Evidence that the mechanisms of fungitoxicity of 8-quinolinol and its bischelate with copper(II) are different

The copper(II) contents of the growth media, Sabouraud dextrose and Czapek-Dox broths, and of the spore inocula of Aspergillus niger (ATCC 1004), Aspergillus oryzae (ATCC 1011), Trichoderma viride (ATCC 8678), and Myrothecium verrucaria (ATCC 9095) were determined by atomic absorption spectrophotometry in a graphite furnace. The test systems composed of Sabouraud dextrose broth and spore inocula of the four fungi contained only a little over 3% of the copper(II) required to form a minimal inhibitory concentration of bis(8-quinolinolato)copper(II). The test system of Czapek-Dox broth and A. oryzae contained slightly less than 65% of the copper(II) required to form a minimal inhibitory concentration of the bischelate of 8-quinolinol with copper(II). When the minimal inhibitory concentrations of 8-quinolinol and bis(8-quinolinolato)copper(II) were added simultaneously to the test system of Czapek-Dox broth and A. oryzae, 10% of the combined mixture of toxicants caused complete inhibition of growth indicating synergism between the toxicants. These results together with the observation that alpha-lipoic acid as well as small aliphatic thiol-containing compounds (cysteine, glutathione, dithioerythritol, and dithiothreitol) reversed the toxicity of 8-quinolinol but not the toxicity of bis(8-quinolinolato)copper(II) led to the conclusion that the mechanisms of fungitoxicity of both toxicants are different.     

Relationship between pKa of 8-quinolinol derivatives and a π-donor ability of the 8-quinolinolato oxygen in linear nitrosylruthenium(II) complexes

The relationship between the pK_a of 8-quinolinol derivatives {8-quinolinol (Hqn), 2-methyl- (H2-Meqn), 2,4-dimethyl- (H2,4-diMeqn), 5-chloro- (H5-Clqn) and 5,7-dichloro-8-quinolinols (H5,7-diClqn)} and a π-donor ability of the 8-quinolinolato oxygens has been investigated by the identification of the structures of the major products, [RuCl(QN)(QN′)NO] (HQN=8-quinolinol derivative; HQN′=different 8-quinolinol derivatives), obtained by the reaction of [RuCl₃(QN or QN′)NO]⁻ with HQN′ or HQN. The results obtained clearly showed that the oxygen of the 8-quinolinol derivative that has a higher pK_a predominantly coordinates in the trans position to the NO ligand and is a better π-electron donor. The order of the π-electron donor ability for the oxygen of the 8-quinolinol derivatives is as follows: H2-Meqn≥H2,4-diMeqn>Hqn≥H5-Clqn>H5,7-diClqn, almost agreeing with the magnitude of the pK_a values of the corresponding 8-quinolinols. The structures of cis-1 [RuCl(5,7-diClqn)₂NO] and cis-1 [RuCl(5,7-diClqn)(2-Meqn)NO] were determined by X-ray diffraction.     

Substituent effect of 8-quinolinolato ligands on photo-induced isomerization for linear nitrosylruthenium(II) complexes - Experimental study

cis-1 [RuCl(QN)(QN′)NO] (HQN or HQN′ = 8-quinolinol, 5-chloro-, 5,7-dichloro-, 2-isopropyl-, 2-ethyl-, 2,4-dimethyl- or 2-methyl-8-quinolinol) complexes and the corresponding trans complexes were prepared. The cis-1 to trans and the trans to cis-1 photo-induced isomerizations were carried out to investigate the substituent effect of the 8-quinolinolato ligands on the isomerization and to elucidate the mechanism. The molar ratio of trans to cis-1 isomer for the isomerization was compared among [RuCl(QN)(QN′)NO], [RuCl(QN′)₂NO] and [RuCl(QN)₂NO]. The results clearly indicate that the chloro group and bulkiness of the alkyl group in the 8-quinolinolato ligands influence on the isomerization.     

Laboratory tests of 8-quinolinol as an additive to volatile fatty acids for preserving hay and other feedstuffs

One part of 8-quinolinol in ten parts of propionic acid, either free or part-neutralised with ammonia, halved the acid required for preserving grass and lucerne hays, beans, rape seed and cereal grains containing sufficient moisture to mould. Propionic acid with 8-quinolinol delays moulding and diminishes the rate of spread of mould growth so that maximum temperatures attained are lowered and growth of thermophilic organisms is prevented. The application of 8-quinolinol and propionic acid to grass on cutting with, or without, use of formic acid as desiccant assisted inhibition of moulding especially in conjunction with ammonium propionate treatment after drying. The additive acts by inhibiting the growth of fungi which tolerate and degrade propionic and related fatty acids. The growth of two such fungi, Paecilomyces varioti and Aspergillus glaucus, is inhibited in culture by much smaller concentrations (less than 200 μM or 30 ppm) of 8-quinolinol than are required on hay, which strongly absorbs the additive and makes it less effective.     

The interaction of cobalt (II) complexes with bovine apocarbonic anhydrase B.

The second-order rate constants for interaction of a number of cobalt(II) complexes (including the aquated ion) with bovine apocarbonic anhydrase have been measured at pH equal to 7.5, 25 degrees C and I equal 0.1 M. The ease of entry of cobalt decreases, in general, as the number of its coordinated watersdecreases. The highest complexes (bis or tris) do not react. The Mono cobalt(II) -8-quinolinol-5-sulfonate and, particularly, 8-quinolinol complexes react very much more rapidly with apoenzyme than does Co(H20)6-2+ ion. The results are discussed.     

Oxidative DNA damage of mixed copper(II) complexes with sulfonamides and 1,10-phenanthroline. Crystal structure of [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)2(1,10-phenanthroline)

Mixed coordination compounds of Cu(II) with sulfonamides and 1,10-phenanthroline as ligands have been prepared and characterised. Single crystal structural determination of the complex [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)(2)(phen)] shows Cu(II) ions are located in a highly distorted octahedral environment, probably as a consequence of the Jahn-Teller effect. The FT-IR and electronic paramagnetic resonance (EPR) spectra are also discussed. The mixed complexes prepared undergo an extensive DNA cleavage in the presence of ascorbate and hydrogen peroxide. Two of the complexes have higher nucleolytic efficiency than the bis(o-phenanthroline)copper(II) complex.     

The complexation of aqueous metal ions relevant to biological applications. 2. Reactions of copper(II) citrate and copper(II) succinate with selected amino acids

Abstract

Addition of amino acids, glycine, alanine, and serine, to poorly soluble copper(II) salts [copper(II) citrate and copper(II) succinate] all increase solubility of the copper(II) salts. Relative increases in solubility follow the polarity trend in the selected amino acids, with serine creating the greatest increase in solubility. Simultaneous equilibria calculations indicate the formation of mixed-ligand complexes in the copper(II) succinate–amino acid systems, the first time such mixed-ligand complexes have been observed. In contrast, mixed-ligand complexes are not predicted in the copper(II) citrate–amino acid systems. Potential bioavailability of copper(II) appears to be increased by the inclusion of amino acids in solution, roughly in parallel with the increase in solubility of the copper(II) salt. Therefore, measurement of the change in solubility caused by addition of amino acids to aqueous solution gives qualitative insight to the potential increase in bioavailability of the metal ion.     

Antimicrobial Activity of 8-Quinolinol, Its Salts with Salicylic Acid and 3-Hydroxy-2-Naphthoic Acid, and the Respective Copper (II) Chelates in Liquid Culture

A study was made of the antimicrobial activities of 8-quinolinol and its salts with salicylic acid and 3-hydroxy-2-naphthoic acid in liquid culture. Comparisons of results were made with those obtained by the discplate method. The mechanism of action of copper chelates was discussed.     

A polarimetric study of the reaction of bis(L-serinato)copper(II) with formaldehyde

Polarimetric data have shown that the base-catalyzed reaction of bis(L-serinato)copper(II) with excess formaldehyde proceeds via the initial dissociation of the proton on the nitrogen atom of the amino acid chelate. A bis(oxazolidine)copper(II) complex appears as an intermediate but this species is not detected polarimetrically at 50°C and above.     

Antimicrobial and mutagenic activity of some carbono- and thiocarbonohydrazone ligands and their copper(II), iron(II) and zinc(II) complexes.

Several mono- and bis- carbono- and thiocarbonohydrazone ligands have been synthesised and characterised; the X-ray diffraction analysis of bis(phenyl 2-pyridyl ketone) thiocarbonohydrazone is reported. The coordinating properties of the ligands have been studied towards Cu(II), Fe(II), and Zn(II) salts. The ligands and the metal complexes were tested in vitro against Gram positive and Gram negative bacteria, yeasts and moulds. In general, the bisthiocarbonohydrazones possess the best antimicrobial properties and Gram positive bacteria are the most sensitive microorganisms. Bis(ethyl 2-pyridyl ketone) thiocarbonohydrazone, bis(butyl 2-pyridyl ketone)thiocarbonohydrazone and Cu(H2nft)Cl2 (H2nft, bis(5-nitrofuraldehyde)thiocarbonohydrazone) reveal a strong activity with minimum inhibitory concentrations of 0.7 microgram ml-1 against Bacillus subtilis and of 3 micrograms ml-1 against Staphylococcus aureus. Cu(II) complexes are more effective than Fe(II) and Zn(II) ones. All bisthiocarbono- and carbonohydrazones are devoid of mutagenic properties, with the exception of the compounds derived from 5-nitrofuraldehyde. On the contrary a weak mutagenicity, that disappears in the copper complexes, is exhibited by monosubstituted thiocarbonohydrazones.     

Investigations into some aryl substituted bis(thiosemicarbazones) and their copper complexes

The synthesis of three bis(thiosemicarbazone) compounds formed by the reaction of benzil with either thiosemicarbazide, 4-methyl-3-thiosemicarbazide or 4-phenyl-3-thiosemicarbazide are reported. The compounds were characterised by NMR spectroscopy, mass spectrometry and in the case of benzil bis(4-methyl-3-thiosemicarbazone) and benzil bis(4-phenyl-3-thiosemicarbazone) by X-ray crystallography. Attempts to purify benzil bis(thiosemicarbazone) and benzil bis (4-methyl-3-thiosemicarbazone) by recrystallisation resulted in the isolation of cyclised products that were characterised by X-ray crystallography. The 3 bis(thiosemicarbazone) compounds were used to synthesise both Cu(II) and Cu(I) complexes. The copper(II) complexes were formed by the reaction of the proligands with copper(II) acetate which gave neutral copper(II) complexes in which the thiosemicarbazone is doubly deprotonated, acting as a dianionic ligand. The copper(II)-benzil bis(4-phenyl-3-thiosemicarbazonato) complex was characterised by X-ray crystallography to show the copper in an essentially square planar N₂S₂ environment. The copper(I) complexes were synthesised by reacting the bis (thiosemicarbazone) ligands with [Cu(CH₃CN)₄]PF₆ to give cationic complexes. The copper(I)-benzil-bis(thiosemicarbazone) complex was characterised by X-ray crystallography which revealed that the complex was a dimeric dication. Each of the benzil bis(thiosemicarbazone) ligands act as a bidentate N,S donor to each copper(I) atom, forming an overall helical structure in which each copper atom is in a strongly distorted tetrahedral N₂S₂ environment. Electrochemical measurements show that the copper(II)-benzil bis(thiosemicarbazonato) complex undergoes a reversible reduction at biologically accessible potentials.     

Copper(II) complexes of some N-substituted bis(aminomethyl)phosphinate ligands. An integrated EPR study of microspeciation and coordination modes by the two-dimensional simulation method

Copper(II) complexes of bis(aminomethyl)phosphinic acid (L1), bis(N-glycino-N-methyl)phosphinic acid (L2), bis(N-benzylglycino-N-methyl)phosphinic acid (L3), bis(l-prolino-N-methyl)phosphinic acid (L4) and bis(iminodicarboxymethyl-N-methyl)phosphinic acid (L5) were studied in aqueous solution by pH-potentiometric and electron paramagnetic resonance (EPR) spectroscopic methods. The EPR spectrum packages recorded at various ligand-to-metal concentration ratios and pH's were analyzed (after matrix rank analysis by the method of residual intensities as a complementary method) by the two-dimensional computer simulation method, which simultaneously determines the formation constants and the EPR parameters of the various (micro)species. L1 forms mono and bis complexes in different protonation states; for the other ligands, the mono complexes are always prevalent. For steric reasons, the formation of CuL is shifted to increasingly higher pH regions in the sequence L2, L3 and L4. CuLH was identified for L3, L4 and L5, and also CuLH(2) for L4 and L5. Cu(2)L(2) was found in small amounts for L3 and L4, while it predominates at pH>4 for L5. For L5, Cu(2)L(2)H(2) was also detected. For the ligands that form dimeric metal complexes in equimolar solution or at a ligand excess, Cu(2)L is formed at a metal ion excess. Ligation of the phosphinate O was suggested by indirect proofs in the protonated complexes of L1. For the ligands L2, L3 and L4, the copper(II) coordination in various species in different protonation states is reminiscent of that in the mono and bis complexes of simple amino acids. For the bis(aminomethyl)phosphinates, however, the cis positions of the amino groups in CuL are ensured by the structure of the ligand, and the isomers differ from each other in the (equatorial or axial) position of the second carboxylate group.     

Effect of copper(II) chloride on suppression of racemization in peptide synthesis by the mixed anhydride and related methods.

In segment couplings by the mixed anhydride method using isobutyloxycarbonyl chloride, the use of copper(II) chloride as an additive suppressed racemization completely in the same manner as in the carbodiimide method reported previously. This was confirmed by employing a number of couplings between Z-dipeptides and amino acid esters. The racemization-suppressing effect of other compounds were also evaluated by employing one of these model couplings to be at best only limitedly effective. Copper(II) chloride was effective also in the related method using EEDQ. Thus, in the couplings where a low level of racemization was observed without an additive, the addition of copper(II) chloride eliminated racemization even at ambient temperature where EEDQ is usually used. The effectiveness of copper(II) chloride was confirmed also in the BOP-Cl method. In the presence of HOBt racemization was reduced to a low but still detectable level, while it was suppressed completely by the addition of copper(II) chloride.     

Synergistic Mixtures of Fungitoxic Monochloro and Dichloro-8-Quinolinols against Five Fungi

Fourteen mono- and dichloro-8-quinolinols were tested against five fungi (Aspergillus niger, A. oryzae, Myrothecium verrucaria, Trichoderma viride, and Mucor circinelloides) and compared with the fungitoxicity of 8-quinolinol in Yeast Nitrogen Base containing 1% D-glucose and 0.088% L-asparagine. All of the compounds were more fungitoxic than 8-quinolinol except for the surprising activity of 8-quinolinol against A. oryzae. Mixtures of the MICs of monochloro- and dichloro-8-quinolinols in which the halogens were in different positions of the quinoline ring showed synergism. Comparable mixtures in which one position of each compound was occupied by the same halogen showed additive activity. In a different study we showed that 3,5,6-, 3,5,7-, 4,5,7-, and 5,6,7-trichloro-8-quinolinols were not toxic to M. circinelloides, whereas the combinations of the correspondingly substituted mono- and dichloro-8-quinolinols as well as 3,6-dichloro- and 5,7-dichloro-8-quinolinols were inhibitory. This indicated that a steric factor can be involved in affecting fungitoxicity.     

Thermodynamic and spectroscopic studies of copper (II) complexes with three bis(amide) ligands derived from L-tartaric acid

The interactions of three bis(amide) ligands derived from tartaric acid with copper (II) were investigated in aqueous solution by a combination of potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance (EPR), and mass spectrometry. The formation constants of the complexes were measured and their relative structures were reported. The sites of complexation of these ligands are investigated based mostly on their electronic and EPR spectra and on the comparison with the behaviour of some analog compounds.     

The computed distribution of copper(II) and zinc(II) ions among seventeen amino acids present in human blood plasma

The equilibrium distribution of copper(II) and zinc(II) ions among a mixture of 17 amino acids has been computed from stability-constant and blood-plasma-composition data. At pH7.4, 98% of the copper(II) in the simulated plasma solution is co-ordinated to histidine and cystine, predominantly as the mixed-ligand complexes [Cu.His.Cystine](-) and [Cu.H.His.Cystine]. Approximately half of the zinc(II) is co-ordinated to cysteine and histidine, but appreciable complex-formation occurs with most of the other amino acids. Stability constants are given for copper(II) and zinc(II) amino acid complexes, including some mixed-ligand species, at 37 degrees C and I=0.15m.     

Prooxidant action of xanthurenic acid and quinoline compounds: Role of transition metals in the generation of reactive oxygen species and enhanced formation of 8-hydroxy-2′-deoxyguanosine in DNA†

Xanthurenic acid, a product of tryptophan–NAD pathway, and quinoline compounds produced reactive oxygen species as a complex with iron. Aconitase, the most sensitive enzyme to oxidative stress was inactivated effectively by xanthurenic acid and to a lesser extent by 8-quinolinol in the presence of ferrous sulfate. The inactivation of aconitase was iron-dependent, and was prevented by TEMPOL, a scavenger of reactive oxygen species, suggesting that reduced iron bound to xanthurenic acid or 8-quinolinol can activate oxygen molecule to form superoxide radical. However, kynurenic acid and quinaldic acid without 8-hydroxyl group did not produce reactive oxygen species. Of the quinoline compounds tested, xanthurenic acid and 8-quinolinol with 8-hydroxyl group stimulated the autooxidation of ferrous ion, but kynurenic acid and quinaldic acid did not affect the oxidation of ferrous ion. Hydroxyl group at 8-positions of quinoline compounds was essential for the binding of iron causing the generation of reactive oxygen species. 8-Quinolinol effectively enhanced the ascorbate/copper-mediated formation of 8-hydroxy-2′-deoxyguanosine in DNA, suggesting the quinolinol/copper-dependent stimulation hydroxyl radical formation. Xanthurenic acid and 8-quinolinol as the metal–chelate complexes can show various cytotoxic effects by generating reactive oxygen species through the ferrous or cuprous ion-dependent activation of oxygen molecule. † This paper is dedicated to centennial of the birthday of the late Professor Emeritus Yahito Kotake, a pioneer of the xanthurenic acid research.     

Synthesis and structural analysis of the copper(II) complexes of N2-(2-pyridylmethyl)-2-pyridinecarboxamide

Previous investigations of the potential of metal-organic compounds as inhibitors of human immunodeficiency virus type I protease (HIV-1 PR) showed that the copper(II) complex diaqua [bis(2-pyridylcarbonyl)amido] copper(II) nitrate dihydrate and the complex bis[N2-(2,3,6-trimethoxybenzyl)-4-2-pyridinecarboxamide] copper(II) behaved as inhibitors of HIV-1 PR. In a search for similar readily accessible ligands, we synthesised and studied the structural properties of N2-(2-pyridylmethyl)-2-pyridinecarboxamide (L) copper(II) complexes. Three different crystal structures were obtained. Two were found to contain ligand L simultaneously in a tridentate and bidentate conformation [Cu(L(tri)L(bi))]. The other contained two symmetry-related ligands, coordinated through the pyridine nitrogen and the amide oxygen atoms [Cu(L(bi))(2)]. A search of the Cambridge Structural Database indicated that L(tri) resulting from nitrogen bound amide hydrogen metal substitution is favoured over chelation through the amide oxygen atom. In our case, we calculated that the conformation of L(tri) is 11 kcal/mol more favourable than that of L(bi). ESI-MS experiments showed that the Cu(L(bi))(2) structure could not be observed in solution, while Cu(L(tri)L(bi))-related complexes were indeed present. The lack of protease inhibition of the pyridine carboxamide copper(II) complexes was explained by the fact that the Cu(L(bi)L(tri)) complex could not fit into the HIV-1 active site.     

Characteristics of the mechanism of action of complex copper (II) compounds with alpha-amino acids

There was no direct inhibition of DNA synthesis in ascites hepatoma 22A cells after intraperitoneal injection of single doses of copper (II) complexes with amino acids into tumor-bearing C3HA mice. Meanwhile cis-dichlorodiamine platinum (II) (DDP) as well as sarcolysine showed such inhibition. Copper (II) complexes with alpha-amino acids displayed as significant superoxide dismutase-like activity at concentrations corresponding to therapeutic doses of these compounds. The complexes of copper (II) combined with DDP give an additive antitumor effect in solid tumors of mice.     

Using Lewis acidity differences in chelating ligands to control molecular structure and supramolecular assembly of Cu(II) complexes

The electronic effects of the fluorine atoms in hfacac (hexafluoroacetylacetonato) compared with acac (acetylacetonato) in Cu(II) complexes are used to control the molecular and supramolecular structure of Cu(II) compounds. While bis(acac)Cu(II) (acac = acetylacetonato) is known to be able to have a fifth-position coordination, bis(hfacac)Cu(II), (hfacac = hexafluoroacetylacetonato) may have two extra ligands. This, together with the reliable “supramolecular reagent” isonicotinamide, as the additional ligand, are used to go from a zero-dimension structure, with Cu-acac, to an extended supramolecular two-dimension network, with Cu-hfacac. The molecular and crystal structure of bis(acetylacetonato-O,O′)-(isonicotinamide-N) copper(II), 1, and bis(hexafluoroacetylacetonato-O,O′)-trans-bis(isonicotinamide-N) copper(II), 2, are reported.