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Lactate dehydrogenase (LDH) is a redox enzyme often overexpressed in cancer cells allowing their survival in stressful metabolic tumor environment. Ruthenium(II) complexes have been shown to impact on the activity of purified horseradish peroxidase and glucose oxidase but the physiological relevance remains unclear. In this study we investigated how ruthenium complexes impact on the activity of LDH in vitro and in cancer cells and performed a comparative study using polypyridine ruthenium(II) complex [Ru(bpy) 3 ] 2 + ( 1 ) and its structurally related cyclometalated 2-phenylpyridinato counterpart [Ru(phpy)(bpy) 2 ] + ( 2 ) (bpy = 2,2′-bipyridine, phpyH = 2-phenylpyridine). We show that the cytotoxicity in gastric and colon cancer cells induced by 2 is significantly higher compared to 1 . The kinetic inhibition mechanisms on purified LDH and the corresponding inhibition constants K i or i 0.5 values were calculated. Though complexes 1 and 2 are structurally very similar (one Ru−C bond in 2 replaces one Ru−N bond in 1 ), their inhibition modes are different. Cyclometalated complex 2 behaves exclusively as a non-competitive inhibitor of LDH from rabbit muscle (LDH rm) , strongly suggesting that 2 does not interact with LDH in the vicinities of either lactate/pyruvate or NAD + /NADH binding sites. Sites of interaction of 1 and 2 with LDH rm were revealed theoretically through computational molecular docking. Inhibition of LDH activity by 2 was confirmed in cancer cells. Altogether, these results revealed an inhibition of LDH activity by ruthenium complex through a direct interaction structurally tuned by a Ru−C bond. [ABSTRACT FROM AUTHOR]

Three cyclometalated and one coordination compounds [Os(C–N) x (bpy)3− x ] m (x/m =0/2+ (4); 1/1+ (3); 2/1+ (2); 3/0 (1); −C–N=2-phenylpyridinato, bpy=2,2′-bipyridine) with drastically different reduction potentials have been used for analyzing the second-order rate constants for one-electron, metal-based osmium(II) to osmium(III) oxidation of the complexes by compound I (k 2) and compound II (k 3) of horseradish peroxidase. Previously unknown k 2 and k 3 have been determined by digital simulation of cyclic voltammograms measured in phosphate buffer of pH7.6 and 21±1°C. Osmium(II) species derived from osmium(III) complexes 1 and 2 were generated electrochemically in situ. Under the conditions used the reduction potentials for the OsIII/II feature equal −0.90, −0.095, 0.23 and 0.85V versus NHE (normal hydrogen electrode) for 1–4, respectively. The rate constants k 2 equal ~5×107, 6×108, 2×106 and 1×105 M−1 s−1 and the rate constants k 3 equal ~9×106, 4×107, 1×106 and 1×105 M−1 s−1 for complexes 1–4, respectively. Both rate constants k 2 and k 3 first increase with increasing the reaction driving force on going from 4 to 2 but then both decrease on going to complex 1 though the reaction driving force is the highest in this case. The system described has been explored theoretically using docking Monte Carlo simulations. [ABSTRACT FROM AUTHOR]

Abstract: Cyclometalation of benzo[h]quinoline (bzqH) by [RuCl(μ-Cl)(η6-C6H6)]2 in acetonitrile occurs in a similar way to that of 2-phenylpyridine (phpyH) to afford [Ru(bzq)(MeCN)4]PF6 (3) in 52% yield. The properties of 3 containing ‘non-flexible’ benzo[h]quinoline were compared with the corresponding [Ru(phpy)(MeCN)4]PF6 (1) complex with ‘flexible’ 2-phenylpyridine. The [Ru(phpy)(MeCN)4]PF6 complex is known to react in MeCN solvent with ‘non-flexible’ diimine 1,10-phenanthroline to form [Ru(phpy)(phen)(MeCN)2]PF6, being unreactive toward ‘flexible’ 2,2′-bipyridine under the same conditions. In contrast, complex 3 reacts both with phen and bpy in MeCN to form [Ru(bzq)(LL)(MeCN)2]PF6 {LL=bpy (4) and phen (5)}. Similar reaction of 3 in methanol results in the substitution of all four MeCN ligands to form [Ru(bzq)(LL)2]PF6 {LL=bpy (6) and phen (7)}. Photosolvolysis of 4 and 5 in MeOH occurs similarly to afford [Ru(bzq)(LL)(MeCN)(MeOH)]PF6 as a major product. This contrasts with the behavior of [Ru(phpy)(LL)(MeCN)2]PF6, which lose one and two MeCN ligands for LL=bpy and phen, respectively. The results reported demonstrate a profound sensitivity of properties of octahedral compounds to the flexibility of cyclometalated ligand. Analogous to the 2-phenylpyridine counterparts, compounds 4–7 are involved in the electron exchange with reduced active site of glucose oxidase from Aspergillus niger. Structure of complexes 4 and 6 was confirmed by X-ray crystallography. [Copyright &y& Elsevier]

Abstract: Cyclometalated 2-phenylpyridine complexes [RuII(o-C6H4-2-py)(LL)2]PF6, LL=2,2′-bipyridine (1) and 1,10-phenanthroline (2) were resolved into Δ and Λ enantiomers using column chromatography on SP Sephadex C-25 in the presence of (+)-2,3-dibenzoyl-D-tartrate. The absolute configuration of enantiomers was established using circular dichroism spectroscopy. The rate constants k et for the electron transfer from reduced glucose oxidase (GO from Aspergillus niger) and PQQ-dependent glucose dehydrogenase (GDH) at the generated RuIII species were measured by cyclic voltammetry and UV–vis spectroscopy. The electron transfer shows enantioselectivity. In the case of GO, the bell-shaped pH profile for the ratio k Λ/k Δ has a maximum at pH 7 (k Λ/k Δ equals 3.4 and 3.9 for 1 and 2, respectively), but its inversion is observed at pH around 5 and 9. The k Λ/k Δ ratio equals 2.0 for 2 and GDH at pH 7. The results of theoretical modeling of biological electron transfer for GO using functional docking Monte-Carlo simulations are presented and analyzed together with the experimental observations. [Copyright &y& Elsevier]

Abstract: Iron complexes of tetraamido macrocyclic ligands (TAML) are unique synthetic oxidation catalysts. In general, the central FeIII ion (S =3/2) is surrounded by four, almost planar, deprotonated amide-N σ-donors although the full suite with new generation systems includes some substitution of amides with related donor functionalities. Oxidation under different conditions affords a variety of high-valent forms of iron–TAMLs. This review provides a summary and discussion of structural and spectroscopic features of complexes oxidized by one equivalent above the ferric state. These comprise FeIV–TAML high spin (S =2) and intermediate spin (S =1) systems, wherein the oxidation equivalent can be taken from the metal (FeIV) or the ligand (TAML radical-cation FeIII), and coupled spin (S =0) systems of μ-oxoiron(IV) dimers. The discussion is principally based on data obtained by X-ray crystallography, Mössbauer spectroscopy, and density functional theory calculations. [Copyright &y& Elsevier]

Abstract: Cyclometalated derivatives of ring-substituted N,N-dimethylbenzylamines with controlled redox potentials as potent mediators of bioelectrochemical electron transport are reported. The cycloruthenation of R1R2R3C6H2CH2NMe2 (R1, R2, R3=H, Me, tBuO, MeO, NMe2, F, CF3, CN, NO2) by [(η6-C6H6)RuCl(μ-Cl)]2 in the presence of NaOH/KPF6 in acetonitrile or pivalonitrile affords cyclometalated complexes [(η6-C6H6)Ru(C6HR1R2R3-o-CH2NMe2)(RCN)]PF6 [R=Me (1) and R=CMe3 (2)] in good yields. Reactions of complexes 1 and 2 with 2,2′-bipyridine (bpy) in acetonitrile or pivalonitrile result in dissociation of η6-bound benzene and the formation of [Ru(C6HR1R2R3-o-CH2NMe2)(bpy)(RCN)2]PF6 [R=Me (3) and R=CMe3 (4)]. All new compounds have been fully characterized by mass spectrometry, 1H/13C NMR, and IR spectroscopy. An X-ray crystal structural investigation of complex 1 (R1/R2/R3=H/H/H) and two complexes of type 3 (R1/R2/R3=MeO/H/H, MeO/MeO/H) has been performed. Acetonitrile ligands of 3 are mutually cis and the σ-bound carbon is trans to one of the bpy nitrogens. Measured by the cyclic voltammetry in MeOH as solvent, the redox potentials of complexes 3 for the RuII/III feature cover the range 320–720 mV (versus Ag/AgCl) and correlate linearly with the Hammett constants. Complexes 3 mediate efficiently the electron transport between the active site of PQQ-dependent glucose dehydrogenase (PQQ=pyrroloquinoline quinone) and a glassy carbon electrode. Determined by cyclic voltammetry the second order rate constant for the oxidation of the reduced (by d-glucose) enzyme active site by RuIII derivative of 3 (R1/R2/R3=H) (generated electrochemically) is as high as 4.8×107 M−1 s−1 at 25 °C and pH 7. [Copyright &y& Elsevier]