Alvin A. Holder

Pulmonary Immunotoxic Potentials of Metals Are Governed by Select Physicochemical Properties: Vanadium Agents

The in situ reactions of metal ions/complexes are important in understanding the mechanisms by which environmental and occupational metal particles alter lung immune responses. A better understanding of these reactions in situ will also allow for the improved specificity and controlled toxicity of novel metallocompounds to be used as inhaled diagnostics or therapeutics. Our previous work showed that inhalation of metals (e.g., chromium, vanadium, nickel) caused altered lung immune cell function and host resistance. The data also suggested that the degree of immunomodulation induced depended not only on the amount of metal deposited, but also the compound used. If specificity governs pulmonary immunomodulatory potential, it follows that physicochemical properties inherent to the metal have a role in the elicited effects. We hypothe-size that major determinants of any metal compounds potential are its redox behavior, valency (generally referred to as oxidation state and considered speciation in chemical literature), and/or solubility. In accord with the extensive work carried out with vanadium (chemical symbol V) compounds showing the importance of form used, differences in potential for a range of V agents (pentavalent [VV] insoluble vanadium pentoxide and soluble sodium metavanadate, tetravalent [VIV] vanadyl dipicolinate, and trivalent [VIII] bis(dipicolinato)vanadium) were quantified based on induced changes in local bacterial resistance after host inhalation of each agent at 100 μ g V/m3 (5 hr/d for 5 d). Differences in effect between VV forms indicated that solubility was a critical property in in situ pulmonary immunotoxicity. Among the soluble forms, oxidizing vanadate had the greatest impact on resistance; reducing VIII altered resistance to a lesser extent. Both the VIV and insoluble VV had no effect. When data was analyzed in the context of pre-infection lung V burdens, soluble V agents with different oxidation states induced varying responses, supporting the hypothesis that differences in immunomodulatory potential might be attributed to redox behavior or valency. Our findings both provide a basis for understanding why some metals could be a greater health risk than others (when encountered in equal amounts) and will assist in the design of inhalable metallopharmaceuticals by allowing researchers to preempt selection of certain metal ions or complexes for use in such products.

Electrochemical and electrogenerated chemiluminescent studies of a trinuclear complex, [((phen)2Ru(dpp))2RhCl2]5+, and its interactions with calf thymus DNA.

The electrochemical behavior of a trinuclear ruthenium(II)-containing complex, [((phen)(2)Ru(dpp))(2)RhCl(2)](5+) (where phen = 1,10-phenanthroline, dpp = 2,3-bis(2-pyridyl)pyrazine), was studied in acetonitrile (MeCN) and aqueous solutions. In MeCN containing 0.10 M tetra-n-butylammonium perchlorate (TBAP), the complex displayed a reversible, overlapping Ru(II/III) redox process with E(1/2) = +1.21 V vs Ag/Ag(+) (10 mM), an irreversible reduction of Rh(III/I) at -0.73 V vs Ag/Ag(+), and two quasi-reversible dpp/dpp(-) couples with E(1/2) = -1.11 and -1.36 V vs Ag/Ag(+) at a Pt electrode with a scan rate of 50 mV s(-1). In 0.20 M Tris buffer solution (pH 7.4), an irreversible, overlapping Ru(II/III) oxidation at +1.48 V vs Ag/AgCl (3 M KCl), and an irreversible reduction of Rh(III/II) at -0.78 V vs Ag/AgCl were observed at a glassy carbon electrode with a scan rate of 50 mV/s. Investigations on the electrogenerated chemiluminescence (ECL) of the complex revealed that 2-(dibutylamino) ethanol (DBAE) was superior to tri-n-propylamine (TPrA) as an ECL coreactant within their entire concentration range of 10-100 mM in MeCN, and in aqueous media, as low as 1.0 nM of the complex can be detected using TPrA coreactant ECL. A maximum ECL emission of 640 nm, which is about 55 nm blue shift to its fluorescence, was observed in MeCN with DBAE as a coreactant. Interactions of the complex with calf thymus DNA (ctDNA) were conducted with a flow-cell based quartz-crystal microbalance, and a binding constant of 2.5 x 10(5) M(-1) was calculated on the basis of the Langmuir isotherm equation.

Effects of metal compounds with distinct physicochemical properties on iron homeostasis and antibacterial activity in the lungs: chromium and vanadium

In situ reactions of metal ions or their compounds are important mechanisms by which particles alter lung immune responses. The authors hypothesized that major determinants of the immunomodulatory effect of any metal include its redox behavior/properties, oxidation state, and/or solubility, and that the toxicities arising from differences in physicochemical parameters are manifest, in part, via differential shifts in lung iron (Fe) homeostasis. To test the hypotheses, immunomodulatory potentials for both pentavalent vanadium (VV; as soluble metavanadate or insoluble vanadium pentoxide) and hexavalent chromium (CrVI; as soluble sodium chromate or insoluble calcium chromate) were quantified in rats after inhalation (5 h/day for 5 days) of each at 100 μg metal/m3. Differences in effects on local bacterial resistance between the two VV, and between each CrVI, agents suggested that solubility might be a determinant of in situ immunotoxicity. For the soluble forms, VV had a greater impact on resistance than CrVI, indicating that redox behavior/properties was likely also a determinant. The soluble VV agent was the strongest immunomodulant. Regarding Fe homeostasis, both VV agents had dramatic effects on airway Fe levels. Both also impacted local immune/airway epithelial cell Fe levels in that there were significant increases in production of select cytokines/chemokines whose genes are subject to regulation by HIF-1 (whose intracellular longevity is related to cell Fe status). Our findings contribute to a better understanding of the role that metal compound properties play in respiratory disease pathogenesis and provide a rationale for differing pulmonary immunotoxicities of commonly encountered ambient metal pollutants.

DNA binding of mixed-metal supramolecular Ru, Pt complexes

Abstract The mixed-metal supramolecular complexes [(tpy)Ru(PEt 2 Ph)(dpp)PtCl 2 ](PF 6 ) 2 and [(tpy)Ru(PEt 2 Ph)(bpm)PtCl 2 ](PF 6 ) 2 are of interest in that they couple light absorbing ruthenium centers to a reactive metal site through a communicative bridge (tpy=2,2 ′ :6 ′ ,2 ′′ -terpyridine, bpm=2,2 ′ -bipyrimidine and dpp=2,3-bis(2-pyridyl)pyrazine). These systems have been studied and shown to avidly bind to DNA, greatly reducing its mobility through an agarose gel.

Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: Synthesis, cytotoxic and antimalarial evaluation

A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine.

Complexation of bisphosphonates with Ytterbium(III): Application of phosphate and ATP detection assay based on Yb3+-pyrocatechol violet

The coordination chemistry of bisphosphonates with Yb(3+) was investigated to evaluate the potential of the UV-vis based detection method using the Yb(3+)-pyrocatechol complexation reaction as a sensor for bisphosphonates. The complexation chemistry of Yb(3+) with phosphate and ATP analogs was previously described (E. Gaidamauskas, K. Saejueng, A.A. Holder, S. Bharuah, B.A. Kashemirov, D.C. Crans, C.E. McKenna, J. Biol. Inorg. Chem. 13 (2008) 1291-1299), and we here studied the complexation chemistry of bisphosphonates in this system. The spectrophotometric assay yields direct evidence for formation of a 4:3 metal to ligand complex at neutral pH. Direct evidence for Yb(3+):methylenebis(phosphonate) complexes with 1:1 and 1:2 stoichiometry was also obtained by potentiometry at acidic and basic pH. Direct evidence for complex formation was obtained using (1)H NMR spectroscopy although the stoichiometry was not accessed at neutral pH. Our results suggest that the spectroscopic observation of the YbPV complex can be used to conveniently measure concentrations of bisphosphonates down to 2-3 microM.

Mechanism of the oxidation of l-ascorbic acid by the molyb-datopentaamminecobalt(III) ion in aqueous solution

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Mechanism of the oxidation of L-ascorbic acid by the bis(pyridine-2,6-dicarboxylate)cobaltate(III) ion in aqueous solution

A detailed investigation of the oxidation of L-ascorbic acid (H2A) by the title complex has been carried out using conventional spectrophotometry at 510 nm, over the ranges: 0.010 ≤ [ascorbate]T ≤ 0.045 mol dm−3, 3.62 ≤ pH ≤ 5.34, and 12.0 ≤ θ ≤ 30.0 °C, 0.50 ≤ I ≤ 1.00 mol dm−3, and at ionic strength 0.60 mol dm−3 (NaClO4). The main reaction products are the bis(pyridine-2,6-dicarboxylate)cobaltate(II) ion and l-dehydroascorbic acid. The reaction rate is dependent on pH and the total ascorbate concentration in a complex manner, i.e., kobs = (k1K1)[ascorbate]T/(K1 + [H+]). The second order rate constant, k1 [rate constant for the reaction of the cobalt(III) complex and HA−] at 25.0 °C is 2.31 ± 0.13 mol−1 dm3 s−1. ΔH‡ = 30 ± 4 kJ mol−1 and ΔS‡ = −138 ± 13 J mol−1 K−1. K1, the dissociation constant for H2A, was determined as 1.58 × 10−4 mol dm−3 at an ionic strength of 0.60 mol dm−3, while the self exchange rate constant, k11 for the title complex, was determined as 1.28 × 10−5 dm3 mol−1 s−1. An outer-sphere electron transfer mechanism has been proposed.

Synthesis of natural phaeosphaeride A derivatives and an in vitro evaluation of their anti-cancer potential

Derivatives of phaeosphaeride A (PPA) were synthesised and characterised; then anti-cancer studies were carried out on the A549 cancer cell line. It was found that the acetyl derivative (compound 3) displayed comparable in vitro cytotoxicity to that of PPA (EC50=49±7 μM and EC50=46±5 μM, respectively), while chloroacetyl derivative 6 (EC50=33±7 μM) was found to have better efficacy towards the A549 cancer cell line.

SYNTHESES, CHARACTERISATION, INFRARED AND 95MO NMR SPECTROSCOPY OF SOME COORDINATED OXO-MOLYBDENUM(VI) COMPLEXES

Abstract Adducts with MoO 4 2− tetrahedra coordinated to Cr(III) or Co(III) complexes have been synthesized and studied by IR and high resolution 95 Mo NMR spectroscopy. The 95 Mo chemical shifts of the adducts with cobalt(III) lie in the range −33.2 to + 49.4 ppm. This may be compared with an overall known chemical shift range in excess of 7000 ppm and implies a similarity in the molybdenum environment in all cases. For adducts with chelated cobalt(III) complexes several rather broad 95 Mo singnals are obtained with linewidths up to 260 Hz.