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PubMed1986

Interactions of gold coordination complexes with DNA.

The interactions of certain gold(I) and gold(III) complexes with isolated plasmid pBR322 DNA were defined and compared to those of cis-diamminedichloroplatinum(II), CDDP, using an agarose gel electrophoresis assay. Trichloro(pyridine)gold(III) appeared to bind to DNA as evidenced by its ability to produce dose-dependent changes in the electrophoretic mobilities of closed circular, supercoiled, closed circular, relaxed, and open circular plasmid DNAs. These effects suggest that the gold containing complex induces conformational changes in the plasmid as a result of the compound binding to the DNA and the subsequent unwinding of the double helix and shorting of the DNA. Auranofin [(2,3,4,6-tetra-O-acetyl-1-thio-beta-D-glucopyranosato-S)-triethyl phosphine gold(I)] did not appear to interact with DNA under any conditions. However, its analog chloro(triethylphosphine) gold(I) interacted with DNA at pH 9.5 in borate buffer and produced electrophoretic mobility changes in pBR322 DNA which were different from those produced by the gold(III) complexes that were evaluated. Binding of chloro(triethylphosphine) gold(I) was inhibited by the co-addition of the thiosugar portion of auranofin suggesting preferential binding of the gold moiety to thiosugar, which results in the production of auranofin (or a sugar containing) gold complex and inhibition of gold binding to DNA. The interactions of a number of gold compounds with DNA were also evidenced by their abilities to inhibit the binding of ethidium bromide to DNA. The results from these studies indicate that: gold containing complexes can bind to, and produce conformational changes in, DNA; gold(I) and gold(III) complexes may interact with DNA via different chemical mechanisms to produce different conformational changes in DNA; and certain coordinating ligands in gold complexes (e.g. Cl, Br and SCN) can be exchanged for binding sites on DNA by gold.

Animals↗
PubMed1999

Insights into the mechanism of Escherichia coli methionine aminopeptidase from the structural analysis of reaction products and phosphorus-based transition-state analogues.

In an effort to differentiate between alternative mechanistic schemes that have been postulated for Escherichia coli methionine aminopeptidase (eMetAP), the modes of binding of a series of products and phosphorus-based transition-state analogues were determined by X-ray crystallography. Methionine phosphonate, norleucine phosphonate, and methionine phosphinate bind with the N-terminal group interacting with Co2 and with the respective phosphorus oxygens binding between the metals, interacting in a bifurcated manner with Co1 and His178 and hydrogen bonded to His79. In contrast, the reaction product methionine and its analogue trifluoromethionine lose interactions with Co1 and His79. The interactions with the transition-state analogues are, in general, very similar to those seen previously for the complex of the enzyme with a bestatin-based inhibitor. The mode of interaction of His79 is, however, different. In the case of the bestatin-based inhibitor, His79 interacts with atoms in the peptide bond between the P(1)' and P(2)' residues. In the present transition-state analogues, however, the histidine moves 1.2 A toward the metal center and hydrogen bonds with the atom that corresponds to the nitrogen of the scissile peptide bond (i.e., between the P(1) and P(1)' residues). These observations tend to support one of the mechanistic schemes for eMetAP considered before, although with a revision in the role played by His79. The results also suggest parallels between the mechanism of action of methionine aminopeptidase and other "pita-bread" enzymes including aminopeptidase P and creatinase.

Amino Acid Substitution↗
PubMedDate not supplied

Synthesis, characterization, and biological evaluation of neutral nitrido technetium(V) mixed ligand complexes containing dithiolates and aminodiphosphines. A novel system for linking technetium to biomolecules.

A new biomolecule labeling method that utilizes the [(99m)Tc(N)(PNP)](2+) metal fragment is presented. Thus, a series of nitrido mixed-ligand M(V) complexes (M = (99m)Tc, (99g)Tc, Re), [M(N)(Ln)(PNP)], where Ln is the dianionic form of a dithiolate or substituted-dithiolate ligand and PNP is an aminodiphosphine, is described. (99m)Tc complexes can be prepared using either a two-step or a three-step procedure starting from generator-eluted pertechnetate through a prereduced mixture of [(99m)Tc(N)]-containing species, followed by sequential or contemporary addition of the relevant dithiolate and aminodiphosphine. The reactions of 2,3-dimercaptopropionic acid (H(2)L1) with [Tc(N)(PNP)](2+) were investigated in detail. It was found that this bidentate ligand coordinated the metal fragment through the [S(-),S(-)] donor atom pair, to yield neutral mixed-ligand complexes [(99m)Tc(N)(L1)(PNP)] in high specific activity. The additional carboxylic functional group was not involved in metal coordination, thus remaining available for conjugation to target-specific molecules. Dithiolates incorporating pendant functional group(s) gave rise to a 1:1 diastereoisomeric mixture of syn-[M(N)(Ln)(PNP)] and anti-[M(N)(Ln)(PNP)] derivatives, depending on the relative orientation of the dithiolate substituent(s) with respect to the terminal nitrido group, and no isomeric conversion was detected. (99m)Tc species had been proven to be identical with the (99g)Tc complexes prepared at the macroscopic level by comparison of the corresponding radiometric and UV/vis HPLC profiles. Challenge experiments with cysteine or glutathione indicated that these physiological agents had no effect on the stability of this class of mixed-ligand (99m)Tc-complexes. Biodistribution studies in rats of selected (99m)Tc-complexes showed a rapid clearance from the blood and tissues after 60 min pi.

Animals↗
PubMed1988

Mechanism of alterations in isolated rat liver mitochondrial function induced by gold complexes of bidentate phosphines.

Au(DPPE)+2 (bis[1,2-bis(diphenylphosphino)ethane] gold(I] is an organo-gold antineoplastic agent that has anti-tumor activity in a variety of in vitro cell lines and in vivo rodent tumor models. Preliminary studies suggested that this compound represented a novel class of inhibitors of mitochondrial function. The purpose of this study was, therefore, to determine the mechanism of mitochondrial dysfunction induced by Au(DPPE)+2. Au(DPPE)+2 induced a rapid, dose-related collapse of the inner mitochondrial membrane potential (EC50 = 28.0 microM) that was not potentiated by Ca2+ preloading. Au(DPPE)+2-induced dissipation of mitochondrial membrane potential was accompanied by an efflux of Ca2+ from mitochondria upon exposure to Au(DPPE)+2. Ca2+ efflux in these experiments was via a reversal of the Ca2+ uniporter as efflux could be inhibited with ruthenium red. Au(DPPE)+2 did not increase the permeability of mitochondria to oxalacetate, indicating that the collapse of membrane potential may not be a result of gross increased inner membrane permeability. However, Au(DPPE)+2 may mediate an increased permeability of the inner membrane to cations and protons. Au(DPPE)+2 caused passive swelling in potassium acetate buffer in the absence of valinomycin, suggesting Au(DPPE)+2 facilitated the exchange of H+ and K+. Ca2+ cycling was not extensive and did not contribute to the decrease in membrane potential. These data suggest that one possible mechanism of Au(DPPE+2-induced uncoupling of mitochondrial oxidative phosphorylation is via increased permeability of the inner mitochondrial membrane to cations. The disruption of mitochondrial function may be a key process leading to hepatocyte cell injury by this drug.

Acetates↗
PubMed1994

Tissue distribution and elimination of indium in male Fischer 344 rats following oral and intratracheal administration of indium phosphide.

The use of indium phosphide (InP) in the semiconductor industry has raised concerns about potential occupational exposure. The tissue distribution and elimination of indium were investigated in adult male Fischer 344 rats following either a single or 14 consecutive daily oral doses, or following an intratracheal instillation of InP (10 mg/kg). The concentrations of indium ions in blood, urine, feces, and tissues were quantified either using direct acid digestion followed by electrothermal atomic absorption spectrophotometry (ET-AAS) or using an extraction method with methyltricapryl ammonium ions to remove indium from the matrix followed by ET-AAS. Indium was poorly absorbed from the gastrointestinal tract in both single and multiple oral dose studies. Upon its absorption, indium was relatively evenly distributed among the major organs such as liver, kidney, lung, spleen, and testes. By 96 h after oral dose treatment, less than 0.11% of the dose of indium was recovered from tissues in the single- or multiple-dose experiment. At 96 h, retention of indium in the body was about 0.36% of the dose (except for lung) following intratracheal instillation of InP. Following oral dose administration, the majority of indium was recovered from the gastrointestinal tract and its contents. The high recovery of indium (73% of the dose) in the feces after intratracheal instillation presumably reflects mucociliary clearance and/or biliary excretion of indium. Urinary indium accounted only for 0.08-0.23% of the dose during a 240-h collection period in both single- and multiple-dose studies. It seems that fecal excretion serves as the major route for indium elimination, and this results from poor absorption. Because of the poor absorption of indium following multiple oral doses or intratracheal instillation of InP, it seems unlikely that indium will accumulate in the body following InP exposure.

Administration, Oral↗
PubMed2006

Improved efficacy of ethyl formate against stored grain insects by combination with carbon dioxide in a 'dynamic' application.

Ethyl formate is being evaluated as a fumigant for stored grain as it is a potential alternative to the ozone-depleting fumigant methyl bromide and to phosphine, which is under pressure owing to the development of strong resistance in stored grain insects. However, use of ethyl formate faces significant challenges, such as poor penetration through grain, significant losses to grain sorption, high concentrations of fumigant required to control insects, and flammability risks, which have limited its further development. In this study it was found that the combination of carbon dioxide (5-20%) with ethyl formate significantly enhanced efficacy of the fumigant against external living stages of the rice weevil, Sitophilus oryzae (L.), the lesser grain borer, Rhyzopertha dominica F., and the flour beetle, Tribolium castaneum (Herbst). Dynamic application of ethyl formate and carbon dioxide mixture (100 mg litre-1 ethyl formate, 20% CO2) pumped through a model silo containing wheat (50 kg) for one gas exchange was also investigated. A flow rate of 6 litres min-1 gave a relatively even distribution of fumigant throughout the grain column and similar mortality levels among cultures of S. oryzae and T. castaneum placed at three positions, the top, middle and bottom of the column. Mortality of 99.8% of mixed stage cultures of T. castaneum and 95.1% of S. oryzae was achieved in 3 h exposures to 111 and 185 mg ethyl formate h litre-1 respectively applied by the dynamic method. It is concluded that the combination of carbon dioxide with ethyl formate and dynamic application enhances distribution and efficacy of the fumigant against stored grain insects.

Animals↗
PubMed2002

Proteomic study of a model causative agent of harmful red tide, Prorocentrum triestinum I: Optimization of sample preparation methodologies for analyzing with two-dimensional electrophoresis.

A comprehensive study to find the optimal sample preparation conditions for two-dimensional electrophoresis (2-DE) analysis of Prorocentrum triestinum, a model causative agent of harmful algal blooms (HABs) was carried out. The four major sample preparation steps for 2-DE: (a) cell disruption: i.e. sonication and homogenization with glass beads; (b) protein extraction : i.e. sequential and independent extraction procedures; (c) pre-electrophoretic treatment: these included (i) treatment with RNAase/DNAase or benzonase; (ii) ultracentrifugation to sediment large macromolecules such as DNA; (iii) desalting and concentration by ultrafiltration through a Microcon centrifugal filter device (MWCO: 3000 daltons); and (iv) desalting by a micro BioSpin chromatography column (MWCO: 6000 daltons); and (d) rehydration buffers, reducing agents and sample application in the first dimension isoelectric focussing were studied. Our results showed that sonication is easy to perform and resulted in a higher protein yield. Among the four extraction buffers, the urea containing buffers resulted in the extraction of the highest amount of protein while tris(hydroxymethyl)aminomethane buffers and trichloroacetic acid (TCA)/acetone precipitation allowed detection of a higher number of protein species (i.e. protein spots). Desalting by BioSpin and ultrafiltration have improved the 2-DE resolution of the water soluble fraction but have less effect on urea containing fractions. TCA/acetone precipitation was able to desalt all protein fractions independent of the extraction media, however extended exposure to this low pH medium has caused protein modification. Introduction of either DNase/RNase or benzonase treatment did not improve the discriminatory power of the 2-DE but this treatment did yield 2-DE with the clearest background. Proteolytic digestion was inhibited by addition of a protease inhibitor cocktail. Taken overall, a combination of sequential extraction and desalting by BioSpin chromatography for sample treatment before first dimension of 2-DE gave best results based on its simplicity and minimal protein loss. Finally, triscarboxyethylphosphine (TCEP) has performed well as a reducing agent in both the rehydration and equilibration buffers. The rehydration buffer found to be best in this study was 8.0 M urea, 2% 3-[(3-cholamidoprphyldimethylamino]-1-propanesulfonate, 4 mM TCEP and 1% immobilized pH gradient buffer. Subsequently, we applied this finding and performed 2-DE analysis on the soluble protein fractions extracted from light-starved cultured algal cells (nonblooming) and cultured cells grown under optimal conditions (blooming). 2-DE maps of these algal cultures were visibly different and many differentially expressed proteins were found.

Acetone↗
PubMedDate not supplied

PAMAM dendrimeric conjugates with a Gd-DOTA phosphinate derivative and their adducts with polyaminoacids: the interplay of global motion, internal rotation, and fast water exchange.

A series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd-DO3A-P(ABn) complexes (monophosphinated analogue of DOTA) was prepared. The chelates were covalently attached to the G1-, G2-, and G4-PAMAM dendrimers through a thiourea linker in high loads (>90%). The prepared conjugates G1-(Gd-DO3A-P(BnN{CS}))(8), G2-(Gd-DO3A-P(BnN{CS}))(16), and G4-(Gd-DO3A-P(BnN{CS}))(59) showed relaxivities of 10.1, 14.1, and 18.6 s(-)(1) mM(-)(1) at 20 MHz and 37 degrees C and pH = 7.5, respectively. A variable-pH study (range 2-12) revealed up to 30% increase in the relaxivity at low pH for the G2-(Gd-DO3A-P(BnN{CS}))(16) conjugate. As confirmed by (1)H NMR titration of the unmodified G2 dendrimer, this is due to protonation of core tertiary amines leading to a more open and rigid structure. The variable-temperature (17)O NMR and (1)H NMRD relaxometric studies confirmed that the relaxivity is not controlled by water exchange but by rotational dynamics. A multiparametrical data evaluation using the Lipari-Szabo approach revealed that the water residence lifetime, (298)tau(M), for the conjugates studied was ca. 45-70 ns, which is longer than the value found for the monomeric model compound Gd-DO3A-P(ABn) (16 ns) but short enough so as not to limit the relaxivity. The global rotational correlation time, (298)tau(Rg), varied from 1.5 to 3.1 ns and seemed to indicate a sufficiently slow molecular tumbling to achieve the high relaxivities measured; however, the rigidity factor S(2) (approximately 0.26), describing the internal flexibility, was far from optimum. The overall relaxivity was significantly increased (e.g. by a factor of 1.8 for the G1-(Gd-DO3A-P(BnN{CS}))(8) conjugate) when a positively charged polyaminoacid like poly(Arg) or poly(Lys) was added to the conjugate solutions. The electrostatic interactions partially "freeze" the internal mobility of the conjugate and also slow down global motion. This assumption was confirmed by an evaluation of (1)H relaxometric data obtained for the G2-(Gd-DO3A-P(BnN{CS}))(16)-poly(Lys)(59) adduct. Importantly, it was proved that the adduct formation did not hamper the water exchange process.

Amino Acids↗
PubMed2003

Ligand-exchangeability of 2-coordinate phosphinegold(I) complexes with AuSP and AuNP cores showing selective antimicrobial activities against Gram-positive bacteria. Crystal structures of [Au(2-Hmpa)(PPh(3))] and [Au(6-Hmna)(PPh(3))] (2-H(2)mpa=2-mercaptopropionic acid, 6-H(2)mna=6-mercaptonicotinic acid).

Selective and effective antimicrobial activities against Gram-positive bacteria (B. subtilis and/or S. aureus) were found in 2-coordinate gold(I)-PPh(3) complexes with AuSP and AuNP cores, i.e. [Au(L)(PPh(3))] (HL=2-H(2)mna [H(2)mna=mercaptonicotinic acid] 3, D-H(2)pen [H(2)pen=penicillamine] 4, D,L-H(2)pen 5, 4-H(2)mba [H(2)mba=mercaptobenzoic acid] 8, Hpz [Hpz=pyrazole] 9, Him [Him=imidazole] 10, 1,2,3-Htriz [Htriz=triazole] 11, 1,2,4-Htriz 12, Htetz [Htetz=tetrazole] 13), whereas no activity was observed in 2-coordinate AuSP core complexes [Au(2-Hmba)(PPh(3))] 6 and [Au(3-Hmba)(PPh(3))] 7. The two novel AuSP core complexes, [Au(2-Hmpa)(PPh(3))] [H(2)mpa=mercaptopropionic acid] 1 and [Au(6-Hmna)(PPh(3))] 2, were prepared and characterized by elemental analysis, FT-IR, TG/DTA, and ((31)P, 1H and 13C) NMR spectroscopy. The crystal structures of 1 and 2 were determined as a supramolecular arrangement of the 2-coordinate AuSP core. Both 1 and 2 significantly showed antibacterial activities. As a model reaction of phosphinegold (I) complexes with the cysteine residue in the biological ligands, we examined if the ligand exchange reactions of the aromatic anions L(1)(-) in [Au(L(1))(PPh(3))] (HL(1)=6-H(2)mna 2, 2-H(2)mna 3, 2-H(2)mba 6, Hpz 9, Him 10, 1,2,3-Htriz 11, 1,2,4-Htriz 12) with aliphatic thiols HL(2) (HL(2)=2-H(2)mpa, D-H(2)pen) occurred under the mild conditions and, also, if the 'reverse' reactions, namely, the ligand exchange reactions of the thiolate anions in [Au(2-Hmpa)(PPh(3))] 1, [Au(D-Hpen)(PPh(3))] 4 and [Au(2-Hmba)(PPh(3))] 6 with the free ligands HL(1) took place under similar conditions. In this work, a relationship of the ligand-exchangeability among 2-coordinate gold(I) complexes (1-4, 6, 9-12) was revealed. Complex 6 was substitution-inert, whereas complexes 1-4 and 9-12 were substitution-labile. The ligand-exchangeability of Au-S and Au-N bonds in the 2-coordinate phosphinegold(I) complexes with AuSP and AuNP cores to form new AuSP cores, with retention of the Au-P bond, was closely related to the observed activities against Gram-positive bacteria, and the ease of the ligand-exchange reaction was strongly related to the intensity of the activities.

Anti-Bacterial Agents↗
PubMed2006

Dioxygen-initiated oxidation of heteroatomic substrates incorporated into ancillary pyridine ligands of carboxylate-rich diiron(II) complexes.

Progress toward the development of functional models of the carboxylate-bridged diiron active site in soluble methane monooxygenase is described in which potential substrates are introduced as substituents on bound pyridine ligands. Pyridine ligands incorporating a thiol, sulfide, sulfoxide, or phosphine moiety were allowed to react with the preassembled diiron(II) complex [Fe(2)(mu-O(2)CAr(R))(2)(O(2)CAr(R))(2)(THF)(2)], where (-)O(2)CAr(R) is a sterically hindered 2,6-di(p-tolyl)- or 2,6-di(p-fluorophenyl)benzoate (R = Tol or 4-FPh). The resulting diiron(II) complexes were characterized crystallographically. Triply and doubly bridged compounds [Fe(2)(mu-O(2)CAr(Tol))(3)(O(2)CAr(Tol))(2-MeSpy)] (4) and [Fe(2)(mu-O(2)CAr(Tol))(2)(O(2)CAr(Tol))(2)(2-MeS(O)py)(2)] (5) resulted when 2-methylthiopyridine (2-MeSpy) and 2-pyridylmethylsulfoxide (2-MeS(O)py), respectively, were employed. Another triply bridged diiron(II) complex, [Fe(2)(mu-O(2)CAr(4)(-)(FPh))(3)-(O(2)CAr(4)(-)(FPh))(2-Ph(2)Ppy)] (3), was obtained containing 2-diphenylphosphinopyridine (2-Ph(2)Ppy). The use of 2-mercaptopyridine (2-HSpy) produced the mononuclear complex [Fe(O(2)CAr(Tol))(2)(2-HSpy)(2)] (6a). Together with that of previously reported [Fe(2)(mu-O(2)CAr(Tol))(3)(O(2)CAr(Tol))(2-PhSpy)] (2) and [Fe(2)(mu-O(2)CAr(Tol))(3)(O(2)CAr(Tol))(2-Ph(2)Ppy)] (1), the dioxygen reactivity of these iron(II) complexes was investigated. A dioxygen-dependent intermediate (6b) formed upon exposure of 6a to O(2), the electronic structure of which was probed by various spectroscopic methods. Exposure of 4 and 5 to dioxygen revealed both sulfide and sulfoxide oxidation. Oxidation of 3 in CH(2)Cl(2) yields [Fe(2)(mu-OH)(2)(mu-O(2)CAr(4)(-)(FPh))(O(2)CAr(4)(-FPh))(3)(OH(2))(2-Ph(2)P(O)py)] (8), which contains the biologically relevant {Fe(2)(mu-OH)(2)(mu-O(2)CR)}(3+) core. This reaction is sensitive to the choice of carboxylate ligands, however, since the p-tolyl analogue 1 yielded a hexanuclear species, 7, upon oxidation.

Carboxylic Acids↗