Solution Equilibrium Studies on Anticancer Ruthenium(II)–eta6-p-cymene Complexes of 3-Hydroxy-2(1H)-pyridones

Ru-II(eta(6)-p-cymene) complexes of bidentate (0,0) alkoxycarbonylmethyl-3-hydroxy-2(1H)-pyridone ligands exhibit in vitro antitumor activity. We determined the stoichiometry and stability in aqueous solution of two examples by pH-potentiometry, H-1 NMR spectroscopy and UV-vis spectrophotometry and also characterized the proton dissociation processes of the ligands. Formation of mono-ligand complexes with moderate stability was found to predominate in the physiological pH range. Moreover, the chlorido/aqua co-ligand exchange processes of the [Ru-II(eta(6)-p-cymene)(L)(H2O)](+) species were also monitored and 55-65% of the aqua ligand was found to be replaced by chloride in 0.2 M KCl-containing aqueous solutions. Under basic conditions, the complexes decompose to dinuclear tri-hydroxido-bridged [Ru-2(I)(eta(6)-p-cymene)(2)(OH)(3)](+) and metal-free ligand and also a hydroxido species [Ru-II(eta(6)-p-cymene)(L)(OH)] was found. Furthermore, the ligands contain an ester functional group, which may hydrolyze at basic pH, which is however negligible at acidic or neutral pH

The development of RAPTA compounds for the treatment of tumors

© 2015 Elsevier B.V. Ruthenium(II)-arene RAPTA-type compounds have been extensively explored for their medicinal properties. Herein a comprehensive review of this class of compounds is provided. A discussion of the basic RAPTA structure is given together with the ways it has been modified to elucidate the key role of each part and to afford targeted derivatives. The various mechanistic studies conducted on RAPTA compounds are described and these are linked to the observed macroscopic biological properties. Ultimately, the review shows that certain RAPTA compounds display quite unique properties that point towards a clinical investigation

Solution Equilibrium Studies of Anticancer Ruthenium(II)-η6-p-cymene Complexes of Pyridinecarboxylic Acids

Stoichiometry and stability of antitumor ruthenium(II)-η6-p-cymene complexes of picolinic acid and its 6-methyl and 6-carboxylic acid derivatives were determined by pH-potentiometry, 1H NMR spectroscopy and UV–Vis spectrophotometry in aqueous solution in the presence or absence of coordinating chloride ions. The picolinates form exclusively mono-ligand complexes in which they can coordinate via the bidentate (O,N) mode and a chloride or a water molecule is found at the third binding site of the ruthenium(II)-η6-p-cymene moiety depending on the conditions. [Ru(η6-p-cymene)(L)(H2O/Cl)] species are predominant at physiological pH in all studied cases. Hydrolysis of the aqua complex or the chlorido/hydroxido co-ligand exchange results in the formation of the mixed-hydroxido species [Ru(η6-p-cymene)(L)(OH)] in the basic pH range. There is no indication for the decomposition of the mono-ligand complexes during 24 h in the ruthenium(II)-η6-p-cymene-picolinic acid system between pH 3 and 11; however, a slight dissociation with a low reaction rate was found in the other two systems leading to the appearance of the dinuclear trihydroxido-bridged species [Ru2(η6-p-cymene)2(OH)3]+ and free ligands at pH > 10. The replacement of the chlorido by an aqua ligand in [Ru(η6-p-cymene)(L)Cl] was also monitored and equilibrium constants for the exchange process were determined

Metabolization of [Ru(η6-C6H5CF3)(pta)Cl2]: a cytotoxic RAPTA-type complex with a strongly electron withdrawing arene ligand

The anticancer ruthenium-arene compd. [Ru(η6-C6H5CF3)(pta)Cl2] (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane), termed RAPTA-CF3, with the electron-withdrawing α,α,α-trifluorotoluene ligand, is one of the most cytotoxic RAPTA compds. known. To rationalize the high obsd. cytotoxicity, the hydrolysis of RAPTA-CF3 in water and brine (100 mM sodium chloride) and its reactions with the protein ubiquitin and a double-stranded oligonucleotide (5'-GTATTGGCACGTA-3') were studied using NMR spectroscopy, high-resoln. Fourier transform ion cyclotron resonance mass spectrometry, and gel electrophoresis. The aquation of the ruthenium-chlorido complex was accompanied by a loss of the arene ligand, independent of the chloride concn., which is a special property of the compd. not obsd. for other ruthenium-arene complexes with relatively stable ruthenium-arene bonds. Accordingly, the mass spectra of the biomol. reaction mixts. contained mostly [Ru(pta)]-biomol. adducts, whereas [Ru(pta)(arene)] adducts typical of other RAPTA compds. were not obsd. in the protein or DNA binding studies. Gel electrophoresis expts. revealed a significant degree of decompn. of the oligonucleotide, which was more pronounced in the case of RAPTA-CF3 compared with RAPTA-C. Consequently, facile arene loss appears to be responsible for the increased cytotoxicity of RAPTA-CF3. Graphical abstr.: RAPTA-CF3 is a fast-acting cytotoxic compd. that degrades DNA and has a mode of action fundamentally different from that of other ruthenium(II)-arene compds

Fragmentation methods on the balance: unambiguous top–down mass spectrometric characterization of oxaliplatin–ubiquitin binding sites

The interaction between oxaliplatin and the model protein ubiquitin (Ub) was investigated in a top-down approach by means of high-resolution electrospray ionization mass spectrometry (ESI-MS) using diverse tandem mass spectrometric (MS/MS) techniques, including collision-induced dissociation (CID), higher-energy C-trap dissociation (HCD), and electron transfer dissociation (ETD). To the best of our knowledge, this is the first time that metallodrug-protein adducts were analyzed for the metal-binding site by ETD-MS/MS, which outperformed both CID and HCD in terms of number of identified metallated peptide fragments in the mass spectra and the localization of the binding sites. Only ETD allowed the simultaneous and exact determination of Met1 and His68 residues as binding partners for oxaliplatin. CID-MS/MS experiments were carried out on orbitrap and ion cyclotron resonance (ICR)-FT mass spectrometers and both instruments yielded similar results with respect to number of metallated fragments and the localization of the binding sites. A comparison of the protein secondary structure with the intensities of peptide fragments generated by collisional activation of the [Ub + Pt-(chxn)] adduct [chxn = (1R,2R)-cyclohexanediamine] revealed a correlation with cleavages in solution phase random coil areas, indicating that the N-terminal beta-hairpin and alpha-helix structures are retained in the gas phase

5-Hydr­oxy-2-methyl-4H-pyran-4-one

The title compound, C6H6O3, is a member of the pyrone family. The mol­ecules are planar (r.m.s. deviation of the asymmetric unit is 0.0248 Å, whereas that of the dimer is 0.0360 Å) and they are dimerized due to inter­molecular O—H⋯O hydrogen bonds. The dimers are connected to each other through hydrogen bonds involving the CH3 group and the hydr­oxy O atom. There are π–π inter­actions between the centroids of the pyrone rings at a distance of 3.8552 (13) Å. A C—H⋯π inter­action also exists between the carbonyl group and the centroid CgA of the pyrone ring, with O⋯CgA = 3.65 (1) Å and C⋯CgA = 4.363 (2) Å