Ruthenium(III) complexes are promising anticancer metallodrugs because of their antimetastatic (migrastatic) potential and significantly lower host toxicity than generally used platinum metallodrugs. On the other hand, the ruthenium(III) complexes generally show low solubility and stability in an aqueous environment but exhibit some toxicity associated with unspecific delivery. For these reasons, numerous ongoing studies deal with their encapsulation into various delivery systems to maximize their therapeutic efficacy. One of these systems can also be crystals of nontoxic metal-organic frameworks (MOFs). In this work, we studied incorporation of a bioactive ruthenium(III) complex (RuC) inside MOFs derived from γ-cyclodextrin (γ-CD) and biocompatible potassium ions, forming CD-MOF-1. Viability studies in vitro were carried out using spheroids of human hepatoblastoma cell line HepG2. These studies revealed that the RuC-CD-MOF-1 system provides effective cancer cell suppression through slow gradual release over a longer period (>10 days) while reducing acute cytotoxic effects associated with naked RuC. This combination was defined for further development and optimization as a drug-delivery platform for metallodrugs.

• MeSH
• Hep G2 Cells MeSH
• Cyclodextrins * chemistry   MeSH
• gamma-Cyclodextrins * chemistry   MeSH
• Coordination Complexes * chemistry   pharmacology   chemical synthesis   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Metal-Organic Frameworks * chemistry   pharmacology   chemical synthesis   MeSH
• Cell Proliferation drug effects   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Ruthenium * chemistry   pharmacology   MeSH
• Drug Screening Assays, Antitumor MeSH
• Cell Survival drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cyclodextrins * MeSH
• gamma-Cyclodextrins * MeSH
• Coordination Complexes * MeSH
• Metal-Organic Frameworks * MeSH
• Antineoplastic Agents * MeSH
• Ruthenium * MeSH

The majority of known metallosupramolecular gels are based on carefully designed ligands using extensive chemical synthesis. Their gelation is often limited to a certain specific metal salt. We demonstrate that in the presence of a wide group of metal salts natural and readily available folic acid (FA) can act as a supergelator. We report a systematic investigation of 17 mechanically robust FA-based metallogels at extremely low concentrations (<0.2 wt%). Using oscillatory rheological measurements, we further show that these metallogels undergo rapid recovery and self-healing, recovering up to 95% of their original stiffness within 1 min. Among the metallogels studied, FA-chromium(III) acetate gel (0.4 wt%) displayed the highest stiffness with a storage modulus of 4 kPa. More importantly, the stiffness, recovery, and sol ↔ gel transitions can be readily tuned by changing either the metal salt or the concentration. Using a combination of various analytical methods, we also suggest a structure of self-assembly in the metallogel network. This study defines non-toxic FA as a robust and sustainable building block for metallogels-mechanically tunable, multi-responsive soft materials. Finally, as a proof-of-concept experiment, we demonstrate that the FA-chromium(III) acetate gel can be considered as a potent sustainable gellator for enhanced oil recovery applications.

• Keywords
• folic acid, gel, metallogel, oil mining, rheology, supramolecular chemistry,
• Publication type
• Journal Article MeSH

ConspectusMagnetic resonance techniques represent a fundamental class of spectroscopic methods used in physics, chemistry, biology, and medicine. Electron paramagnetic resonance (EPR) is an extremely powerful technique for characterizing systems with an open-shell electronic nature, whereas nuclear magnetic resonance (NMR) has traditionally been used to investigate diamagnetic (closed-shell) systems. However, these two techniques are tightly connected by the electron-nucleus hyperfine interaction operating in paramagnetic (open-shell) systems. Hyperfine interaction of the nuclear spin with unpaired electron(s) induces large temperature-dependent shifts of nuclear resonance frequencies that are designated as hyperfine NMR shifts (δHF).Three fundamental physical mechanisms shape the total hyperfine interaction: Fermi-contact, paramagnetic spin-orbit, and spin-dipolar. The corresponding hyperfine NMR contributions can be interpreted in terms of through-bond and through-space effects. In this Account, we provide an elemental theory behind the hyperfine interaction and NMR shifts and describe recent progress in understanding the structural and electronic principles underlying individual hyperfine terms.The Fermi-contact (FC) mechanism reflects the propagation of electron-spin density throughout the molecule and is proportional to the spin density at the nuclear position. As the imbalance in spin density can be thought of as originating at the paramagnetic metal center and being propagated to the observed nucleus via chemical bonds, FC is an excellent indicator of the bond character. The paramagnetic spin-orbit (PSO) mechanism originates in the orbital current density generated by the spin-orbit coupling interaction at the metal center. The PSO mechanism of the ligand NMR shift then reflects the transmission of the spin polarization through bonds, similar to the FC mechanism, but it also makes a substantial through-space contribution in long-range situations. In contrast, the spin-dipolar (SD) mechanism is relatively unimportant at short-range with significant spin polarization on the spectator atom. The PSO and SD mechanisms combine at long-range to form the so-called pseudocontact shift, traditionally used as a structural and dynamics probe in paramagnetic NMR (pNMR). Note that the PSO and SD terms both contribute to the isotropic NMR shift only at the relativistic spin-orbit level of theory.We demonstrate the advantages of calculating and analyzing the NMR shifts at relativistic two- and four-component levels of theory and present analytical tools and approaches based on perturbation theory. We show that paramagnetic NMR effects can be interpreted by spin-delocalization and spin-polarization mechanisms related to chemical bond concepts of electron conjugation in π-space and hyperconjugation in σ-space in the framework of the molecular orbital (MO) theory. Further, we discuss the effects of environment (supramolecular interactions, solvent, and crystal packing) and demonstrate applications of hyperfine shifts in determining the structure of paramagnetic Ru(III) compounds and their supramolecular host-guest complexes with macrocycles.In conclusion, we provide a short overview of possible pNMR applications in the analysis of spectra and electronic structure and perspectives in this field for a general chemical audience.

• Publication type
• Journal Article MeSH

Theoretical interpretation of hyperfine interactions was pioneered in the 1950s-1960s by the seminal works of McConnell, Karplus, and others for organic radicals and by Watson and Freeman for transition-metal (TM) complexes. In this work, we investigate a series of octahedral Ru(III) complexes with aromatic ligands to understand the mechanism of transmission of the spin density from the d-orbital of the metal to the s-orbitals of the ligand atoms. Spin densities and spin populations underlying ligand hyperfine couplings are analyzed in terms of π-conjugative or σ-hyperconjugative delocalization vs spin polarization based on symmetry considerations and restricted open-shell vs unrestricted wave function analysis. The transmission of spin density is shown to be most efficient in the case of symmetry-allowed π-conjugative delocalization, but when the π-conjugation is partially or fully symmetry-forbidden, it can be surpassed by σ-hyperconjugative delocalization. Despite a lower spin population of the ligand in σ-hyperconjugative transmission, the hyperfine couplings can be larger because of the direct involvement of the ligand s-orbitals in this delocalization pathway. We demonstrate a quantitative correlation between the hyperfine couplings of aromatic ligand atoms and the characteristics of the metal-ligand bond modulated by the trans substituent, a hyperfine trans effect.

• Publication type
• Journal Article MeSH

In recent decades, transition-metal coordination compounds have been extensively studied for their antitumor and antimetastatic activities. In this work, we synthesized a set of symmetric and asymmetric Ru(III) and Rh(III) coordination compounds of the general structure (Na+/K+/PPh4+/LH+) [trans-MIIIL(eq)nL(ax)2]- (M = RuIII or RhIII; L(eq) = Cl, n = 4; L(eq) = ox, n = 2; L(ax) = 4-R-pyridine, R = CH3, H, C6H5, COOH, CF3, CN; L(ax) = DMSO-S) and systematically investigated their structure, stability, and NMR properties. 1H and 13C NMR spectra measured at various temperatures were used to break down the total NMR shifts into the orbital (temperature-independent) and hyperfine (temperature-dependent) contributions. The hyperfine NMR shifts for paramagnetic Ru(III) compounds were analyzed in detail using relativistic density functional theory (DFT). The effects of (i) the 4-R substituent of pyridine, (ii) the axial trans ligand L(ax), and (iii) the equatorial ligands L(eq) on the distribution of spin density reflected in the "through-bond" (contact) and the "through-space" (pseudocontact) contributions to the hyperfine NMR shifts of the individual atoms of the pyridine ligands are rationalized. Further, we demonstrate the large effects of the solvent on the hyperfine NMR shifts and discuss our observations in the general context of the paramagnetic NMR spectroscopy of transition-metal complexes.

• Publication type
• Journal Article MeSH

Nuclear magnetic resonance (NMR) spectroscopy of paramagnetic molecules provides detailed information about their molecular and electron-spin structure. The paramagnetic NMR spectrum is a very rich source of information about the hyperfine interaction between the atomic nuclei and the unpaired electron density. The Fermi-contact contribution to ligand hyperfine NMR shifts is particularly informative about the nature of the metal-ligand bonding and the structural arrangements of the ligands coordinated to the metal center. In this account, we provide a detailed experimental and theoretical NMR study of compounds of Cr(III) and Cu(II) coordinated with substituted acetylacetonate (acac) ligands in the solid state. For the first time, we report the experimental observation of extremely paramagnetically deshielded 13C NMR resonances for these compounds in the range of 900-1200 ppm. We demonstrate an excellent agreement between the experimental NMR shifts and those calculated using relativistic density-functional theory. Crystal packing is shown to significantly influence the NMR shifts in the solid state, as demonstrated by theoretical calculations of various supramolecular clusters. The resonances are assigned to individual atoms in octahedral Cr(acac)3 and square-planar Cu(acac)2 compounds and interpreted by different electron configurations and magnetizations at the central metal atoms resulting in different spin delocalizations and polarizations of the ligand atoms. Further, effects of substituents on the 13C NMR resonance of the ipso carbon atom reaching almost 700 ppm for Cr(acac)3 compounds are interpreted based on the analysis of Fermi-contact hyperfine contributions.

• Publication type
• Journal Article MeSH

The kinetics of the hydration reaction on trans-[Pt(NH3)2(pyrX)Cl]+ (pyr = pyridine) complexes (X = OH-, Cl-, F-, Br-, NO2 -, NH2, SH-, CH3, C≡CH, and DMA) was studied by density functional theory calculations in the gas phase and in water solution described by the implicit polarizable continuum model method. All possible positions ortho, meta, and para of the substituent X in the pyridine ring were considered. The substitution of the pyr ligand by electron-donating X's led to the strengthening of the Pt-N1(pyrX) (Pt-NpyrX) bond and the weakening of the trans Pt-Cl or Pt-Ow bonds. The electron-withdrawing X's have exactly the opposite effect. The strengths of these bonds can be predicted from the basicity of sigma electrons on the NpyrX atom determined on the isolated pyrX ligand. As the pyrX ring was oriented perpendicularly with respect to the plane of the complex, the nature of the X···Cl electrostatic interaction was the decisive factor for the transition-state (TS) stabilization which resulted in the highest selectivity of ortho-substituted systems with respect to the reaction rate. Because of a smaller size of X's, the steric effects influenced less importantly the values of activation Gibbs energies ΔG ⧧ but caused geometry changes such as the elongation of the Pt-NpyrX bonds. Substitution in the meta position led to the highest ΔG ⧧ values for most of the X's. The changes of ΔG ⧧ because of electronic effects were the same in the gas phase and the water solvent. However, as the water solvent dampened electrostatic interactions, 2200 and 150 times differences in the reaction rate were observed between the most and the least reactive mono-substituted complexes in the gas phase and the water solvent, respectively. An additional NO2 substitution of the pyrNO2 ligand further decelerated the rate of the hydration reaction, but on the other hand, the poly-NH2 complexes were no more reactive than the fastest o-NH2 system. In the gas phase, the poly-X complexes showed the additivity of the substituent effects with respect to the Pt-ligand bond strengths and the ligand charges.

• Publication type
• Journal Article MeSH