A Study of the Antitumour Activity of Four Triorganophosphinegold(I) Thiolates: R(3) PAu(SR'), R = Ph, Cy, Et; SR'H = 6-Mercaptopurine and R = Et; SR'H = 6-Thioguanine

The antitumour activities of four triorganophosphinegold(I) thiolates, R(2)PAu(S'R) [R = Ph, Cy, Et; SR'H = 6-mercaptopurine and R Et; SR'H = 6-thioguanine] against the National Cancer Institute (NCI) panel of 60 cell lines are reported The [Cy(3)PAu(6-MP)] complex proved to be the more cytotoxic of the four complexes tested. For the 6-MP series, an order of cytotoxicity was established such that the activity followed the order R = Cy > Ph > Et. Sub-panel selectivity against the Leukemia cell lines was found for each of [Cy(3) PAu(6-MP)] and [Et(3)PAu(6-TG)].     

Characterisation and in vitro cytotoxicity of triorganophosphinegold(i) 2-mercaptobenzoate complexes

The preparation and full NMR ((1)H, (13)C and (31)P) characterisation of three [R(3)PAu(2mba)] complexes, Where R = Et, Ph and Cy, and 2mba is the anion derived from 2-mercaptobenzoic acid is reported. An interesting solvent dependence in the (1)H spectra is rationalised in terms of competing intra- and inter-molecular hydrogen bonding. An X-ray analysis of the [Ph(3) PAu(2mba)] species reveals a linear P-Au-S arrangement and association in the lattice via the familar carboxylic acid dimer motif. The in Vitro cytotoxicity against seven human tumout lines is also described. The complexes display moderate to very high activity. Particularly noteworthy is their greater activity against the H226 cell line (non-small cell lung cancer) compared with that displayed by a range of cytotoxic drugs.     

In vitro antitumour activity of some triorganophosphinegold(i) thionucleobases

A series of phosphinegold(I) thionucleobase analogues, [R(3)PAu(SR(x))] (R = Et, Ph or chexyl; HSR(1) = 2-mercaptobenzoic acid, HSR(2) = 2-thiouracil, HSR(3) = 6-mercaptopurine and HSR(4) = 6-thioguanine) have been examined for their in vitro cytotoxicity in L1210 murine leukemia cells in culture. The range of ID(50) values (continuous 48 h exposure) for the complexes is 0.041 - 0.131 muM. The complexes with SR(3) and SR(3) are generally the most active; however, there is no clear trend associated with the phosphine ligands.     

Synthesis, structural characterization, and pro-apoptotic activity of 1-indanone thiosemicarbazone platinum(II) and palladium(II) complexes: potential as antileukemic agents

In the search for alternative chemotherapeutic strategies against leukemia, various 1‐indanone thiosemicarbazones, as well as eight novel platinum(II) and palladium(II) complexes, with the formula [MCl₂(HL)] and [M(HL)(L)]Cl, derived from two 1‐indanone thiosemicarbazones were synthesized and tested for antiproliferative activity against the human leukemia U937 cell line. The crystal structure of [Pt(HL1)(L1)]Cl^.2M eOH, where L1=1‐indanone thiosemicarbazone, was solved by X‐ray diffraction. Free thiosemicarbazone ligands showed no antiproliferative effect, but the corresponding platinum(II) and palladium(II) complexes inhibited cell proliferation and induced apoptosis. Platinum(II) complexes also displayed selective apoptotic activity in U937 cells but not in peripheral blood monocytes or the human hepatocellular carcinoma HepG2 cell line used to screen for potential hepatotoxicity. Present findings show that, in U937 cells, 1‐indanone thiosemicarbazones coordinated to palladium(II) were more cytotoxic than those complexed with platinum(II), although the latter were found to be more selective for leukemic cells suggesting that they are promising compounds with potential therapeutic application against hematological malignancies.     

Synthesis, In vitro Antifungal and Antitumour Activity of Some Triorganotin(IV) N,C,N-Chelates

The in vitro antifungal activity of compounds 1-3 ({[(CH3)2NCH2]2C6H3}R2SnX; (where X=Cl, R=n-Bu for 1, X=Br, R=n-Bu for 2 and x=PF6, R=n=Bu for 3)) was estimated with the help of a modified microdilution format of the M27-A guidelines and was compared with in vitro activity of their diphenyltin(IV) analogues 4 and 5 (where X=Br, R=Ph for 4 and X=PF6, R=Ph for 5), and of drugs currently in clinical use (ketoconazole, fluconazole and amphotericin B). It was found that in coordinating solvents the more soluble derivative 2 is less active than the phenyl one (4), and compounds 1 and 3 are even inactive.In this paper, the in vitro antitumour activity of ionic diphenyltin(IV) complexes 4 and 5 against seven tumoural cell lines of human origin is also reported. The preparation and characterization (H1, C13 and Sn119 NMR spectroscopy and electrospray ionization mass spectrometry) of the novel compound 3 is mentioned too.     

Reactions of organic disulfides and gold(i) complexes

Gold-thiolate/disulfide exchange reactions of (p-SC(6)H(4)Cl)(2) with Ph(3)PAu(SC(6)H(4)CH(3)), dppm(AuSC(6)H(4)CH(3))(2), and dppe(AuSC(6)H(4)CH(3)) (2) were investigated. The rate of reactivity of the gold-thiolate complexes with (p-SC(6)H(4)Cl)(2) is: dppm(AuSC(6)H(4)CH(3))(2)> dppe(AuSC(6)H(4)CH(3))(2)>Ph(2)PAu (SC(6)H(4)CH(3)). This order correlates with conductivity measurements and two ionic mechanisms have been evaluated. (1)H NMR experiments demonstrate that in the reaction of dppm(AuSC(6)H(4)CH(3))(2) with (p-SC(6)H(4)Cl)(2), the mixed disulfide, ClC(6)H(4)SSC(6)H(4)CH(3), forms first, followed by the formation of (p-SC(6)H(4)CH(3))(2). The rate law is first order in (pp-SC(6)H (4)Cl)(2) and partial order in dppm(AuSC(6)H(4)CH(3))(2). Results from electrochemical and chemical reactivity studies suggest that free thiolate is not involved in the gold-thiolate/disulfide exchange reaction. A more likely source of ions is the dissociation of a proton from the methylene backbone of the dppm ligand which has been shown to exchange with D(2)O. The implications of this are discussed in terms of a possible mechanism for the gold-thiolate/disulfide exchange reaction.     

Study of the anticancer properties of tin(IV) carboxylate complexes on a panel of human tumor cell lines

A group of organotin(IV) complexes were prepared: [SnCy₃(DMNI)] ( 1 ), [SnCy₃(BZDO)] ( 2 ), [SnCy₃(DMFU)] ( 3 ), and [SnPh₂(BZDO)₂] ( 4 ), for which DMNIH=2,6‐dimethoxynicotinic acid, BZDOH=1,4‐benzodioxane‐6‐carboxylic acid, and DMFUH=2,5‐dimethyl‐3‐furoic acid. The cytotoxic activities of compounds 1 – 4 were tested against pancreatic carcinoma (PANC‐1), erythroleukemia (K562), and two glioblastoma multiform (U87 and LN‐229) human cell lines; they show very high antiproliferative activity, with IC₅₀ values in the 150–700 nM range after incubation for 72 h. Distribution of cellular DNA upon treatment with 1 – 4 revealed that whereas compounds 1 – 3 induce apoptosis in most of the cell lines, compound 4 does not affect cell viability in any cell line tested, indicating a possible difference in cytotoxic mechanism. Studies with the daunomycin‐resistant K562/R cell line expressing P‐glycoprotein (Pgp) showed that compounds 1 – 4 are not substrates of this protein efflux pump, indicating that these compounds do not induce acquisition of multidrug resistance, which is associated with the overexpression of Pgp.     

Solid-phase synthesis, characterization, and antibacterial activities of metallocene-peptide bioconjugates

This work shows how the introduction of an organometallic group enhances and modifies the specificity of biologically active peptides. Ferrocene was chosen as an organometallic group because it has been shown to alter the pharmacodynamic profile of bioactive compounds. A comparison with the isosteric cobaltocenium group allows one to explore the influence of charge and redox potential on the biological activity of the conjugates. Arginine and tryptophan containing peptides H-WRWRWR-NH(2) and H-RWRWRW-NH(2) and the metallocene peptide bioconjugates [M]-C(O)-RWRWR-NH(2) and [M]-C(O)-WRWRW-NH(2), where [M]=[Co(Cp)(C(5)H(4))](+), [Fe(Cp)(C(5)H(4))] were prepared by solid-phase peptide synthesis (SPPS). They were purified by HPLC, characterized by ESIMS and NMR spectroscopy, and tested for antibacterial properties against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus using the minimum inhibitory concentration (MIC) test. In most cases, no metal-specific activity could be observed. However, the conjugate [Fe(Cp)(C(5)H(4))-C(O)-WRWRW-NH(2)] 6 was found to be particularly effective against the Gram-positive S. aureus. The activity of this metallocene-pentapeptide conjugate (7.1 microM) was even better than the 20 amino acid naturally occurring pilosulin 2, which was used as a positive control. Unlike all other compounds tested, which were most active against the Gram-negative E. coli strain, the ferrocene conjugate 6 was the only compound in this series that was most active against Gram-positive bacteria. Given the health concerns resulting from multidrug resistant S. aureus strains, the incorporation of metallocenes may provide a novel line of attack.     

Ag(I)(Et(2)PCH(2)CH(2)PPh(2))(2)]NO(3): An Antimitochondrial Silver Complex

The silver(I) complex [Ag(eppe)(2)]NO(3) (eppe = Et(2)PCH(2)CH(2)PPh(2)) is shown by X-ray crystallography to be tetrahedral with Ag - PEt(2) and Ag - P Ph(2) bond lengths of 2.482 and 2.518 A, respectively. The complex is selectively antimitochondrial and inhibits the growth of a number of yeast strains in non-fermentable media at concentrations as low as 2.5 muMu and induces the mitochondrial mutation petite The effect is largely reversed by the presence of aspirin. The complex is shown to be stable in the cell culture media and in the presence of glutathione, but readily reacts with disulfides of oxidized glutathione and serum albumin. Surprisingly, neither [Au(eppe)(2)]Cl nor [Au(eppe)(2)]Cl (dppe = Ph(2)PCH(2)CH(2)PPh(2)) showed any mitochondrial selectivity in the same screening protocol.     

Toxicity of Certain Penta-Coordinated Organotin(IV) and Tetra-Coordinated Tin(II) Complexes of Heterocyclic beta-Diketones Against the Larvae of Aedes Aegypti (Liston)

Some organotin(IV) and tin(II) complexes of composition R(3)Sn[R'COC:CON(C(6)H(5))N:CCH(3)] (where R=C(4)H(9), R'=CH(3), C(3)H(5), p-ClC(6)H(4); R=C(6)H(5), R'=C(6)H(5) and p-ClC(6)H(4)) and Sn[p-ClC(6)H(4)COC:CON(C(6)H(5))N:CCH(3)](2) were screened for their toxicity against Aedes aegypti larvae. Organotin(IV) complexes were more active than tin(II) complexes.     

Cytotoxic Activities of O-Cholesteryl-O-Phenyl-N-Phenylphosphoramidate and Its Organometallic Tin(lV) Derivatives

O-Cholesteryl-O-phenyl-N-phenylphosphoramidate (1) and four organotin (lV) derivatives of the ambidentate O-cholesteryl-O -phenyl phosphorothioate ligand formulated as Me(3) SnOSPR'R"(2), Ph(3)SnOSPR'R"(3), O(CH(2)CH(2)S)(2)Sn(n-Bu)OSPR'R"(4), S(CH(2)CH(2)S)(2)Sn(n-Bu)OSPR'R"(5), (R' = O-phenyl; R"= O-cholesteryl) were subjected to cytotoxicity screening against KB (nasopharingel carcinoma), OVCAR-5 (ovarium carcinoma) and SQC-1 UlSO (squamous cell cervix carcinoma) cell cultures. The results of the bioassay showed that these compounds possess potent antitumor activities against the studied human carcinoma cell lines.     

Electrochemical degradation of organic dyes with a porous gold electrode

Electrochemical degradation of methylene blue (MB) and rhodamine B (RhB) was studied at porous gold (PAu) electrode in presence of KCl as supporting electrolytes. PAu electrode with three-dimensional porous structure was prepared by paper-based method and used as working electrode. Based on the cyclic voltammetric test, the redox potential of of MB and RhB contained in KCl solution was found and the electrochemical degradation was conducted at fixed applied voltage. The direct oxidation of organic dyes involved using PAu and Pt electrodes, while the indirect electrolysis was mediated by active chlorine electro-generated from KCl solution. The results showed that PAu electrode with porous structure has high electrochemical activity with fast kinetics for the destruction of RhB (0.0448 min^-1) and low energy consumption (0.315 kWh/m³), compared to smooth Au foil and reported others. In addition, the durability test for 10 serial degradation showed that PAu electrode has a good reproducibility and high adaptability for practical application.     

Electrochemical sensor applications of Pt supported porous gold electrode prepared using cellulose-filter

A facile and rapid method for the synthesis of porous gold (PAu) electrodes on cellulose-filters is proposed. Morphology and active surface area of the electrode greatly influence the electrochemical properties of sensor. Compared to smooth electrode and glassy carbon, PAu and Pt/PAu electrode showed high roughness due to porous structure, which is helpful in electrochemical sensing of target molecules. The electrochemical sensing performance of Pt/PAu electrode was evaluated to detect hydrogen peroxide, glucose, and perchloric acid. The amperometric results with various concentrations of target molecules showed potential applications of Pt/PAu electrode in sensitive and effective chemical sensors.     

A Screening Strategy for Metal Antitumor Agents as Exemplified by Gold(III) Complexes

The use of a screening strategy based on human tumor cell lines, which are also tumorigenic in immune-deprived mice, is described. Activity against the human tumor cells in vitro and in vivo, is complemented with studies on the mechanism of action. This aporoach is demonstrated using 2-[(dimethylamino)-methyl]phenyl (damp) gold(III) compounds of the type [Au X2(damp)], where X = chloride, thiocyanate, acetate, or the bidentate ligands oxalate and malonate. All compounds were shown to be selectively active against a human bladder tumor cell line (HT1376) in vitro, and active in an in vitro panel of ovarian tumor cell lines. The acetato complex was shown to be active in experimental animal models of both the HT1376 bladder tumor, and the CH1 ovarian tumor. Although the [AuX2(damp)] compounds share structural features in common with cisplatin, and exhibit interesting in vivo activity against human tumor cells, the data indicate that they have a very different biochemical mechanism from platinum-based drugs and represent a potentially new class of metal-based antitumor agents.     

Copper(II) Complexes Containing Natural Flavonoid Pomiferin Show Considerable In Vitro Cytotoxicity and Anti-inflammatory Effects

A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO₃·2MeOH (1), [Cu(L)(dimebpy)]NO₃·2H₂O (2), [Cu(L)(phen)]NO₃·2MeOH (3), [Cu(L)(bphen)]NO₃·MeOH (4), [Cu(L)(dppz)]NO₃·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b′]dipyran-4-one, (pomiferin) and bpy = 2,2′-bipyridine, dimebpy = 4,4′-dimethyl-2,2′-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2′,3′-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC₅₀ values of 2.2–13.0 μM for the best performing complexes 3 and 5. All the complexes 1–5 showed the best activity against the A2780R cells (IC₅₀ = 2.2–6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC₅₀ > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.     

Transition Metal Ion Complexes of Schiff-bases. Synthesis, Characterization and Antibacterial Properties

Some novel transition metal [Co(II), Cu(II), Ni(II) and Zn(II)] complexes of substituted pyridine Schiff-bases have been prepared and characterized by physical, spectral and analytical data. The synthesized Schiff-bases act as deprotonated tridentate for the complexation reaction with Co(II), Ni(II) and Zn(II) ions. The new compounds, possessing the general formula [M(L)(2)] where [M=Co(II), Cu(II), Ni(II) and Zn(II) and HL=HL(1), HL(2), HL(3) and HL(4)] show an octahedral geometry. In order to evaluate the effect of metal ions upon chelation, the Schiff bases and their complexes have been screened for antibacterial activity against the strains such as Escherichia coli,Staphylococcus aureus, and Pseudomonas aeruginosa. The complexed Schiff bases have shown to be more antibacterial against one more bacterial species as compared to uncomplexed Schiff-bases.     

Synthesis, Spectral and Antibacterial Studies of Copper(II) Tetraaza Macrocyclic Complexes

A novel family of tetraaza macrocyclic Cu(II) complexes [CuLX(2)] (where L = N(4) donor macrocyclic ligands) and (X = Cl(-), NO(3) (-)) have been synthesized and characterized by elemental analysis, magnetic moments, IR, EPR, mass, electronic spectra and thermal studies. The magnetic moments and electronic spectral studies suggest square planar geometry for [Cu(DBACDT)]Cl(2) and [Cu(DBACDT)](NO(3))(2) complexes and distorted octahedral geometry to the rest of the ten complexes. The biological activity of all these complexes against gram-positive and gram-negative bacteria was compared with the activity of existing commercial antibacterial compounds like Linezolid and Cefaclor. Six complexes out of twelve were found to be most potent against both gram-positive as well as gram-negative bacteria due to the presence of thio group in the coordinated ligands.     

Interaction of [Rh(2)(O(2)CCH(3))(4)(H(2)O)(2)] and [Rh(2)(O(2)CCH(OH)Ph)(2)(phen)(2)(H(2)O)(2)](O(2)C-CH(OH)Ph)(2) With Sulfhydryl Compounds and Ceruloplasmin

The interaction of binuclear rhodium(II) complexes [Rh(2)(OOCCH(3))(4)(H(2)O)(2)], [Rh(2){OOCCH(OH)Ph}(2)(phen)(2)(H(2)O)(2)] {OOCCH(OH)Ph}(2), [Rh(2)(OOCCH(3))(2)(bpy)(2)(H(2)O)(2)](OOCCH(3))(2) and [Rh(2)Cl(2)(OOCMe)(2)(bpy)(2)](3H(2)O) with ceruloplasmin, cysteine, glutathione and coenzyme A have been investigated using. UV-Vis and CD spectroscopies. The complexes containing phen or bpy at pH = 7.4 and 4.0 are readily reduced with sulfhydryl compounds, while rhodium(II) acetate is relatively stable in these conditions. Complex [Rh(2){OOCCH(OH)Ph}(2)(phen)(2)(H(2)O)(2)] strongly changes structure of ceruloplasmin leading to the decrease of of alpha-helix content and loss of oxidase activity.     

Cellular uptake, cytotoxicity, and metabolic profiling of human cancer cells treated with ruthenium(II) polypyridyl complexes [Ru(bpy)2(N--N)]Cl2 with N--N=bpy, phen, dpq, dppz, and dppn

A series of five ruthenium(II) polypyridyl complexes [Ru(bpy)2(N--N)]Cl2 was tested against human HT-29 and MCF-7 cancer cell lines. Cellular uptake efficiency and cytotoxicity were found to increase with the size of the aromatic surface area of the N--N ligand. The most active compound carrying the dppn ligand exhibits a low micromolar IC(50) value against both cell lines comparable to that of cisplatin under similar conditions. Continuous measurement of oxygen consumption, extracellular acidification rate, and impedance of the cell layer with a chip-based sensor system upon exposure to the complexes showed only small changes for the first two parameters throughout the series. A significant and irreversible decrease in impedance was, however, found for the dppn compound. This suggests that its biological activity is related to modifications in cell morphology or cell-cell and cell-matrix contacts.     

Synthetic, Spectroscopic and Biocidal Aspects of Heterobimetallic Complexes Comprising Platinum(II) and a Group Four or Fourteen Element

Heterobimetallic complexes with varying amines have been synthesized by the reaction of [Pt(C(2)H(8)N(2))(2)]Cl(2) with group four or fourteen organometallic dichlorides, viz., R(2)MCl(2) and Cp(2)M'Cl(2) in a 1:2 molar ratio in MeOH (where M=Si or Sn, M'= Ti or Zr and R=Ph or Me). These complexes have been characterized by elemental analysis, molecular weight determinations, magnetic measurements, conductance, IR, (1)H NMR and electronic spectra. The spectral data suggest a square planar geometry for all the complexes. Conductivity data suggest that they behave as electrolytes. These monometallic precursors along with their complexes have been screened in vitro against a number of pathogenic fungi and bacteria to assess their growth inhibiting potential.