Ruthenium nitrosyl complexes of the general formulas (cation)+[cis-RuCl4(NO)(Hazole)]−, where (cation)+ = (H2ind)+, Hazole = 1H-indazole (Hind) (1c), (cation)+ = (H2pz)+, Hazole = 1H-pyrazole (Hpz) (2c), (cation)+ = (H2bzim)+, Hazole = 1H-benzimidazole (Hbzim) (3c), (cation)+ = (H2im)+, Hazole = 1H-imidazole (Him) (4c) and (cation)+[trans-RuCl4(NO)(Hazole)]−, where (cation)+ = (H2ind)+, Hazole = 1H-indazole (1t), (cation)+ = (H2pz)+, Hazole = 1H-pyrazole (2t), as well as osmium analogues of the general formulas (cation)+[cis-OsCl4(NO)(Hazole)]−, where (cation)+ = (n-Bu4N)+, Hazole =1H-indazole (5c), 1H-pyrazole (6c), 1H-benzimidazole (7c), 1H-imidazole (8c), (cation)+ = Na+; Hazole =1H-indazole (9c), 1H-benzimidazole (10c), (cation)+ = (H2ind)+, Hazole = 1H-indazole (11c), (cation)+ = H2pz+, Hazole = 1H-pyrazole (12c), (cation)+ = (H2im)+, Hazole = 1H-imidazole (13c), and (cation)+[trans-OsCl4(NO)(Hazole)]−, where (cation)+ = n-Bu4N+, Hazole = 1H-indazole (5t), 1H-pyrazole (6t), (cation)+ = Na+, Hazole = 1H-indazole (9t), (cation)+ = (H2ind)+, Hazole = 1H-indazole (11t), (cation)+ = (H2pz)+, Hazole = 1H-pyrazole (12t), have been synthesized. The compounds have been comprehensively characterized by elemental analysis, ESI mass spectrometry, spectroscopic techniques (IR, UV–vis, 1D and 2D NMR) and X-ray crystallography (1c·CHCl3, 1t·CHCl3, 2t, 3c, 6c, 6t, 8c). The antiproliferative activity of water-soluble compounds (1c, 1t, 3c, 4c and 9c, 9t, 10c, 11c, 11t, 12c, 12t, 13c) in the human cancer cell lines A549 (nonsmall cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon adenocarcinoma) has been assayed. The effects of metal (Ru vs Os), cis/trans isomerism, and azole heterocycle identity on cytotoxic potency and cell line selectivity have been elucidated. Ruthenium complexes (1c, 1t, 3c, and 4c) yielded IC50 values in the low micromolar concentration range. In contrast to most pairs of analogous ruthenium and osmium complexes known, they turned out to be considerably more cytotoxic than chemically related osmium complexes (9c, 9t, 10c, 11c, 11t, 12c, 12t, 13c). The IC50 values of Os/Ru homologs differ by factors (Os/Ru) of up to ∼110 and ∼410 in CH1 and SW480 cells, respectively. ESI-MS studies revealed that ascorbic acid may activate the ruthenium complexes leading to hydrolysis of one M–Cl bond, whereas the osmium analogues tend to be inert. The interaction with myoglobin suggests nonselective adduct formation; i.e., proteins may act as carriers for these compounds.
Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (2, KP1339) are promising redox-active anticancer drug candidates that were investigated with X-ray absorption near edge structure spectroscopy. The analysis was based on the concept of the coordination charge and ruthenium model compounds representing possible coordinations and oxidation states in vivo. 1 was investigated in citrate saline buffer (pH 3.5) and in carbonate buffer (pH 7.4) at 37 °C for different time intervals. Interaction studies on 1 with glutathione in saline buffer and apo-transferrin in carbonate buffer were undertaken, and the coordination of 1 and 2 in tumor tissues was studied too. The most likely coordinations and oxidation states of the compound under the above mentioned conditions were assigned. Microprobe X-ray fluorescence of tumor thin sections showed the strong penetration of ruthenium into the tumor tissue, with the highest concentrations near blood vessels and in the edge regions of the tissue samples.
A one-pot synthesis of osmium(IV) complexes with two different tautomers of indazole, 1H-indazole and 2H-indazole, namely (H2ind)[OsIVCl5(2H-ind)] (1) and (H2ind)[OsIVCl5(1H-ind)] (2) is reported. Both compounds have been comprehensively characterized by NMR spectroscopy, ESI (electrospray ionization) mass spectrometry, electronic absorption spectroscopy, IR spectroscopy, cyclic voltammetry and tested for antiproliferative activity in vitro in three human cancer cell lines, CH1 (ovarian carcinoma), A549 (non-small cell lung cancer) and SW480 (colon carcinoma), as well as in vivo in a Hep3B SCID mouse xeno-transplantation model. 2H-Indazole tautomer stabilization in 1 has been confirmed by X-ray diffraction.
By controlled Anderson type rearrangement reactions complexes of the general formula trans-[OsIVCl4(Hazole)2], where Hazole = 1H-pyrazole, 2H-indazole, 1H-imidazole, and 1H-benzimidazole, have been synthesized. Note that 2H-indazole tautomer stabilization in trans-[OsIVCl4(2H-indazole)2] is unprecedented in coordination chemistry of indazole. The metal ion in these compounds possesses the same coordination environment as ruthenium(III) in (H2ind)[RuIIICl4(Hind)2], where Hind = 1H-indazole, (KP1019), an investigational anticancer drug in phase I clinical trials. These osmium(IV) complexes are appropriate precursors for the synthesis of osmium(III) analogues of KP1019. In addition the formation of an adduct of trans-[OsIVCl4(Hpz)2] with cucurbit[7]uril is described. The compounds have been comprehensively characterized by elemental analysis, EI and ESI mass spectrometry, spectroscopy (IR, UV–vis, 1D and 2D NMR), cyclic voltammetry, and X-ray crystallography. Their antiproliferative acitivity in the human cancer cell lines CH1 (ovarian carcinoma), A549 (nonsmall cell lung carcinoma), and SW480 (colon carcinoma) is reported.
Synthesis and X-ray diffraction structures of cis and trans isomers of ruthenium and osmium metal complexes of general formulas (nBu4N)[cis-MCl4(NO)(Hind)], where M = Ru (1) and Os (3), and (nBu4N)[trans-MCl4(NO)(Hind)], where M = Ru (2) and Os (4) and Hind = 1H-indazole are reported. Interconversion between cis and trans isomers at high temperatures (80–130 °C) has been observed and studied by NMR spectroscopy. Kinetic data indicate that isomerizations correspond to reversible first order reactions. The rates of isomerization reactions even at 110 °C are very low with rate constants of 10–5 s–1 and 10–6 s–1 for ruthenium and osmium complexes, respectively, and the estimated rate constants of isomerization at room temperature are of ca. 10–10 s–1. The activation parameters, which have been obtained from fitting the reaction rates at different temperatures to the Eyring equation for ruthenium [ΔHcis-trans‡= 122.8 ± 1.3; ΔHtrans-cis‡= 138.8 ± 1.0 kJ/mol; ΔScis-trans‡= −18.7 ± 3.6; ΔStrans-cis‡= 31.8 ± 2.7 J/(mol·K)] and osmium [ΔHcis-trans‡= 200.7 ± 0.7; ΔHtrans-cis‡= 168.2 ± 0.6 kJ/mol; ΔScis-trans‡= 142.7 ± 8.9; ΔStrans-cis‡= 85.9 ± 3.9 J/(mol·K)] reflect the inertness of these systems. The entropy of activation for the osmium complexes is highly positive and suggests the dissociative mechanism of isomerization. In the case of ruthenium, the activation entropy for the cis to trans isomerization is negative [−18.6 J/(mol·K)], while being positive [31.0 J/(mol·K)] for the trans to cis conversion. The thermodynamic parameters for cis to trans isomerization of [RuCl4(NO)(Hind)]−, viz. ΔH° = 13.5 ± 1.5 kJ/mol and ΔS° = −5.2 ± 3.4 J/(mol·K) indicate the low difference between the energies of cis and trans isomers. The theoretical calculation has been carried out on isomerization of ruthenium complexes with DFT methods. The dissociative, associative, and intramolecular twist isomerization mechanisms have been considered. The value for the activation energy found for the dissociative mechanism is in good agreement with experimental activation enthalpy. Electrochemical investigation provides further evidence for higher reactivity of ruthenium complexes compared to that of osmium counterparts and shows that intramolecular electron transfer reactions do not affect the isomerization process. A dissociative mechanism of cis↔trans isomerization has been proposed for both ruthenium and osmium complexes.
By exploring the Anderson type rearrangement reactions, osmium(IV) complexes of the general formula [cation](+)[Os(IV)Cl(5)(Hazole)](-), where [cation](+) = n-Bu(4)N(+), Hazole = 1H-pyrazole (Hpz) (1), 1H-indazole (Hind) (2), 1H-imidazole (Him) (3), 1H-benzimidazole (Hbzim) (4), 1H,2,4-triazole (Htrz) (5), have been synthesized. To improve water solubility of tetrabutylammonium compounds, complexes with [cation](+) = Na(+) [Hazole = Hpz 6), Hind (7), Htrz (8)] or H(2)azole(+) [Hazole = Hpz (9), Hind (10), Htrz (11)] have been also prepared with the aim of testing them for cytotoxicity in cancer cells. In addition, the preparation of the complex {(n-Bu(4)N)(2)[Os(IV)Cl(6)]}(2)[Os(IV)Cl(4)(Him)(2)] (12) is also reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization (ESI) mass spectrometry, spectroscopy (IR, UV-vis, 1D and 2D NMR), cyclic voltammetry, X-ray crystallography (1-6 and 12) and magnetic susceptibility (5). Complexes 6, 7, 9 are kinetically inert in aqueous solution and resistant to hydrolysis. Compounds 6-11 were found to possess modest antiproliferative acitivity in vitro against CH1 (ovarian carcinoma), A549 (non-small cell lung carcinoma), and SW480 (colon adenocarcinoma) cells with IC(50) values in the 10(-4) M concentration range. Replacement of azolium cations by sodium had significant effects; cytotoxicity increased in the case of the pyrazole system from 3 (A549) to the 5.5-fold (CH1).
Abstract"Kramers pairs symmetry breaking" is evaluated at the 2-component (2c) Kramers unrestricted and/or general complex Hartree-Fock (GCHF) level of theory, and its analogy with "spin contamination" at the 1-component (1c) unrestricted Hartree-Fock (UHF) level of theory is emphasized. The GCHF "Kramers pairs symmetry breaking" evaluation is using the square of overlaps between the set of occupied spinorbitals with the projected set of Kramers pairs. In the same fashion, overlaps between α and β orbitals are used in the evaluation of "spin contamination" at the UHF level of theory. In this manner, UHFŜ 2 expectation value is made formally extended to the GCHF case. The directly evaluated GCHF expectation value of theŜ 2 operator is considered for completeness. It is found that the 2c GCHF Kramers pairs symmetry breaking has a very similar extent in comparison to the 1c UHF spin contamination. Thus higher excited states contributions to the 1c so 2c unrestricted wave functions of open shell systems have almost the same extent and physical consequences. Moreover, it is formally shown that a single determinant wave function in the restricted open shell Kramers case has the expectation value ofK 2 operator equal to the negative number of open shell electrons, while the eigenvalue ofK 2 for the series of simple systems (H, He, He*-triplet, Li and Li*-quartet) are found to be equal to minus the square of the number of open shell electrons. The concept of unpaired electron density is extended to the GCHF regime and compared to UHF and restricted open shell Hartree-Fock spin density. The "collinear" and "noncollinear" analogs of spin density at the GCHF level of theory are considered as well. Spin contamination and/or Kramers pairs symmetry breaking, spin
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