Mutagenicity of a series of hexacoordinate rhodium(III) compounds

19 rhodium(III) compounds have been tested for genetic damaging capabilities using an Escherichia coli differential repair assay and for mutagenicity in the strains of Salmonella typhimurium. 10 of these were active in both assays. Presence of the plasmid pKM101 was required for mutagenicity in Salmonella. Both the composition of the ligands and the three-dimensional structures of the coordination complexes profoundly affect genetic activity. In general, the structure—activity relationships appear to favor complexes with (1) a +1 charge, (2) 2 relatively labile leaving groups with 4 more strongly bonded amine ligands, and (3) a relatively slow rate of exchange of the ligands which is characteristic of substitutionally inert coordination complexes.     

Mutagenicity, carcinogenicity and teratogenicity of cobalt metal and cobalt compounds

Cobalt metal and cobalt compounds are extensively used for the production of high-temperature alloys, diamond tools, cemented carbides and hard metals, for the production of various salts used in electroplating and as catalysts, drying agents in paints, additives in animal feeds and pigments. Cobalt oxides are used not only in the enameling industry and for pigments, but also in catalytic applications. There is no indication that cobalt metal and cobalt compounds constitute a health risk for the general population. Allergic reactions (asthma, contact dermatitis) can be induced by certain cobalt compounds. Interstitial fibrosis has also been observed in workers exposed to high concentrations of dust containing cobalt, tungsten, iron, etc., mainly in the cemented carbides and the diamond-polishing industries. Several experiments have demonstrated that single or repeated injections of cobalt metal powder or some forms of cobalt salt and cobalt oxide may give rise to injection site sarcoma in rats and in rabbits but the human health significance of such data is questionable. Intratracheal administration of a high dose of one type of cobalt oxide induces lung tumors in rats but not in hamsters. In the latter long-term inhalation of cobalt oxide (10 mg/m3) did not increase the incidence of lung cancer. The human data are too limited to assess the potential carcinogenic risk for workers. Co2+ interacts with protein and nucleic acid synthesis and displays only weak mutagenic activity in microorganisms. Some cobalt salts have been reported to enhance morphological transformation of Syrian hamster embryo cells. Cobalt chloride displays some limited mutagenic activity in yeast and some cobalt compounds are able to produce numerical and structural chromosome aberrations in plant cells. Cobalt and its salts appear to be devoid of mutagenic and clastogenic activity in mammalian cells. Cobaltous acetate and cobaltous chloride have not been found to be teratogenic in hamsters and rats respectively.     

Antiviral properties of cobalt(III)-complexes

We have investigated the potential antiviral activity of three cobalt(III) compounds. Two compounds, Co(III)-cyclen-methylbenzoic acid and its methyl ester derivative, are based on the macrocyclic chelator, cyclen, and were synthesized in our laboratory. Both compounds have been shown to bind tightly to nucleic acids and to hydrolyze phosphodiester bonds. However, neither compound exhibited any significant antiviral activity in an in vitro model of Sindbis virus replication. In contrast, a third compound, Co(III)hexammine, significantly inhibited Sindbis virus replication in baby hamster kidney (BHK) cells in a dose- and time-dependent manner. In plaque assays, the incubation of Co(III)hexammine with Sindbis virus resulted in a dose-dependent decrease in virus replication when measured at both 24 and 48-h post-infection. Over the concentration range of 0-5mM Co(III)hexammine, the IC(50) for the inhibition of viral replication was determined to be 0.10+/-0.04mM at 48h. Additionally, when BHK cell monolayers were pretreated with Co(III)hexammine for 6h prior to Sindbis infection, optimal cellular morphology and plasma membrane integrity were observed at 0.6-1.2mM Co(III)hexammine. Analysis by flow cytometry confirmed that Co(III)hexammine mediated a concomitant dose-dependent increase in BHK cell viability and a decrease in the percentage of Sindbis virus-infected cells (IC(50)=0.13+/-0.04mM). Our findings demonstrate for the first time that Co(III)hexammine possesses potent antiviral activity. We discuss our findings within the context of the ability to further functionalize Co(III)hexammine to render it a highly specific antiviral therapeutic reagent.     

Synthesis of rhodium(III), iridium(III) and osmium(III) complexes with tris(2-aminoethanethiolato)cobalt(III)

Polynuclear sulfur bridged complexes where the neutral complex tris(2-aminoethanethiolato)cobalt(III) acts as a tridentate ligand to rhodium(III), iridium(III) and osmium(III) have been prepared. These complexes have been characterized by electronic spectroscopy, vibrational spectroscopy and nuclear magnetic resonance spectroscopy. Along with the previously prepared complexes of iron(III), ruthenium(III) and cobalt(III), these complexes form two series of complexes with the group 8 and group 9 elements from all three transition series.     

Complexation of sucrose with cobalt(III)bis(phenanthroline)

The delta-[Co(III)bis(phenanthroline)(sucrose)]3+ complex forms with little perturbation of the sucrose conformation, and complexation by HO-2(g) and HO-1(f).     

Mutagenicity of polycyclic hydrocarbons III. Monitoring genetic hazards of benz(a)anthracene

Mutagenicity tests (micronucleus test and chromosome aberrations) have been performed with benz (a) anthracene in spermatogonia and bond marrow cells of Chinese hamsters and in NMRI mice oocytes. Mutagenic effects of the polycyclic hydrocarbon could be demonstrated.     

Reactivity of a cobalt(III)-peroxo complex in oxidative nucleophilic reactions

A mononuclear cobalt(III)-peroxo complex bearing a macrocyclic tetradentate N₄ ligand, [Co^III(TMC)(O₂)]⁺ (TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), was generated in the reaction of [Co^II(TMC)]²⁺ and H₂O₂ in the presence of triethylamine in CH₃CN. The reactivity of the cobalt(III)-peroxo complex was investigated in aldehyde deformylation with various aldehydes and compared with that of iron(III)- and manganese(III)-peroxo complexes, such as [Fe^III(TMC)(O₂)]⁺ and [Mn^III(TMC)(O₂)]⁺. In this reactivity comparison, the reactivities of metal-peroxo species were found to be in the order of [Mn^III(TMC)(O₂)]⁺ > [Co^III(TMC)(O₂)]⁺ > [Fe^III(TMC)(O₂)]⁺. A positive Hammett ρ value of 1.8, obtained in the reactions of [Co^III(TMC)(O₂)]⁺ and para-substituted benzaldehydes, demonstrates that the aldehyde deformylation by the cobalt(III)-peroxo species occurs via a nucleophilic reaction.     

Stereoselective reduction of cobalt(III) complexes by bacteria

A strain of Enterobacter cloacae, isolated from soil, reduces racemic abdtriglycinatocobalt(III), triglycinatocobalt(III), stereoselectively under anaerobic conditions. Washed suspensions of cells, grown anaerobically in the absence of triglycinatocobalt(III) initially reduce the L-enantiomer stereospecifically under argon yielding a labile Co(II) chelate. An approximately 5-fold increase in the rate of reduction of the complex occurs using cells disrupted by 2-phenylethanol; decomposition now proceeds with a slight preference for the D-enantiomer. Reduction of triglycinatocobalt(III) under argon by cell-free extracts, prepared by sonication, exhibits similar stereoselectivities to cells disrupted by 2-phenylethanol. However, extracts contain a factor capable of reducing D-triglycinatocobalt(III) with high stereoselectivity under molecular hydrogen. The behaviour of Enterobacter cloacae is compared with that of Aerobacter aerogenes, Proteus vulgaris, Escherichia anaerogenes and Serratia marcescens. Stereoselective effects are also observed in the bacterial reduction of other cobalt(III) complexes.     

Mutagenicity of free-radical spin-trapping compounds

Spin-trapping compounds are used to detect the presence of free-radical intermediates in various chemical and biological processes. We have tested the mutagenicity of several newly synthesized and some commonly used spin-traps. Commonly used spin-traps were non-mutagenic at the levels tested; however, a few of the newly synthesized spin-traps are slightly mutagenic.     

Mutagenicity of various chemicals including nickel and cobalt compounds in cultured mouse FM3A cells

Employing a suspension culture of FM3A cells, we examined the cytotoxic and mutagenic effects of various chemical compounds. Mutagenicity of various types of mutagens (MNNG, ENNG, sterigmatocystin, mitomycin C, Trp-P-1, and X-rays) was sensitively detected by this assay. Mutagenicity of Trp-P-2 was detected in the presence of an activating enzyme system. Nickel(II) and cobalt(II) compounds (NiCl2, Ni(CH3COO)2, nickel complex [(C2H5)4N]2 [NiCl4], CoCl2, and a cobalt complex [(C2H5)4N]2-[CoCl4]) were cytotoxic to FM3A cells at concentrations of over 1 X 10(-4) M, and produced 2-6-fold increases of the control in the average number of 6-thioguanine-resistant (6TGr) colonies over a very narrow concentration range of 2-4 X 10(-4) M. Comparison of the mutagenicity of various chemical compounds suggested that some of the nickel(II) and cobalt(II) compounds were very weak mutagens.     

Reaction of bis(diethylenetriamine)cobalt(III) with formaldehyde and ammonia

Condensation reactions of three isomers of bis(diethylenetriamine)cobalt(III) with formaldehyde and ammonia were studied. The s-fac isomer gave a main product containing two molecules of the cyclic amine, 1,3,5,8-tetraazacyclodecane. It was unstable in acidic solution to give several decomposition products. The encapsulated complex in which all the nitrogens were attacked by formaldehyde could not be obtained. The main product of the u-fac isomer was a half encapsulated complex, i.e., three of the four primary amino groups reacted with formaldehyde and ammonia to produce a cobalt(III) complex of 3-(7-amino-2,5-diazaheptyl)-1,3,5,8-tetraazacyclodecane. The mer isomer gave a complex of 1,4,7,9,11,14,17-heptaazaheptadecane, together with the same reaction product as the one from the u-fac isomer.     

Light-induced nicking of deoxyribonucleic acid by cobalt(III) bleomycins

The anticancer drug bleomycin is a glycopeptide that causes strand scission of DNA both in vivo and in vitro. Cleavage of DNA by bleomycin has been studied extensively in vitro, with the findings that ferrous ion and molecular oxygen must be present and that addition of reducing agents greatly enhances the reaction. To date, only iron has been shown to be an effective metal cofactor for the cleavage of DNA by bleomycin. Here it is reported that two stable cobalt(III) complexes of bleomycin are strikingly effective in causing single-strand breaks (nicks) in supercoiled DNA in the presence of ultraviolet or visible radiation. For example, 366-nm light from an 18-W long-wavelength mercury lamp for 1 h causes 10(-6) M cobalt(III) bleomycin to completely convert supercoiled phi X174 DNA (10(-8) M DNA, 10(-4) M phosphate) into the nicked circular form. Furthermore, numerous alkali-labile sites are produced on the DNA during this treatment. The observed reactions are not caused by adventitious iron, and they occur only in the presence of cobalt(III) bleomycin and light.     

Some complexes of cobalt(III) and iron(III) are radiosensitizers of hypoxic EMT6 cells

The radiosensitizing potential in hypoxic EMT6 cells of several complexes of Co(III) and Fe(III) has been examined. The cytotoxicity of each of the agents toward oxygenated and hypoxic EMT6 cells was tested over the concentration range of 1 to 500 micron for 1-h drug exposure. There was no statistically significant difference between the cytotoxicity of these complexes toward oxygenated and hypoxic cells. Based on these findings, 100 micron was selected as the drug concentration for the initial assessment of radiosensitizing potential. The radiation survival of EMT6 cells in the presence of 100 microM drug for a series of Co(III) complexes in which the number of nitro ligands was varied showed that the hexanitro and the triamine-trinitro complexes are very effective radiosensitizers. The trans-tetrammine dinitro complex was a more effective radiosensitizer than the corresponding cis-dinitro complex. The diethylenetriamine and 1,10-phenanthroline complexes were very effective radiosensitizers, producing dose-modifying factors of 2.4. The trans-tetrammine dichloro complex was moderately effective, giving a dose-modifying factor of 1.9. On the other hand, the hexammine and triammine tricyano complexes and the trans-dinitro complex with negatively charged acetylacetonate ligands were ineffective as radiosensitizers in this system. Finally, three complexes with cyclopentadienyl ligands were examined. The ferricenium salt itself was a moderately effective radiosensitizer, giving a dose-modifying factor of 2.0. However, both the dimethylferricenium salt and the analogous cobalt complex were ineffective. The FSaIIC fibrosarcoma was used to study radiosensitizing potential in vivo. The trans-tetramminedinitro complex was administered at doses of 100, 200, or 300 mg/kg as a single ip injection 1 h prior to irradiation or as three daily ip injections. There was increasing dose modification with increasing drug dosage. With a fractionated radiation protocol in which five daily fractions of 2, 3, or 4 Gy were administered to the tumor-bearing limb with ip drug injections of 100 or 200 mg/kg given 1 h prior to irradiation, a dose-modifying effect of 1.6 was observed with 5 X 200 mg/kg of the drug.     

Studies on antimicrobial activity of cobalt(III) ethylenediamine complexes

A series of cobalt(III) mixed ligand complexes of type [Co(en)2L]+3, where L is bipyridine, 1,10-phenanthroline, imidazole, methylimidazole, ethyleimidazole, dimethylimidazole, urea, thiourea, acetamide, thioacetamide, semicarbazide, thiosemicarbazide, or pyrazole, have been isolated and characterized. The structural elucidation of these complexes has been explored by using absorption, infrared, and 1H NMR nuclear magnetic resonance spectral methods. The infrared spectral data of all these complexes exhibit a band at 1450/cm and 1560-1590/cm, which correspond to C=C and C=N, a band at 575/cm for Co-N (en), and a band at 480/cm for Co-L (ligand). All these complexes were found to be potent antimicrobial agents. The antibacterial activity was studied in detail in terms of zone inhibition, minimum bactericidal, and time period of lethal action. Among all, complexes bipyridine, 1,10-phenanthroline, dimethylimidazole, and pyrazole, possess the highest antibacterial activity. Antifungal activity was done by disc-diffusion assay and 50% inhibitory concentrations that possess high antifungal activity.     

Synthetic routes to mixed-ligand cobalt(III) dithiocarbamato complexes containing imidazole, amine and pyridine donors and the X-ray crystal structure of a cobalt(III) bis(dithiocarbamato) histamine complex

The binuclear cobalt complex [Co(2)(Me(2)dtc)(5)](+) reacts with a range of nitrogen donor ligands L' or L' to form an equimolar mixture of Co(Me(2)dtc)(3) and the mixed-ligand complexes [Co(Me(2)dtc)(2)(L')(2)](+) or [Co(Me(2)dtc)(2)(L')](+), where (L')(2) is two monodentate ligands and (L') is one bidentate ligand. The complexes prepared by this route contain the monodentate ligands L'=1-methyl-imidazole, 1-methyl-5-nitro-imidazole and benzimidazole, all of which coordinate to cobalt through an imidazole nitrogen atom. Symmetrical bidentate ligand complexes contain the bisimidazole L'=2,2'-bis(4,5-dimethylimidazole), the diamine L'=1,2-diaminobenzene and the pyridine donors L'=2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine and 1,10-phenanthroline. Two examples of complexes with unsymmetrical bidentate imidazole-amine donors were prepared in which L'=4-(2-aminoethyl)imidazole (histamine) and 2-aminomethylbenzimidazole. All new complexes were fully characterised, and the X-ray crystal structure of the histamine complex [Co(Me(2)dtc)(2)(hist)]ClO(4) is also reported.     

Synthesis and structure of chloro(ligand)bis(diphenylglyoximato)cobalt(III) complexes

The synthesis and characterization of trans-chloro- (ligand)bis(diphenylglyoximato)cobalt(III) complexes [ligand = pyridine (py), α-, β-, or γ-picoline (α-pic, β-pic, γ-pic), 3,5-lutidine (lut), p-toluidine (p-tol) and PPh₃] is presented. X-ray crystal structure determination of the pyridine (1) and p-toluidine (6) derivatives has been carried out. Compound 1 crystallizes in the monoclinic system, space group P2₁/n, with Z = 4 and unit cell parameters a = 23.124(4), b = 13.009(3) and c = 11.204(3) Å, and β= 93.14(2)°. Compound 6 crystallizes in the monoclinic system, space group P2₁/n, with Z = 4 and unit cell parameters a = 18.792(3), b = 12.540(2) and c = 15.346(3) Å, and β = 97.54(2)°.