaciclononano, TACN). Finalmente, realizouse unha análise detallada in vitro da capacidade destes novos sistemas para actuar coma axentes de contraste apoiada en estudos computacionais (DFT e CASSCF /NEVPT2). Estes estudos permitiron obter información estrutural e do comportamento en disolución dos sistemas preparados, así como información a nivel molecular sobre os mecanismos polos que darían resposta en IRM.Xunta de Galicia; ED181A-2018/314Gracias a la Conselleria de Cultura, Educación e Ordenación Universitaria y a la Conselleria de Economía, Emprego e Industria de la Xunta de Galicia por la concesión de la ayuda de apoyo a la etapa predoctoral de la que he sido beneficiaria (ED481A-2018/314)

Rigid versions of PDTA4- incorporating a 1,3-diaminocyclobutyl spacer for Mn2+ complexation: stability, water exchange dynamics and relaxivity

Rigid derivatives of the acyclic ligand PDTA4- (H4PDTA = propylenediamine-N,N,N',N'-tetraacetic acid) were prepared by functionalization of a 1,3-diaminocyclobutyl spacer. The new ligands contain either four acetate groups attached to the central scaffold (H4L1) or incorporate pyridyl (H2L2) or propylamide (H2L3) units replacing two of the carboxylate groups. The ligand protonation constants and the stability constants of their Mn2+ complexes were determined using potentiometric and spectrophotometric titrations. The stability of the [Mn(L1)]2- complex was found to be significantly higher than that of the flexible [Mn(PDTA)]2- derivative (log KMnL = 10.78 and 10.01, respectively). A detailed study of the 1H Nuclear Magnetic Relaxation Dispersion (NMRD) profiles and 17O NMR measurements evidence that the [Mn(L1)]2- and [Mn(L2)] complexes display a hydration equilibrium in solution involving a seven-coordinate species with an inner-sphere water molecule and a six-coordinate species that lacks a coordinated water molecule. As a result the 1H relaxivities of these complexes are somewhat lower than that of [Mn(EDTA)]2- and related systems. The introduction of propylamide groups in [Mn(L3)] shifts the hydration equilibrium to the seven-coordinate species, which results in a 1H relaxivity (r1p = 3.7 mM-1 s-1 at 22 MHz and 25 °C) exceeding that of [Mn(EDTA)]2- (r1p = 3.3 mM-1 s-1 at 22 MHz and 25 °C). The parameters that control the relaxivities in this family of complexes were determined by simultaneous fitting of the experimental 1H NMRD and 17O NMR data (transverse relaxation rates and chemical shifts), with the aid of computational studies performed at the DFT and CASSCF/NEVPT2 levels. These studies provide detailed insight of the parameters that control the efficiency of these relaxation agents at the molecular level

On the dissociation pathways of copper complexes relevant as PET imaging agents

International audienc

Expanding the Ligand Classes Used for Mn(II) Complexation: Oxa-aza Macrocycles Make the Difference

International audienceWe report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A2−) or piperidineacetamide (tO2DO2AMPip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A)(H2O)]·2H2O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (I = 0.15 M NaCl, T = 25 °C). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based tDO2A2− ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (I = 0.15 M NaCl, T = 25 °C). Dissociation of the [Mn(tO2DO2A)(H2O)] complex occurs through both proton− and metal−assisted pathways, while the [Mn(tO2DO2AMPip)(H2O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of tO2DO2A2− is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using 17O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and 1H nuclear magnetic relaxation dispersion (NMRD) profiles