Perspectives for Novel Mixed Diruthenium-Organic Drugs as Metallopharmaceuticals in Cancer Therapy

Ruthenium compounds have been actively studied as metallodrugs for cancer therapy. Representatives of ruthenium-based antitumor drugs are the classes of ruthenium(III)-chlorido-(N-ligand)complexes, including the drugs namely NAMI-A and KP1019 in clinical trials, and ruthenium(II)-arene organometallics, with some compounds currently undergoing advanced preclinical testing. An alternative approach for tumor-inhibiting metallodrugs is the coordination of metal ions to organic pharmaceuticals. The combination of antitumor-active ruthenium ion with biologically-active pro-ligands in single compounds can result in the enhancement of activity, for example through synergistic effects. In the present article, some developments in the ruthenium-based antitumor drugs field are briefly highlighted and recent studies on mixed diruthenium-organic drugs as metallopharmaceuticals in cancer therapy are described. Novel organic pharmaceuticals-containing diruthenium(II, III)complexes have shown promising antitumor activity for C6 rat glioma - a model for glioblastoma multiforme (GBA).

Supramolecular assemblies of a new class of nonplanar cationic metalloporphyrins and anionic metallophthalocyanines

The heteroaggregation behavior between a new class of nonplanar cationic beta-octabrominated meso-alkylpyridinium zinc(II)-porphyrins (beta-Br(8)(ZnP)) and anionic tetrasulfonated metallophthalocyanines (MTSPc, M = Ni(II) and Cu(II)) has been studied by UV-Vis electronic spectroscopy, in dimethylsulfoxide (DMSO) solution. The heteroaggregate stoichiometry and the association constants were determined by means of Job plots. Dimers and unexpected trimers, taking into account the existence of axially coordinated DMSO molecules to the central metal in both beta-Br(8)(ZnP) and MTSPc complexes, are formed in solution. The spectroscopic properties of the heteroaggregates are markedly different from those observed in the correspondent planar cationic derivatives, the heteroaggregates showing major changes predominantly in the beta-Br(8)(ZnP) Soret band region and minor effects in the MTSPc Q bands. The observed changes in the Soret band region (red/blue shifts, decrease in the absorption intensities) depend on the nature of the alkyl substituent attached to the meso-pyridinium group. The greater versatility of the nonplanar porphyrins accommodating the meso-substituents in out-of-plane and in-plane conformations is proposed to explain the observed stoichiometries and the differences on the heteroaggregates spectroscopic properties for each beta-Br(8)(ZnP) compound. The likely conformations assumed by the meso-substituents in these beta-Br(8)(ZnP) compounds and its spectroscopic characteristics are in accordance with the participation of the substituents as the main factor on the extent of the observed red-shifted spectra in nonplanar porphyrins. The obtained association constants (K(IP)) for the dimers and trimers are lower than those previously found for the similar planar cationic porphyrin systems, due to the lack of extensive pi-pi interactions and to the less effective approximation between the ionic groups, resulting in loosened heteroaggregates, particularly for the trimeric systems. Furthermore, the experimental results suggest that the NiTSPc is more distorted in DMSO solution than the CuTSPc derivative, favoring the interaction with the nonplanar beta-Br(8)(ZnP) compounds. (C) 2007 Elsevier B.V. All rights reserved.

Determination of ciclopirox olamine in pharmaceutical products by capillary electrophoresis with capacitively coupled contactless conductivity detection

This paper describes the determination of ciclopirox olamine in pharmaceutical formulations using capillary electrophoresis with capacitively coupled contactless conductivity detection. In an alkaline medium, ciclopirox olamine is converted into an anionic species and its detection is possible in capillary electrophoresis with capacitively coupled contactless conductivity detection without an electroosmotic flow modifier, because it is a low-mobility species. A linear working range from 2.64 to 264 mu g/mL in sodium hydroxide electrolyte as well as low detection limit (0.39 mu g/mL) and a good repeatability (RSD = 3.4% for 264 mu g/mL ciclopirox solution (n = 10)) were achieved. It was also possible to determine olamine in its cationic form when acetic acid was used as the electrolyte solution. The results obtained include a linear range from 26.4 to 184.8 mu g/mL and a detection limit of 2.6 mu g/mL olamine. The proposed methods were applied to the analysis of commercial pharmaceutical products and the results were compared with the values indicated by the manufacturer as well as those obtained using a titrimetric method recommended by American Pharmacopoeia.

Micellar properties of surface active ionic liquids: A comparison of 1-hexadecyl-3-methylimidazolium chloride with structurally related cationic surfactants

Ionic liquids, ILs, carrying long-chain alkyl groups are surface active, SAIIs. We investigated the micellar properties of the SAIL 1-hexadecyl-3-methylimidazolium chloride, C(16)MeImCl, and compared the data with 1-hexadecylpyridinium chloride, C(16)PYCl, and benzyl (3-hexadecanoylaminoethyl)dimethylammonium chloride, C(15)AEtBzMe(2)Cl. The properties compared include critical micelle concentration, cmc; thermodynamic parameters of micellization; empirical polarity and water concentrations in the interfacial regions. In the temperature range from 15 to 75 degrees C, the order of cmc in H(2)O and in D(2)O is C(16)PYCl > C(16)MeImCl > C(15)AEtBzMe(2)Cl. The enthalpies of micellization, Delta H(mic)(degrees), were calculated indirectly from by use of the van`t Hoff treatment; directly by isothermal titration calorimetry, ITC. Calculation of the degree of counter-ion dissociation, alpha(mic), from conductivity measurements, by use of Evans equation requires knowledge of the aggregation numbers, N(agg), at different temperatures. We have introduced a reliable method for carrying out this calculation, based on the volume and length of the monomer, and the dependence of N(agg) on temperature. The N(agg) calculated for C(16)PyCl and C(16)MeImCl were corroborated by light scattering measurements. Conductivity- and ITC-based Delta H(mic)(degrees) do not agree; reasons for this discrepancy are discussed. Micelle formation is entropy driven: at all studied temperatures for C(16)MeImCl; only up to 65 degrees C for C(16)PyCl; and up to 55 degrees C for C(15)AEtBzMe(2)Cl. All these data can be rationalized by considering hydrogen-bonding between the head-ions of the monomers in the micellar aggregate. The empirical polarities and concentrations of interfacial water were found to be independent of the nature of the head-group. (C) 2010 Elsevier Inc. All rights reserved.

Synthesis, spectroscopic characterization and radiosensitizing properties of acetato-bridged copper(II) complexes with 5-nitroimidazole drugs

Three novel acetato-bridged dinuclear copper(II) complexes with 5-nitroimidazoles (CuAcNtrim) and the known copper-acetato-metronidazole have been prepared by an environment-friendly route and spectroscopically characterized. The CuAcNtrim compounds of formula [Cu(2)(mu-O(2)CCH(3))(4)Ntrim(2)], where Ntrim = metronidazole (1), secnidazole (2), tinidazole (3) or nimorazole (4), exhibit dimeric copper-acetato paddle-wheel structures with Ntrim axial ligands coordinated to copper(II) ions through the N(3) atoms of the imidazole rings. EPR data indicate antiferromagnetic behavior for this novel series of copper complexes. The constant coupling has been found to decrease along with the increasing of basicity of the Ntrim axial ligand. The CuAcNtrim complexes and the correspondent Ntrim parent drugs have shown radiosensitizer properties for Hep2 (human larynx cancer) cell line in vitro. The best enhancement of radiosensitizer activity upon coordination of the Ntrim drug to copper(II) has been found for the nimorazole compound which has the strongest Cu-Ntrim bond and exhibits the highest lipophilicity within the series of CuAcNtrim complexes. (C) 2010 Elsevier B.V. All rights reserved.

Simultaneous analysis of five antidepressant drugs using direct injection of biofluids in a capillary restricted-access media-liquid chromatography-tandem mass spectrometry system

Direct analysis, with minimal sample pretreatment, of antidepressant drugs, fluoxetine, imipramine, desipramine, amitriptyline, and nortriptyline in biofluids was developed with a total run time of 8 min. The setup consists of two HPLC pumps, injection valve, capillary RAM-ADS-C18 pre-column and a capillary analytical C 18 column connected by means of a six-port valve in backflush mode. Detection was performed with ESI-MS/MS and only 1 mu m of sample was injected. Validation was adequately carried out using FLU-d(5) as internal standard. Calibration curves were constructed under a linear range of 1-250 ng mL(-1) in plasma, being the limit of quantification (LOQ), determined as 1 ng mL(-1), for all the analytes. With the described approach it was possible to reach a quantified mass sensitivity of 0.3 pg for each analyte (equivalent to 1.1-1.3 fmol), translating to a lower sample consumption (in the order of 103 less sample than using conventional methods). (C) 2008 Elsevier B.V. All rights reserved.

Cationic and neutral phenylmercury(II) complexes with heterocyclic thione ligands. X-ray structures of [HgPh(dmpymtH)][BF(4)] center dot H(2)O and [{HgPh}(2)(mu-dtu)]

The neutral complex [HgPh(dmpymt)] 1 (dmpymtH = 4,6-dimethylpyrimidine-2(1H)-thione) reacts with HBF(4) to give the cationic complex [HgPh(dmpymtH)][BF(4)] 2. The X-ray molecular structure of the later revealed a [2+1] coordination sphere about the mercury(II) atom (C-Hg-S and Hg center dot center dot center dot N). In the dinuclear complex [(HgPh)(2)(mu-dtu)] 3 [dtuH(2) = 2,4(1H,3H)-pyrimidinedithione or dithiouracil] the coordination spheres are also [2+1] although dissimilar regarding the Hg center dot center dot center dot N secondary bonds. NMR spectroscopy ((1)H, (13)C and (199)Hg) studies were undertaken in solution and the results discussed in the light of the X-ray structures. (C) 2008 Elsevier B. V. All rights reserved.