Overcoming Resistance of Caco-2 Cells to 5-Fluorouracil through Diruthenium Complex Encapsulation in PMMA Nanoparticles.

Drug resistance, one of the main drawbacks in cancer chemotherapy, can be tackled by employing a combination of drugs that target different biological processes in the cell, enhancing the therapeutic efficacy. Herein, we report the synthesis and characterization of a new paddlewheel diruthenium complex that includes 5-fluorouracil (5-FU), a commonly used anticancer drug. This drug was functionalized with a carboxylate group to take advantage of the previously demonstrated release capacity of carboxylate ligands from the diruthenium core. The resulting hydrophobic complex, [Ru2Cl(DPhF)3(5-FUA)] (Ru-5-FUA) (DPhF = N,N'-diphenylformamidinate; 5-FUA = 5-fluorouracil-1-acetate) was subsequently entrapped in poly(methyl methacrylate) (PMMA) nanoparticles (PMMA@Ru-5-FUA) via a reprecipitation method to be transported in biological media. The optimized encapsulation procedure yielded particles with an average size of 81.2 nm, a PDI of 0.11, and a zeta potential of 29.2 mV. The cytotoxicity of the particles was tested in vitro using the human colon carcinoma cell line Caco-2. The IC50 (half maximal inhibitory concentration) of PMMA@Ru-5-FUA (6.08 µM) was just slightly lower than that found for the drug 5-FU (7.64 µM). Most importantly, while cells seemed to have developed drug resistance against 5-FU, PMMA@Ru-5-FUA showed an almost complete lethality at ∼30 µM. Conversely, an analogous diruthenium complex devoid of the 5-FU moiety, [Ru2Cl(DPhF)3(O2CCH3)] (PMMA@RuA), displayed a reduced cytotoxicity at equivalent concentrations. These findings highlight the effect of combining the anticancer properties of 5-FU with those of diruthenium species. This suggests that the distinct modes of action of the two chemical species are crucial for overcoming drug resistance.

Rapid Discrimination of Crystal Handedness by X-ray Natural Circular Dichroism (XNCD) Mapping.

An original method for determining the handedness of individual non-centrosymmetric crystals in a mixture using a tightly-focused, circularly polarized X-ray beam is presented. The X-ray natural circular dichroism (XNCD) spectra recorded at the metal K-edge on selected crystals of [Δ-M(en)3 ](NO3 )2 and [Λ-M(en)3 ](NO3 )2 (M=CoII , NiII ) show extrema at the metal pre-edge (7712 eV for Co, 8335 eV for Ni). A mapping of a collection of some 220 crystals was performed at the respective energies by using left and right circular polarizations. The difference in absorption for the two polarizations, being either negative or positive, directly yielded the handedness of the crystal volume probed by the beam. By using this technique, it was found that the addition of l-ascorbic acid during the synthesis of [Co(en)3 ](NO3 )2 resulted in an enantiomeric enrichment of the Λ-isomer of 67±13 %, whereas the Ni analogue was similarly, but conversely, enriched in the Δ-isomer (65±22 %).

pH- and Time-Dependent Release of Phytohormones from Diruthenium Complexes.

The controlled release of functionally active compounds is important in a variety of applications. Here, we have synthesized, characterized, and studied the magnetic properties of three novel metal-metal-bonded tris(formamidinato) Ru25+ complexes. We have used different auxin-related hormones, indole-3-acetate (IAA), 2,4-dichlorophenoxyacetate (2,4-D), and 1-naphthaleneacetate (NAA), to generate [Ru2Cl(µ-DPhF)3(µ-IAA)] (RuIAA), [Ru2Cl(µ-DPhF)3(µ-2,4-D)] (Ru2,4-D), and [Ru2Cl(µ-DPhF)3(µ-NAA)] (RuNAA) (DPhF = N,N'-diphenylformamidinate). The crystal structures of RuIAA, RuIAA·THF, Ru2,4-D·CH2Cl2, and RuNAA·0.5THF have been determined by single-crystal X-ray diffraction. To assess the releasing capacity of the bound hormone, we have employed a biological assay that relied on Arabidopsis thaliana plants expressing an auxin reporter gene and we demonstrate that the release of the phytohormones from RuIAA, Ru2,4-D, and RuNAA is pH- and time-dependent. These studies serve as a proof of concept showing the potential of these types of compounds as biological molecule carriers.

The Origin of Magnetic Anisotropy and Single-Molecule Magnet Behavior in Chromium(II)-Based Extended Metal Atom Chains.

Chromium(II)-based extended metal atom chains have been the focus of considerable discussion regarding their symmetric versus unsymmetric structure and magnetism. We have now investigated four complexes of this class, namely, [Cr3(dpa)4X2] and [Cr5(tpda)4X2] with X = Cl- and SCN- [Hdpa = dipyridin-2-yl-amine; H2tpda = N2,N6-di(pyridin-2-yl)pyridine-2,6-diamine]. By dc/ac magnetic techniques and EPR spectroscopy, we found that all these complexes have easy-axis anisotropies of comparable magnitude in their S = 2 ground state (|D| = 1.5-1.8 cm-1) and behave as single-molecule magnets at low T. Ligand-field and DFT/CASSCF calculations were used to explain the similar magnetic properties of tri- versus pentachromium(II) strings, in spite of their different geometrical preferences and electronic structure. For both X ligands, the ground structure is unsymmetric in the pentachromium(II) species (i.e., with an alternation of long and short Cr-Cr distances) but is symmetric in their shorter congeners. Analysis of the electronic structure using quasi-restricted molecular orbitals (QROs) showed that the four unpaired electrons in Cr5 species are largely localized in four 3d-like QROs centered on the terminal, "isolated" Cr2+ ion. In Cr3 complexes, they occupy four nonbonding combinations of 3d-like orbitals centered only on the two terminal metals. In both cases, then, QRO eigenvalues closely mirror the 3d-level pattern of the terminal ions, whose coordination environment remains quite similar irrespective of chain length. We conclude that the extent of unpaired-electron delocalization has little impact on the magnetic anisotropy of these wire-like molecular species.

Resolution, structures, and vibrational circular dichroism of helicoidal trinickel and tricobalt paddlewheel complexes.

It has been recently shown that enantiomers of the helicoidal paddlewheel complex [Co3 (dpa)4 (CH3 CN)2 ]2+ (dpa = the anion of 2,2'-dipyridylamine) can be resolved using the chiral [As2 (tartrate)2 ]2- anion (AsT) and that these complexes demonstrate a strong chiroptical response in the ultraviolet-visible and X-ray energy regions. Here we report that the nickel congener, [Ni3 (dpa)4 (CH3 CN)2 ]2+ , can likewise be resolved using AsT. Depending on the stereochemistry of the enantiopure AsT anion, one or the other of the trinickel enantiomers crystallize from CH3 CN and diethyl ether in space group P421 2 as the (NBu4 )2 [Ni3 (dpa)4 (CH3 CN)2 ](AsT)2 ·[solvent] salt. After resolution, the AsT salts were converted into the PF6 - salts by anion exchange, with retention of the chirality of the trinickel complex. The enantiopure [Ni3 (dpa)4 (CH3 CN)2 ](PF6 )2 ·2CH3 CN and [Co3 (dpa)4 (CH3 CN)2 ](PF6 )2 ·CH3 CN·C4 H10 O compounds crystallize in space groups C2 and P21 , respectively. Both the Ni(II) and Co(II) complex cations are stable towards racemization in CH3 CN. Vibrational circular dichroism (VCD) data obtained in CD3 CN demonstrate the expected mirror image spectra for the enantiomers, the observed peaks arising from the dpa ligand. The VCD response is significant, with Δε values up to 6 Lmol-1 cm-1 and vibrational dissymmetry factors on the order of 10-3 . Density functional theory calculations well reproduce the experimental spectra, showing little difference between the peak position, sign, and intensity in the VCD for the cobalt and nickel complexes. These results suggest that VCD enhancement of these peaks is unlikely, and their remarkable intensity may be due to their rigid helicoidal structure.

Design and Study of Structural Linear and Nonlinear Optical Properties of Chiral [Fe(phen)3]2+ Complexes.

The dependence of nonlinear optical properties upon the spin state in molecular switches is still an unexplored area. Chiral [Fe( phen)3]2+ complexes are excellent candidates for those studies because they are expected to show nonlinear optical properties of interest and at the same time show photoconversion to a short-lived metastable high-Spin state by ultrafast optical pumping. Herein, we present the synthesis, crystallographic, and spectroscopic comparison of chiral [Fe( phen)3]2+ complexes obtained with chiral anions, a new lipophilic derivative of the D2-symmetric (As2(tartrate)2)2-, and D3-symmetric tris(catechol)phosphate(V) (TRISCAT), tris(catechol)arsenate(V) (TRISCAS), and 3,4,5,6-tetrachlorocatechol phosphate(V) (TRISPHAT). Complexes [Fe( phen)3]( rac-TRISCAT)2 (2) and [Fe( phen)3](X-TRISCAS)2 (X = rac (3), Δ (4), Λ (5)) were found to be isomorphous in the R32 Sohncke space group with twinning by inversion correlated with the starting chiral anion optical purity. The structures show the [Fe( phen)3]2+ complex interacting strongly along its 3-fold axis with two anions. Only the structure of a [Fe( phen)3]( rac-TRISPHAT)2 solvate (6) could be obtained, which showed no particular anion/cation interaction contrary to what was observed previously in solution. The [Fe( phen)3](X-As2(tartrate)2) (X = Δ (7), Λ (8), and racemic mixture (9)) crystallizes in enantiomorphic space groups P3121/ P3221 with the same solid-state packing. Dichroic electronic absorption studies evidenced racemization for all chiral complexes in solution due to ion pair dissociation, whereas the asymmetric induction is conserved in the solid state in KBr pellets. We evidenced on chiral complexes 4 and 5 strong nonlinear second harmonic generation, the intensity of which could be correlated with the complex electronic absorption.

Synthesis, Spectroelectrochemical Behavior, and Chiroptical Switching of Tris(ß-diketonato) Complexes of Ruthenium(III), Chromium(III), and Cobalt(III).

Five tris(ß-diketonato) complexes of ruthenium(III), chromium(III), and cobalt(III) [Ru(Buacac)3 (1), Ru(Oacac)3 (2), Cr(Buacac)3 (3), Cr(Oacac)3 (4), and Co(Buacac)3 (5), where Buacac = 3-butylpentane-2,4-dionato and Oacac = 3-octylpentane-2,4-dionato] with a chiral propeller-like structure have been prepared. Ligands and complexes syntheses are presented together with characterization of the compounds by 1H and 13C NMR spectroscopy, mass spectrometry, IR, UV-vis, electronic circular dichroism (ECD) spectroscopy, electrochemistry studies, and first-principles calculations. The crystal structures of 1 and 5 have also been obtained and analyzed. A comparison of the 1H NMR spectra of diamagnetic (ligands and 5) and paramagnetic (1 and 2) species is presented. Optical resolution of the five complexes has been achieved for the first time by supercritical fluid chromatography using a chiral column, giving rise to very high purity grades in all cases. ECD measurements and calculations have led to the assignment of the absolute configuration, Δ or Λ, of each enantiomer for 1-5. Spectroelectrochemical UV-vis and ECD studies have been performed on ruthenium Λ-2 and chromium Λ-4 complexes, revealing their redox-triggered chiroptical switching confirming the noninnocence character of the ß-diketonate ligands.

Crystal structure of poly[[trans-di-aqua-bis-[µ2-trans-4,4'-(diazenedi-yl)dipyridine]-nickel(II)] diiodide ethanol disolvate].

In the title compound, {[Ni(C10H8N4)2(H2O)2]I2·2C2H5OH} n , the complex shows an octa-hedral environment of the Ni(2+) cation in which it is located on a centre of symmetry, linked to two water mol-ecules and the pyridine-N atoms of four 4,4'-(diazenediyl)dipyridine ligands bridging Ni(2+) cations along the b- and c-axis directions, giving rise to a two-dimensional arrangement. The Ni-N bond lengths are in the range 2.109 (4)-2.186 (3) Šand the Ni-O bond length is 2.080 (3) Å. The 4,4'-(diazenedi-yl)dipyridine ligand lies on an inversion centre. An O-H⋯O hydrogen-bond inter-action is observed between water and ethanol mol-ecules. The I(-) ions can be regarded as free anions in the crystal lattice.

Modulation of the magnetic properties of two-dimensional compounds [NiX2(N-N)] by tailoring their crystal structure.

A series of 2-D nickel compounds with the stoichiometry [NiCl2(N-N)] has been prepared, [N-N = pyrazine (1), 4,4'-bipyridine (2), trans-4,4'-azopyridine (3), trans-1,2-bis(4-pyridyl)ethylene (4), and 1,2-bis(4-pyridyl)ethane (5)]. The complex [NiBr2(4,4'-bpy)] (6) was also obtained for comparative reasons. Compound 2 is the ß phase of the previously reported complex [NiCl2(4,4'-bpy)]. The syntheses of complexes 1-6 were carried out using solvothermal and microwave techniques. The compounds have been characterized by elemental analysis, infrared spectroscopy, thermogravimetry, and powder X-ray diffraction. The crystal structures of compounds 1, 4, and 5 have been solved using ab initio X-ray powder diffraction methods. Compounds 1-6 show the same arrangement, and their structures are described as layers formed by [NiX2] chains linked perpendicularly by N-N ligands. The magnetic properties of the compounds are explained as a balance between the ferromagnetic interactions along the [NiX2] chains and the antiferromagnetic interactions between chains from different layers. This work demonstrates that this balance can be tuned by the length of the N-N ligand.

New insights into progressive ligand replacement from [Ru2Cl(O2CCH3)4]: synthetic strategies and variation in redox potentials and paramagnetic shifts.

The complete series of [Ru2Cl(Dp-FPhF)x(O2CCH3)4-x] (x = 1-4; Dp-FPhF- = N,N'-bis(4-fluorophenyl)formamidinate) compounds, has been prepared and characterized by a multi-technique approach, including single crystal X-ray diffraction. A careful study of the different methodologies has allowed us to prepare four compounds with good yields and without an inert atmosphere or further purification. Specifically, [Ru2Cl(Dp-FPhF)(O2CCH3)3] (1) was obtained using an ultrasound-assisted (USS) method, while [Ru2Cl(Dp-FPhF)4] (4) was prepared by microwave assisted solvothermal synthesis (MWS). The intermediate substitution products cis-[Ru2Cl(Dp-FPhF)2(O2CCH3)2] (2) and [Ru2Cl(Dp-FPhF)3(O2CCH3)] (3) have been prepared by conventional heating, controlling the molar ratio of the starting materials. ESI-MS and infrared spectroscopy were used to follow all the reactions and permitted a qualitative evaluation of the axial reactivity in this series. Magnetic and absorption measurements confirmed a high spin σ2π4δ2(π*δ*)3 electronic configuration in all cases. However, the effect of the gradual modification of the electronic density in the diruthenium core markedly affects other properties. The cyclic voltammograms of the compounds show a strong decrease in the one electron oxidation potential and an increase in the reduction potential in the series from 1 to 4. Furthermore, despite their paramagnetic nature, 1H- and 19F-NMR spectra were recorded, and a correlation between the paramagnetic shift of the signals and the substitution degree of the diruthenium species was observed. These results provide a comprehensive guide to synthesise and understand the effects of equatorial ligand substitution on the properties of Ru25+ compounds.

Ultrasound-assisted synthesis of water-soluble monosubstituted diruthenium compounds.

The elusive monosubstituted diruthenium complexes [Ru2Cl(DAniF)(O2CMe)3] (1), [Ru2Cl(DPhF)(O2CMe)3] (2), [Ru2Cl(D-p-CNPhF)(O2CMe)3] (3), [Ru2Cl(D-o-TolF)(O2CMe)3] (4), [Ru2Cl(D-m-TolF)(O2CMe)3] (5), [Ru2Cl(D-p-TolF)(O2CMe)3] (6) and [Ru2Cl(p-TolA)(O2CMe)3] (7) have been synthesized using for the first time ultrasound-assisted synthesis to carry out a substitution reaction in metal-metal bonded dinuclear compounds (DAniF- = N,N'-bis(4-anisyl)formamidinate; DPhF- = N,N'-diphenylformamidinate; D-p-CNPhF- = N,N'-bis(4-cyanophenyl)formamidinate; D-o/m/p-TolF- = N,N'-bis(2/3/4-tolyl)formamidinate; p-TolA- = N-4-tolylamidate). This is a simpler and greener method than the tedious procedures described in the literature, and it has permitted to obtain water-soluble complexes with good yields in a short period of time. A synthetic study has been implemented to find the best experimental conditions to prepare compounds 1-7. Two different types of ligands, formamidinate and amidate, have been used to check the generality of the method for the preparation of monosubstituted complexes. Five new compounds (2-6) have been obtained using a formamidinate ligand, the synthesis of the previously described compound 1 has been improved, and an unprecedented monoamidate complex has been achieved (7). The crystal structures of compounds 3 and 7 have been solved by single crystal X-ray diffraction. These compounds show the typical paddlewheel structure with three acetate ligands and one formamidinate (3) or amidate (7) bridging ligand at the equatorial positions. The axial positions are occupied by the chloride ligand giving rise to one-dimensional polymer structures that were previously unknown for monosubstituted compounds.

Heteronuclear Dirhodium-Gold Anionic Complexes: Polymeric Chains and Discrete Units.

In this article, we report on the synthesis and characterization of the tetracarboxylatodirhodium(II) complexes [Rh2(µ-O2CCH2OMe)4(THF)2] (1) and [Rh2(µ-O2CC6H4-p-CMe3)4(OH2)2] (2) by metathesis reaction of [Rh2(µ-O2CMe)4] with the corresponding ligand acting also as the reaction solvent. The reaction of the corresponding tetracarboxylato precursor, [Rh2(µ-O2CR)4], with PPh4[Au(CN)2] at room temperature, yielded the one-dimensional polymers (PPh4)n[Rh2(µ-O2CR)4Au(CN)2]n (R = Me (3), CH2OMe (4), CH2OEt (5)) and the non-polymeric compounds (PPh4)2{Rh2(µ-O2CR)4[Au(CN)2]2} (R = CMe3 (6), C6H4-p-CMe3 (7)). The structural characterization of 1, 3·2CH2Cl2, 4·3CH2Cl2, 5, 6, and 7·2OCMe2 is also provided with a detailed description of their crystal structures and intermolecular interactions. The polymeric compounds 3·2CH2Cl2, 4·3CH2Cl2, and 5 show wavy chains with Rh-Au-Rh and Rh-N-C angles in the ranges 177.18°-178.69° and 163.0°-170.4°, respectively. A comparative study with related rhodium-silver complexes previously reported indicates no significant influence of the gold or silver atoms in the solid-state arrangement of these kinds of complexes.

Synthesis and Structural Characterization of a Series of One-Dimensional Heteronuclear Dirhodium-Silver Coordination Polymers.

Herein, we describe the preparation of heteronuclear dirhodium-silver complexes by reaction between molecular Rh(II)-Rh(II) compounds [Rh2(µ-O2CR)4L2] (R = Me, Ph (1), CH2OEt (2); L = solvent molecules) with paddlewheel structure and PPh4[Ag(CN)2]. One-dimensional coordination polymers of (PPh4)n[Rh2(µ-O2CR)4Ag(CN)2]n (R = Me (3), Ph (4), CH2OEt (5)) formula have been obtained by replacement of the two labile molecules in the axial positions of the paddlewheel structures by a [Ag(CN)2]- bridging unit. The crystal structures of 3⁻5 display a similar arrangement, having anionic chains with a wavy structure and bulky (PPh4)⁺ cations placed between the chains. The presence of the (PPh4)⁺ cations hinders the existence of intermolecular Ag-Ag interactions although several C-H····π interactions have been observed. A similar reaction between [Rh2(µ-O2CCMe3)4(HO2CCMe3)2] and PPh4[Ag(CN)2] led to the molecular compound (PPh4)2{Rh2(µ-O2CCMe3)4[Ag(CN)2]2} (6) by replacement of the axial HO2CCMe3 ligands by two [Ag(CN)2]- units. The trimethylacetate ligand increases the solubility of the complex during the crystallization favouring the formation of discrete heteronuclear species.

Tetracarbonatodiruthenium Fragments and Lanthanide(III) Ions as Building Blocks to Construct 2D Coordination Polymers.

Two-dimensional coordination polymers of [Pr(DMSO)2(OH2)3][Ru2(CO3)4(DMSO)(OH2)]·5H2O (Prα) and [Ln(OH2)5][Ru2(CO3)4(DMSO)]·xH2O (Ln = Sm (Smß), Gd (Gdß)) formulae have been obtained by reaction of the corresponding Ln(NO3)3·6H2O dissolved in dimethyl sulphoxide (DMSO) and K3[Ru2(CO3)4]·4H2O dissolved in water. Some DMSO molecules are coordinated to the metal atoms reducing the possibilities of connection between the [Ru2(CO3)4]3- and Ln3+ building blocks giving rise to the formation of two-dimensional networks. The size of the Ln3+ ion and the synthetic method seem to have an important influence in the type of two-dimensional structure obtained. Slow diffusion of the reagents gives rise to Prα that forms a 2D net that is built by Ln3+ ions as triconnected nodes and two types of Ru25+ units as bi- and tetraconnected nodes with (2-c)(3-c)2(4-c) stoichiometry (α structure). An analogous synthetic procedure gives Smß and Gdß that display a grid-like structure, (2-c)2(4-c)2, formed by biconnected Ln3+ ions and two types of tetraconnected Ru25+ fragments (ß structure). The magnetic properties of these compounds are basically explained as the sum of the individual contributions of diruthenium and lanthanide species, although canted ferrimagnetism or weak ferromagnetism are observed at low temperature.

Enantiopure Chiral Coordination Polymers Based on Polynuclear Paddlewheel Helices and Arsenyl Tartrate.

Herein, we report the preparation of chiral, one-dimensional coordination polymers based on trinuclear paddlewheel helices [M3(dpa)4]2+ (M = Co(II) and Ni(II); dpa = the anion of 2,2'-dipyridylamine). Enantiomeric resolution of a racemic mixture of [M3(dpa)4]2+ complexes was achieved by chiral recognition of the respective enantiomer by [Δ-As2(tartrate)2]2- or [Λ-As2(tartrate)2]2- in N,N-dimethylformamide (DMF), affording crystalline coordination polymers formed from [(Δ-Co3(dpa)4)(Λ-As2(tartrate)2)]·3DMF (Δ-1), [(Λ-Co3(dpa)4)(Δ-As2(tartrate)2)]·3DMF (Λ-1), [(Δ-Ni3(dpa)4)(Λ-As2(tartrate)2)]·(4 - n)DMF∙nEt2O (Δ-2) or [(Λ-Ni3(dpa)4)(Δ-As2(tartrate)2)]·(4 - n)DMF∙nEt2O (Λ-2) repeating units. UV-visible circular dichroism spectra of the complexes in DMF solutions demonstrate the efficient isolation of optically active species. The helicoidal [M3(dpa)4]2+ units that were obtained display high stability towards racemization as shown by the absence of an evolution of the dichroic signals after several days at room temperature and only a small decrease of the signal after 3 h at 80 °C.

Enantiomeric resolution and X-ray optical activity of a tricobalt extended metal atom chain.

A simple procedure based on anion exchange was employed for the enantiomeric resolution of the extended metal atom chain (EMAC) [Co3(dpa)4(MeCN)2]2+. Use of the chiral salt (NBu4)2[As2(tartrate)2], (Λ-1 or Δ-1), resulted in the selective crystallization of the EMAC enantiomers as [Δ-Co3(dpa)4(MeCN)2](NBu4)2[Λ-As2(tartarte)2]2, (Δ-2) and [Λ-Co3(dpa)4(MeCN)2](NBu4)2[Δ-As2(tartrate)2]2 (Λ-2), respectively, in the P4212 space group, whereas a racemic mixture of 1 yielded [Co3(dpa)4(MeCN)2][As2(tartrate)2]·2MeCN (rac-3), which crystallized in the C2/c space group. The local electronic and magnetic structure of the EMAC enantiomers was studied, exploiting a variety of dichroisms in single crystals. A strong linear dichroism at the Co K-edge was observed in the orthoaxial configuration, whereas it vanished in the axial orientation, thus spectroscopically confirming the D4 crystal symmetry. Compounds Δ-2 and Λ-2 are shown to be enantiopure materials as evidenced by mirror-image natural circular dichroism spectra in the UV/vis in solution and in the X-ray range at the Co K-edge in single crystals. The surprising absence of detectable X-ray magnetic circular dichroism or X-ray magnetochiral dichroism signals at the Co K-edge, even at low temperature (3 K) and a high magnetic field (17 T), is ascribed to a strongly delocalized spin density on the tricobalt core.