Copper(II) Complexes of Pyridine-2,6-dicarboxamide Ligands with High SOD Activity.

Copper(II) complexes of pyridine-based ligands functionalized with alanine (PydiAla) and tyrosine (PydiTyr) moieties have been synthesized as novel superoxide dismutase mimics. The complexes were characterized by pH-potentiometric, spectroscopic (UV-vis, circular dichroism, mass spectrometry, electron paramagnetic resonance spectroscopy), computational (DFT), and X-ray diffraction methods. Both ligands form high stability copper(II) complexes via the (Npy,N-,N-) donor set supported by the binding of the carboxylate pendant arms. Although the coordination mode is the same for the two systems, the tyrosine containing counterpart exhibits increased copper(II) binding affinity, which is most likely due to the presence of the aromatic moiety of the side chains. Both copper(II) complexes are capable of binding N-methylimidazole, and the formation of the corresponding ternary species was observed at physiological pH. The binary and ternary copper(II) complexes exhibit high SOD activity. The PydiTyr complex exhibits about 1 order of magnitude higher activity than the PydiAla complex. This is probably due to the presence of the phenolic OH group in the former species, which promotes the binding of the superoxide anion radical to the metal center. The results serve as a basis for designing highly efficient copper(II) mimics for medical and practical applications.

Donor Atom Preference of Organoruthenium and Organorhodium Cations on the Interaction with Novel Ambidentate (N,N) and (O,O) Chelating Ligands in Aqueous Solution.

Two novel, pyridinone-based chelating ligands containing separated (O,O) and (Namino,Nhet) chelating sets (Namino = secondary amine; Nhet = pyrrole N for H(L3) (1-(3-(((1H-pyrrole-2-yl)methyl)-amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one) or pyridine N for H(L5) (3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one)) were synthesized via reduction of the appropriate imines. Their proton dissociation processes were explored, and the molecular structures of two synthons were assessed by X-ray crystallography. These ambidentate chelating ligands are intended to develop Co(III)/PGM (PGM = platinum group metal) heterobimetallic multitargeted complexes with anticancer potential. To explore their metal ion binding ability, the interaction with Pd(II), [(η6-p-cym)Ru]2+ and [(η5-Cp*)Rh]2+ (p-cym = 1-methyl-4-isopropylbenzene, Cp* = pentamethyl-cyclopentadienyl anion) cations was studied in aqueous solution with the combined use of pH-potentiometry, NMR and HR ESI-MS. In general, organorhodium was found to form more labile complexes over ruthenium, while complexation of the (N,N) chelating set was slower than the processes of the pyridinone unit with (O,O) coordination. Formation of the organoruthenium complexes starts at lower pH (higher thermodynamic stabilities of the corresponding complexes) than for [(η5-Cp*)Rh]2+ but, due to the higher affinity of [η6-p-cym)Ru]2+ towards hydrolysis, the complexed ligands are capable of competing with hydroxide ion in a lesser extent than for the rhodium systems. As a result, under biologically relevant conditions, the rhodium binding effectivity of the ligands becomes comparable or even slightly higher than their effectivity towards ruthenium. Our results indicate that H(L3) is a less efficient (N,N) chelator for these metal ions than H(L5). Similarly, due to the relative effectivity of the (O,O) and (N,N) chelates at a 1:1 metal-ion-to-ligand ratio, H(L5) coordinates in a (N,N) manner to both cations in the whole pH range studied while, for H(L3), the complexation starts with (O,O) coordination. At a 2:1 metal-ion-to-ligand ratio, H(L3) cannot hinder the intensive hydrolysis of the second metal ion, although a small amount of 2:1 complex with [(η5-Cp*)Rh]2+ can also be detected.

Synthesis, characterization and cytotoxicity studies of Co(III)-flavonolato complexes.

Hypoxia activated Co(III) complexes as prodrugs may provide with a selective delivery of cytotoxic or antibacterial compounds. Whithin this field sixteen novel Co(III) ternary complexes with the general formula [Co(4N)(flav)](ClO4)2, where 4N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa) and flav = deprotonated form of differently substituted flavonols have been synthesized, characterized, and their cytotoxicity assayed under both normoxic and hypoxic conditions. Molecular structures of two free flavonols and seven complexes are also reported. In all the complexes the bioligands exhibited the expected (O,O) coordination mode and the complexes showed a slightly distorted octahedral geometry. Cyclic voltammetric studies revealed that both the substituents of the flavonoles and the type of 4N donor ligands had an impact on the reduction potential of the complex. The ones containing tren demonstrated significantly higher stability than the tpa analogues, making these former compounds promising candidates for the development of hypoxia-activated prodrug complexes. Tpa complexes showed higher activity against both selected human cancer cell lines (A549, A431) than their free ligand flavonols, indicating that the anticancer activity of the bioligand can be enhanced upon complexation. However, slight hypoxia-selectivity was found only for a tren complex (11) with moderate cytotoxicity.

Synthesis, characterization and biological evaluation of Co(III) complexes with quinolone drugs.

Nine novel cobalt(III) ternary complexes bearing 4N donor ligands (tris(2-aminoethyl)amine (tren) or tris(2-methylpyridyl)amine (tpa)) and (fluoro)quinolones (quinH) with antibacterial and potential antitumor activity have been synthesized, characterized and screened in various biological assays. The molecular structures of [Co(tpa)(nal)](PF6)2 (3) and [Co(tpa)(nor)(Co(tpa)(norH)](PF6)3(Cl)2∙5MeOH (8) (nal = deprotonated form of nalidixic acid, norH = norfloxacin) with the expected octahedral geometry and (O,O) coordination of the quinolone ligands are also reported. Cyclic voltammetric studies revealed that the 4N donor ligands have much higher effect on the reduction potential of these ternary complexes than the quinolones. Due to the π-back-bonding interaction of the metal ion with the pyridyl-N atoms, the tpa containing compounds demonstrated lower stability and were easier to get reduced in a reversible manner. This character makes them unlikely candidates for development of effective, highly selective hypoxia-activated pro-drug complexes, but this goal might be achieved by substitution of tpa by tren. [Co(tren)(cip)](PF6)2 (4) and [Co(tpa)(cip)](PF6)2 (5) (cip = deprotonated form of ciprofloxacin) showed slightly less antibacterial activity against Escherichia coli than free ciprofloxacin (cipH) and they found to have very low toxicity towards both selected cancer (HeLa, MCF 7, MDA-MB-239) and noncancerous (MRC5 pd30) cells. Interaction of 4 and 5 with calf thymus DNA studied by UV-Vis, flow linear dichroism, viscometry and DNA melting indicated the complexes to bind to DNA as intercalators. DNA electrophoresis revealed that, unlike Co(II) complexes, 4 and 5 are not capable of cleaving DNA, but they can inhibit bacterial DNA gyrase 5 being slightly more active than 4.

Novel 9'-substituted-noscapines: synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation.

Tubulin is a major molecular target for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its ß-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class of agents. In particular, 9'-bromonoscapine (EM011) has been identified as a potent noscapine analog. Here we present high yielding, efficient synthetic methods based on Suzuki coupling of 9'-alkyl and 9'-arylnoscapines and an evaluation of their antiproliferative properties. Our results showed that 9'-alkyl and 9'-aryl derivatives inhibit proliferation of human cancer cells. The most active compounds were the 9'-methyl and the 9'-phenyl derivatives, which showed similar cytotoxic potency in comparison to the 9'-brominated derivative. Interestingly these newly synthesized derivatives did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. All of these derivatives, except 9'-(2-methoxyphenyl)-noscapine, efficiently induced a cell cycle arrest in the G2/M phase of the cell cycle in HeLa and Jurkat cells. Furthermore, we showed that the most active compounds in HeLa cells induced apoptosis following the mitochondrial pathway with the activation of both caspase-9 and caspase-3. In addition, these compounds significantly reduced the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2.

Interaction of [Ru(η6-p-cym)(H2O)3]²âº with citrate and tricarballate ions in aqueous solution; X-ray crystal structure of novel half-sandwich Ru(II)-citrato complexes.

The interaction between [Ru(η(6)-p-cym)(H(2)O)(3)](2+) and an important low molecular weight serum component, citric acid (citrH(3)), was studied with the aid of combined pH-potentiometric, (1)H NMR, (13)C NMR and electrospray ionization mass spectrometry (ESI-MS) methods in aqueous solution. For comparative purposes propane-1,2,3-tricarboxylic acid (tricarballylic acid, tricH(3)) having no alcoholic-OH group in position 2 was also investigated. Stoichiometries, stability constants and the most plausible solution structures of the complexes formed in the systems were determined. Depending upon the pH, citrate was found to coordinate to the metal ion via [COO(-), COO(-), OH] or [COO(-), COO(-), O(-)] fashion yielding mononuclear complexes with high stability. As a consequence at physiological pH the hydrolysis of the metal ion is completely hindered even at 1:1 metal to ligand ratio. Crucial role of the alcoholic/alcoholate function of the citric acid in [Ru(η(6)-p-cym)(H(2)O)(3)](2+) binding is reflected in the low stability of the species formed with tricarballylic acid. The X-ray crystal structures of [Ru(η(6)-p-cym)(citrH)]·H(2)O·CH(3)OH and 2[Ru(η(6)-p-cym)(citrH)]·3H(2)O being the first published structures of an organometallic Ru(II)-citrate and both featuring a [COO(-), COO(-), OH] coordinated ligand, are also reported.

Solution pH: A Selectivity Switch in Aqueous Organometallic Catalysis-Hydrogenation of Unsaturated Aldehydes Catalyzed by Sulfonatophenylphosphane-Ru Complexes.

The equilibribrium distribution of water-soluble ruthenium hydrides [HRuCl(tppms)3 ] and [H2 Ru(tppms)4 ] (tppms = (3-sulfonatophenyl)diphenylphosphane) in the reaction with H2 is governed by the pH value. As a consequence, the selectivity in the hydrogenation of cinnamaldehyde for reaction at C=C or C=O can be completely inverted by changing the pH value (see drawing below).