The electrochemical properties of a series of alpha-N-heterocyclic chalcogensemicarbazones (HL), namely, thiosemicarbazones, selenosemicarbazones, and semicarbazones, and their gallium(III), iron(III), and ruthenium(III) complexes with the general formula [ML(2)][Y] (M = Ga, Fe or Ru; Y = PF(6)(-), NO(3)(-), or FeCl(4)(-)) were studied by cyclic voltammetry. The novel compounds were characterized by elemental analysis, a number of spectroscopic methods (NMR, UV-vis, IR), mass spectrometry and by X-ray crystallography. All complexes show several, mostly reversible, redox waves attributable to the reduction of the noninnocent chalcogensemicarbazone ligands at lower potentials (<-0.4 V vs NHE) than the metal-centered iron or ruthenium redox waves (>0 V vs NHE) in organic electrolyte solutions. The cyclic voltammograms of the gallium complexes display at least two consecutive reversible one-electron reduction waves. These reductions are shifted by approximately 0.6 V to lower potentials in the corresponding iron and ruthenium complexes. The electrochemical, chemical, and spectroscopic data indicate that the ligand-centered reduction takes place at the CH(3)CN double bond. Quantum chemical calculations on the geometric and electronic structures of 2-acetylpyridine (4)N,(4)N-dimethylthiosemicarbazone (HL(B)), the corresponding metal complexes [Ga(L(B))(2)](+) and [Fe(II)(L(B))(2)], and the one-electron reduction product for each of these species support the assignment of the reduction site and elucidate the observed order of the ligand-centered redox potentials, E(1/2)([Fe(II)(L)(2)]) < E(1/2)(HL) < E(1/2)([Ga(L)(2)](+)). The influence of water on the redox potentials of the complexes is reported and the physiological relevance of the electrochemical data for cytotoxicity as well as for ribonucleotide reductase inhibitory capacity are discussed.
Two novel paullone derivatives, namely, 6-(alpha-picolylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (L1) and 9-bromo-6-(alpha-picolylamino)-7,12-dihydroindolo[3,2-d][1]benzazepine (L2), have been prepared. The reaction of cis-[RuCl2(DMSO)4] (DMSO=dimethyl sulfoxide) with L1 and L2 in a 1:1 molar ratio in dry ethanol at 50 degrees C afforded the complexes trans-[RuIICl2(DMSO)2L1] (1a) and trans-[RuIICl2(DMSO)2L2] (1b) in 26 and 30% yield, respectively. The reaction carried out from the same starting compounds in a 1:2 molar ratio at 75 degrees C led to the formation of [RuIICl(DMSO)(L1)2]Cl (2a) and [RuIICl(DMSO)(L2)2]Cl (2b) in 16 and 23% yield, correspondingly. The products were characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, electrospray ionization mass spectrometry, IR spectroscopy, electronic spectra, cyclic voltammetry, and X-ray crystallography (L1, L2, 1a, and 2b). Complexes 2a and 2b exhibit remarkable antiproliferative activity in three human carcinoma cell lines, A549 (non-small cell lung carcinoma), CH1 (ovarian carcinoma), and SW480 (colon carcinoma). The novel complexes show an intercalative mode of interaction with DNA, which may render them attractive alternatives to metal compounds with a coordinative mode of interaction.
Reaction of the antitumor complex trans-[Ru(III)Cl4(Hind)2]- (Hind = indazole) with an excess of dimethyl sulfoxide (dmso) in acetone afforded the complex trans,trans,trans-[Ru(II)Cl2(dmso)2(Hind)2] (1). Two other isomeric compounds trans,cis,cis-[Ru(II)Cl2(dmso)2(Hind)2] (2) and cis,cis,cis-[Ru(II)Cl2(dmso)2(Hind)2] (3) have been obtained on refluxing cis-[Ru(II)Cl(2)(dmso)(4)] with 2 equiv. of indazole in ethanol and methanol, respectively. Isomers 1 and 2 react with acetonitrile yielding the complexes trans-[Ru(II)Cl2(dmso)(Hind){HN=C(Me)ind}].CH3CN (4.CH3CN) and trans,cis-[Ru(II)Cl2(dmso)2{HN=C(Me)ind}].H2O (5.H2O), respectively, containing a cyclic amidine ligand resulting from insertion of the acetonitrile C triple bond N group in the N1-H bond of the N2-coordinated indazole ligand in the nomenclature used for 1H-indazole. These are the first examples of the metal-assisted iminoacylation of indazole. The products isolated have been characterized by elemental analysis, IR spectroscopy, UV-vis spectroscopy, electrospray mass-spectrometry, thermogravimetry, differential scanning calorimetry, 1H NMR spectroscopy, and solid-state 13C CP MAS NMR spectroscopy. The isomeric structures of 1-3 and the presence of a chelating amidine ligand in 4 and 5 have been confirmed by X-ray crystallography. The electrochemical behavior of 1-5 and the formation of 5 have been studied by cyclic voltammetry.
Two ruthenium(III) complexes {(HIm)[trans-RuCl4(DMSO)(Im)] (NAMI-A) and (HInd)[trans-RuCl4(Ind)2] (KP1019), DMSO = dimethyl sulfoxide, Im = imidazole, Ind = indazole} have been tested in phase I clinical trials as potential anticancer drugs. Ru(III) anticancer agents are likely activated in vivo upon reduction to their Ru(II) analogs. Aiming at benchmarking implicit solvation methods in DFT studies of ruthenium pharmaceuticals at the B3LYP level, we have calculated the standard redox potentials (SRPs) of Ru(III/II) pairs that were electrochemically characterized in the literature. 80 SRP values in four solvents were calculated using three implicit solvation methods and five solute cavities of molecular shape. Comparison with experimental data revealed substantial errors in some of the combinations of solvation method and solute cavity. For example, the overall mean unsigned error (MUE) with the PCM/UA0 combination, which is the popular default in Gaussian 03, amounts to 0.23 V (5.4 kcal/mol). The MUE with the CPCM/UAKS combination, which was employed by others for recent computational studies on the hydrolysis of NAMI-A and trans-[RuCl4(Im)2](-), amounts to 0.30 V (7.0 kcal/mol) for all compounds and to 0.60 V (13.9 kcal/mol) for a subset of compounds of the medicinally relevant type, trans-[RuCl4(L)(L')](-). The SRPs calculated with the PCM or CPCM methods in Gaussian 03 can be significantly improved by a more compact solute cavity constructed with Bondi's set of atomic radii. Earlier findings that CPCM performs better than PCM cannot be confirmed, as the overall MUE amounts to 0.19 V (4.3-4.4 kcal/mol) for both methods in combination with Bondi's set of radii. The Poisson-Boltzmann finite element method (PBF) implemented in Jaguar 7 together with the default cavity performs slightly better, with the overall MUE being 0.16 V (3.7 kcal/mol). Because the redox pairs considered in this study bear molecular charges from +3/+2 to -1/-2 and the prediction of solvation free energies is most challenging for highly charged species, the present work can serve as a general benchmarking of the implicit solvation methods.
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