Trihydroxamic Acids Research Articles

Deferoxamine-Modified Hybrid Materials for Direct Chelation of Fe(III) Ions from Aqueous Solutions and Indication of the Competitiveness of In Vitro Complexing toward a Biological System.

Deferoxamine (DFO) is one of the most potent iron ion complexing agent belonging to a class of trihydroxamic acids. The extremely high stability constant of the DFO–Fe complex (log β = 30.6) prompts the use of deferoxamine as a targeted receptor for scavenging Fe(III) ions. The following study aimed at deferoxamine immobilization on three different supports: poly(methyl vinyl ether-alt-maleic anhydride), silica particles, and magnetite nanoparticles, leading to a class of hybrid materials exhibiting effectiveness in ferric ion adsorption. The formed deferoxamine-loaded hybrid materials were characterized with several analytical techniques. Their adsorptive properties toward Fe(III) ions in aqueous samples, including pH-dependence, isothermal, kinetic, and thermodynamic experiments, were investigated. The materials were described with high values of maximal adsorption capacity qm, which varied between 87.41 and 140.65 mg g–1, indicating the high adsorptive potential of the DFO-functionalized materials. The adsorption processes were also described as intense, endothermic, and spontaneous. Moreover, an exemplary magnetically active deferoxamine-modified material has been proven for competitive in vitro binding of ferric ions from the biological complex protoporphyrin IX–Fe(III), which may lead to a further examination of the materials’ biological or medical applicability.

Lanthanide(III) complexes of some natural siderophores: A thermodynamic, kinetic and relaxometric study

Stability constants of the complexes formed between the natural trihydroxamic acids desferrioxamine B (DFB) and desferricoprogen (DFC) with NdIII, GdIII and YbIII ions were determined using pH-potentiometry. The equilibrium in these systems can be described by models containing mononuclear protonated (Ln(HL), Ln(H2L) and Ln(H3L)), deprotonated (LnL) and ternary hydroxo Ln(H−1L) complexes, but for both ligands dinuclear complexes of low stability were also detected. The stability constants for the Ln(HDFB)+ complexes are 11.95 (NdIII), 13.16 (GdIII) and 14.67 (YbIII), while these values of the Ln(DFC) complexes are considerably higher (14.42 (NdIII), 15.14 (GdIII) and 16.49 (YbIII)). The stability constants of the complexes of DFB and DFC are much lower than those of the Ln(L)3 complexes formed with some aromatic hydroxamic acids indicating that the relatively long spacer between the hydroxamic acid moieties in DFB and DFC is unfavorable for LnIII complexation. The relaxometric study conducted for the Gd(HDFB)+ species revealed an interesting pH dependence of the relaxivity associated with a large hydration number (bishydrated complex) and fast water exchange (kex=(29.9±0.4)×106s−1), which would be favorable for CA use. However the dissociation of Gd(HDFB)+ is fairly fast (<2ms) under all conditions employed in the present work thus the kinetically labile Gd(HDFB)+ is not suitable for in vivo CA applications. Some low stability ternary complexes were also detected with K(Gd(HDFB)(HCO3))=17.5±1.9 and K(Gd(HDFB)(Lactate))=8.4±3.2 but in the presence of citrate and phosphate ions the Gd(HDFB)+ complex was found to dissociate.

Characterization of Mn(II) and Mn(III) binding capability of natural siderophores desferrioxamine B and desferricoprogen as well as model hydroxamic acids

Complexes formed between Mn(II) ion and acetohydroxamic acid (HAha), benzohydroxamic acid (HBha), N-methyl-acetohydroxamic acid (HMeAha), DFB model dihydroxamic acids (H2(3,4-DIHA), H2(3,3-DIHA), H2(2,5-DIHA), H2(2,5-H,H-DIHA), H2(2,4-DIHA), H2(2,3-DIHA)) and two trihydroxamate based natural siderophores, desferrioxamine B (H4DFB) and desferricoprogen (H3DFC) have been investigated under anaerobic condition (and some of them also under aerobic condition). The pH-potentiometric results showed the formation of well-defined complexes with moderate stability. Monohydroxamic acids not, but all of the dihydroxamic acids and trihydroxamic acids were able to hinder the hydrolysis of the metal ion up to pH ca. 11. Maximum three hydroxamates were found to coordinate to the Mn(II) ion, but presence of water molecule in the inner-sphere was also indicated by the corresponding relaxivity values even in the tris-chelated complexes. Moreover, prototropic exchange processes were found to increase the relaxation rate of the solvent water proton over the value of [Mnaqua]2+ in the protonated Mn(II)–siderophore complexes at physiological pH. The much higher stability of Mn(III)–hydroxamate (especially tris-chelated) complexes compared to the corresponding Mn(II)-containing species results in a significantly decreased formal potential compared to the Mn(III)aqua/Mn(II)aqua system. As a result, air oxygen becomes an oxidizing agent for these manganese(II)–hydroxamate complexes above pH 7.5. The oxidation processes, followed by UV–Vis spectrophotometry, were found to be stoichiometric only in the case of the tris-chelated complexes of siderophores, which predominate above pH 9. ESI-MS provided support about the stoichiometry and cyclic-voltammetry was used to determine the stability constants for the tris-chelated complexes, [Mn(HDFB)]+ and [MnDFC].

Electrochemical Behavior of the Fe(III) Complexes of the Cyclic Hydroxamate Siderophores Alcaligin and Desferrioxamine E.

The redox behavior of Fe(III) complexes of the cyclic hydroxamate siderophores alcaligin and desferrioxamine E was investigated by cyclic voltammetry. The limiting, pH independent redox potential (E(1/2) vs NHE) is -446 mV for alcaligin above pH 9 and -477 mV for ferrioxamine E above pH 7.5. At lower pH values, the redox potential for both complexes shifts positive, with a loss of voltammetric reversibility which is interpreted to be the consequence of a secondary dissociation of Fe(II) from the reduced form of the complexes. These observations are of biological importance, since they suggest the possibility of a reductive mechanism in microbial cells which utilize these siderophores to acquire Fe. For comparison purposes, cyclic voltammograms were obtained for Fe(III) complexes with trihydroxamic acids of cyclic (ferrioxamine E) and linear (ferrioxamine B) structures, with dihydroxamic acids of cyclic (alcaligin) and linear (rhodotorulic and sebacic acids) structures, and with monohydroxamic acids (acetohydroxamic and N-methylacetohydroxamic acids) at identical conditions. The observed redox potentials allow us to estimate the overall stability constants for fully coordinated Fe(II) complexes as log beta(II)(Fe(2)alcaligin(3)) = 24.6 and log beta(II)(ferrioxamine E) = 12.1. A linear correlation between E(1/2) and pM was found, and the basis for this relationship is discussed in terms of structural (denticity and cyclic/acyclic) and electronic differences among the {alkyl-NOH-CO-alkyl} type of hydroxamic acid ligands studied.

ChemInform Abstract: Phase‐Transfer‐Catalyzed Preparation of N‐Alkylated Trihydroxamic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Phase-transfer-catalysed Preparation of N-Alkylated Trihydroxamic Acids†

We describe a synthetic route involving phase transfer catalysis leading to a series of tripodal N-alkylated hydroxamic acids as models of desferrioxamine; iron(III) exchange reactions between their iron complexes and EDTA were investigated.

Siderophore-mediated iron (III) transport in the mycelia of the cultivated fungus, Agaricus bisporus

Three structurally diverse iron (III) sequestering compounds (siderophores) were isolated from the supernatants of early stationary phase iron-deficient cultures of vegetative mycelia of the cultivated mushroom, Agaricus bisporus (ATCC 36416). The compounds were purified as their ferric chelates to homogeneity by gel permeation, cation exchange, and low-pressure reversed phase C 18 chromatographies, and characterized as trihydroxamic acids. The chelates were identified as ferrichrome, ferric fusarinine C, and an unusual compound, des (diserylglycyl) ferrirhodin (DDF) by HPTLC cochromatography and electrophoresis against authentic samples, hydrolysis and amino acid analysis, and FAB-MS and 1H NMR spectroscopy. The iron transport activities of the three compounds (and of some structurally similar exogenous compounds) in young mycelial cells were determined by time- and concentration-dependent kinetic assays and inhibition experiments (CN −, N 3 −) using 55Fe 3+-labeled chelates. 55Iron (III) uptake mediated by all three compounds was found to be via high affinity, energy-dependent processes; transport effectiveness was in the order: ferrichrome > DDF ⪢ ferric fusarinine C. The relative uptake of iron by Λ- cis ferrichromes was: ferrichrome > ferrirhodin ⪢ ferrichrome A; transport activity by the Δ- cis fusarinines was: ferric fusarinine C > tris cis- (and trans-) fusarinine iron (III) ⪢ ferric N 1-triacetylfusarinine C.

Some correlations involving the stability of complexes of transuranium metal ions and ligands with negatively charged oxygen donors

Established ligand design principles are extended to transuranium elements and were tested out for Pu(IV) complexation by the trihydroxamic acids, desferrioxamine B (DFB) and N,N′,N″-tris[2-( N- hydroxycarbamoyl)ethyl]-1,3,5-benzenetricarboxamide (BAMTPH). Nd(III) was used as a simulant for Am(III) to characterise its complexation with BAMTPH. Log K 1 values for Pu were measured using an optical fibre system coupled to a spectrophotometer and were found to be 30.8±0.1 and 30.0±0.2 for the Pu(IV)-DFB and Pu(IV)-BAMTPH complexes, respectively. The stability constant for the Nd-BAMTPH complex was measured potentiometrically and was found to be 16.7±0.01. These values were plotted onto existing correlations between log K 1(L) versus log K 1(OH −1) and found to fit very well.

N-hydroxy amides. Part 9. Synthesis and lron(III) complexes of tripodal hydroxamic acids derived from ω-(N-hydroxyamino)alkanoic acids and tris(2-aminoethyl)amine

Tripodal oligoamide hydroxamic acids with different chain lengths (compounds 8a–d) are prepared via condensation of N-hydroxysuccinimide esters of N-acyl-N-benzyloxyaminoalkanoic acids with tris-(2-aminoethyl)amine. These synthetic trihydroxamic acids form iron(III) complexes in aqueous DMF solution. The behaviour of these iron(III) complexes is investigated in terms of absorption vs pH and of iron(III) exchange reactions with EDTA. A biological assay performed with Aureobacterium flavescens reveals that the trihydroxamic acids have substantial growth-promoting activity although weak relative to that of natural desferrioxamine B.

ChemInform Abstract: N‐Hydroxy Amides. Part 8. Synthesis and Iron(III)‐Holding Properties of Di‐ and Trihydroxamic Acids Extending from Benzene‐di‐ and ‐tricarbonyl Units Through Oligo(ethyleneoxy) Arms.

AbstractThe title compounds (III) or (IV) ‐ the latter being prepared analogously ‐ form 1:3 complexes with Fe(III) at pH 7 or pH 4 and pH 7, respectively.

N-hydroxy amides. Part 8. Synthesis and iron(III)-holding properties of di- and tri-hydroxamic acids extending from benzene-di- and -tri-carbonyl units through oligo(ethyleneoxy) arms

Benzene-ring centred di- and tri-hydroxamic acids (9a–c and 10a–c) having oligo(ethyleneoxy) chains are prepared by reaction of benzene-di- and -tri-carbonyl chlorides with amino [oligo(ethyleneoxy]ethyl hydroxylamine derivatives (6a–c). Trihydroxamic acids (10a–c) form more stable iron(III) complexes than dihydroxamic acids (9a–c) in several respects. In iron(III) transport experiments using a H2O–CHCl3/CCl4 system, however, compounds (9a–c) show greater rates than compounds (10a–c). The number of ethyleneoxy units in the arm apparently influences these iron(III) holding properties and the iron-transport rates.

Synthesis of linear and cyclic trihydroxamic acids as models for ferrioxamines E and G

Linear and cyclic trihydroxamic acids including the 6-aminohexanoyl-3-(hydroxyamino)propanoyl sequence have been synthesized in a stepwise manner from the appropriately protected acyl derivatives and used as iron(III) chelating compounds.

Reaction of cyanide with hydroxamic acid iron complexes to distinguish trihydroxamates from simple monohydroxamates

At high pH primary hydroxamic acid-iron complexes react rapidly with potassium cyanide to yield a deep blue iron complex. Secondary, or N-substituted, monohydroxamic acid-iron complexes also react with loss of the red color typical of these complexes but with no formation of the blue product. Under the same conditions, trihydroxamates do not react at a significant rate. The blue complex is similar in many respects to the previously described Fe(CN) 5NO 3− but is noteworthy in its stability to oxidation and extremely high pH. Lack of formation of the blue complex with secondary hydroxamates is attributed to the absence of inorganic hydroxylamine so that the nitrosyl group cannot be formed. Lack of reactivity of siderophore trihydroxamates is due to the much greater stability of their iron complexes. The reaction is a simple, convenient method of distinguishing primary, secondary, and siderophore trihydroxamic acids.

A convenient assay for siderochrome hydrolytic enzymes

Conditions are described under which ethylenediaminetetraacetate (EDTA) rapidly dissociates ferric ion from chelation with monohydroxamic acids and dihydroxamic acids, but under which the metal is not dissociated from natural trihydroxamic acids (siderochromes). Based upon this observation, enzymes which hydrolyze siderochromes to monohydroxamic acid subunits can be conveniently assayed spectrophotometrically. The characteristic absorption at 425–440 nm of the siderochrome decreases linearly during hydrolysis. The application of this assay to an enzyme isolated from an unidentified species of penicillium is described.

Hydroxamatkomplexe II. Die Anwendung der pH‐Methode

AbstractThe equilibria between acethydroxamic acid and 16 metal cations, and their complexes have been elucidated. For the results see table 1. The complex Formation of desferri‐ferrioxamine B and desferri‐ferrioxamin E, which are trihydroxamic acids, with various bivalent and trivalent metal ions have been studied in a similar manner. For the results see tables 2 and 3.