pFe Values Research Articles

Study of Iron Piperazine-Based Chelators as Potential Siderophore Mimetics.

Gram-negative bacteria’s resistance such as Pseudomonas aeruginosa and the Burkholderia group to conventional antibiotics leads to therapeutic failure. Use of siderophores as Trojan horses to internalize antibacterial agents or toxic metals within bacteria is a promising strategy to overcome resistance phenomenon. To combat the Pseudomonas sp, we have synthesized and studied two piperazine-based siderophore mimetics carrying either catecholate moieties (1) or hydroxypyridinone groups (2) as iron chelators. These siderophore-like molecules were prepared in no more than four steps with good global yields. The physicochemical study has highlighted a strong iron affinity since their pFe values were higher than 20. 1 possesses even a pFe value superior than those of pyoverdine, the P. aeruginosa endogenous siderophore, suggesting its potential ability to compete with it. At physiological pH, 1 forms mainly a 2:3 complex with iron, whereas two species are observed for 2. Unfortunately, the corresponding Ga(III)-1 and 2 complexes showed no antibacterial activity against P. aeruginosa DSM 1117 strain. The evaluation of their siderophore-like activity showed that 1 and 2 could be internalized by the bacteria.

Comparative solution studies and cytotoxicity of gallium(III) and iron(III) complexes of 3-hydroxy-2(1H)-pyridinones

The stoichiometry and stability constants of the gallium(III) and iron(III) complexes of two alkoxycarbonylmethyl-3-hydroxy-2(1H)-pyridinone ligands were determined by means of pH-potentiometry, UV–Vis spectrophotometry and 1H and 71Ga NMR spectroscopy in aqueous solution. The cytotoxicity of one of the gallium(III) complexes was also measured in multidrug resistant/non-resistant human colon adenocarcinoma cell lines. Iron(III) forms complexes with the studied 3-hydroxy-2-pyridinones of higher stability than gallium(III), while the obtained pFe values are significantly lower (pFe: 14.95, 15.06; pH 7.4, cM = 1 µM, cL = 10 µM) compared to those of typical iron binders such as deferiprone or transferrin. The moderate gallium(III) and iron(III) binding ability of the compounds stands for lower solution complex stability compared to that of analogous bidentate non-substituted 3-hydroxy-2-pyridinone or 3-hydroxy-4-pyridinone (O,O) donor ligands. Tris-ligand complexes of the general formula [ML3] (M = Ga, Fe) predominate at physiological pH for both ligands. No interaction with cell culture medium components was observed in the millimolar concentration range of gallium(III) complexes, however they can suffer significant decomposition at biologically relevant low concentrations leading to negligible cytotoxic activity. The redox potential of the studied iron–3-hydroxy-2-pyridinone complex (E1/2 = −597 mV at pH 7.4) falls into the range that is typical of iron(III) complexes with conventional bidentate (O,O) donor-containing chelators.

A New Soil Testing Programme for the Evaluation of Intensity and Quantity Factors of Iron

Deficiency of Fe in rice mainly occurs under upland condition, particularly in alkaline and calcareous soils. The plants respond directly to changes in the activities of ions in the soil solution. Baker soil test (BST) is a new approach to soil testing which not simply determine the concentrate bioavailability but also provides the activity of an ion. A greenhouse experiment was conducted with special reference to iron for relating the data with content of efficient and inefficient cultivars of aerobically grown rice for iron availability. Alkaline, calcareous, acid and lime-treated soils could be rated as normal in respect of labile Fe status. Intensity parameter of Fe (pFe) for alkaline and calcareous was rated to be low, while it was normal for other two soils. Comparison of pFe values of Fe(III) in different soils with plant Fe content reveals the positive impact of intensity parameter of Fe(III) in soil is reflected well in plant Fe content data in both the rice cultivars. Similar were the relationships of intensity parameter of Fe with grain and straw yield of rice. BST, particularly intensity parameter of Fe, can be a good index of availability of Fe in soils.

Synthesis and biological evaluation of deferiprone-resveratrol hybrids as antioxidants, Aβ1–42 aggregation inhibitors and metal-chelating agents for Alzheimer's disease

A series of deferiprone-resveratrol hybrids have been designed and synthesized as multitarget-directed ligands (MTDLs) through merging the chelating moiety 3-hydroxypyridin-4-one into the structure of resveratrol, a natural antioxidant agent and β-amyloid peptide (Aβ) aggregation inhibitor. The in vitro biological evaluation revealed that most of these newly synthesized compounds exhibited good inhibitory activity against self-induced Aβ1–42 aggregation, excellent antioxidant activity and potent metal chelating capability. Compounds 3i and 4f were identified as the most promising MTDLs with triple functions, possessing micromolar IC50 values for Aβ1–42 aggregation inhibition, greater 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS•+) scavenging activity than Trolox and similar pFe(III) values to that of deferiprone.

Hexadentate 3-hydroxypyridin-4-ones with high iron(III) affinity: Design, synthesis and inhibition on methicillin resistant Staphylococcus aureus and Pseudomonas strains

A range of hexadentate 3-hydroxypyridin-4-ones have been synthesized. These compounds were found to possess a high affinity for iron(III), with logK1 values of about 34 and pFe values over 30. Antimicrobial assays indicated that they can inhibit the growth of three clinical isolates of methicillin resistant Staphylococcus aureus (MRSA) and three clinical isolates of Pseudomonas, suggesting that hexadentate 3-hydroxypyridin-4-ones have potential application in the treatment of wound infections.

Design, synthesis, and antimicrobial evaluation of hexadentate hydroxypyridinones with high iron(III) affinity.

A range of hexadentate 3-hydroxypyridin-4-ones (HPOs) with high affinity for iron(III) has been synthesized. The log stability constants of two HPO-iron complexes (logK1 ) were determined to be over 34, and pFe values of the two HPOs were determined to be over 31. Antimicrobial assay indicated that they are able to markedly inhibit the growth of both Gram-positive and Gram-negative bacteria. Compounds 14a and 14e were found to exhibit the strongest inhibitory activity against Staphyloccocus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, with MIC values of 8, 8, 16, and 8 μg/mL, respectively. These results indicate that hexadentate 3-hydroxypyridin-4-ones have potential application as antimicrobial agents, especially in the treatment of wound infection.

IronIII and aluminiumIII complexes with substituted salicyl-aldehydes and salicylic acids

The chelating properties toward ironIII and aluminiumIII of variously substituted salicyl-aldehydes and salicylic acids have been evaluated, together with the effect of methoxy and nitro substituents in ortho and para position with respect to the phenolic group. The protonation and iron and aluminium complex formation equilibria have been studied by potentiometry, UV–visible spectrophotometry and 1H NMR spectroscopy. The overall results highlight that salicyl-aldehydes present good chelating properties toward ironIII, with pFe ranging from 14.2 with nitro to 15.7 with methoxy substituent, being ineffective toward aluminium; the pFe values for salicylic acids are generally lower than those for salicyl-aldehydes, and about 4 units higher than the corresponding pAl values. The effect of the two substituents on the chelating properties of the ligands can be rationalized in terms of the Swain–Lupton treatment which accounts for the field and resonance effects. The structural characterization of the 1:2 iron complex with p-nitro salicylic acid shows that ironIII ion exhibits an octahedral surrounding where two salicylate chelating ligands supply two O-phenolate and two O-carboxylate donor atoms in a roughly equatorial plane. The trans-apical sites are occupied by two aqua ligands.

A novel fluorescence method for determination of pFe3+

The fluorescence intensity of probe CP645 in the presence of iron and a competing ligand is associated with pFe(3+) of the competing ligand. A linear correlation was found to exist between the fluorescence and pFe(3+) values. The pFe(3+) values of well studied ligands calculated from the standard curve are consistent with reported values. This novel fluorescence method can be used to determine the pFe(3+) values of ligands which are difficult to measure using conventional spectrophotometric or potentiometric methods.

Oxinobactin and Sulfoxinobactin, Abiotic Siderophore Analogues to Enterobactin Involving 8-Hydroxyquinoline Subunits: Thermodynamic and Structural Studies

The synthesis of two new iron chelators built on the tris-l-serine trilactone scaffold of enterobactin and bearing a 8-hydroxyquinoline (oxinobactin) or 8-hydroxyquinoline-5-sulfonate (sulfoxinobactin) unit has been described. The X-ray structure of the ferric oxinobactin has been determined, exhibiting a slightly distorted octahedral environment for Fe(III) and a Δ configuration. The Fe(III) chelating properties have been examined by potentiometric and spectrophotometric titrations in methanol-water 80/20% w/w solvent for oxinobactin and in water for sulfoxinobactin. They reveal the extraordinarily complexing ability (pFe(III) values) of oxinobactin over the p[H] range 2-9, the pFe value at p[H] 7.4 being 32.8. This was supported by spectrophotometric competition showing that oxinobactin removes Fe(III) from ferric enterobactin at p[H] 7.4. In contrast, the Fe(III) affinity of sulfoxinobactin was largely lower as compared to oxinobactin but similar to that of the ligand O-TRENSOX having a TREN backbone. These results are discussed in relation to the predisposition by the trilactone scaffold of the chelating units. Some comparisons are also made with other quinoline-based ligands and hydroxypyridinonate ligand (hopobactin).

Glycosiderophores: Synthesis of tris-hydroxamate siderophores based on a galactose or glycero central scaffold, Fe(III) complexation studies

A series of five new hexadentate tris-hydroxamate ligands based on a d-galactose or a glycerol scaffold have been synthesized. Protonation and ferric complex formation constants have been determined from solution studies by potentiometric and spectrophotometric titrations. All ligands form 1:1 Fe:L complexes. The calculated pFe values at pH 7.4 span over the range 19.2–23.0 depending on the scaffold and on the length of the spacers between hydroxamate and central scaffold and on the N-methyl substitution. This new kind of artificial siderophores based on a glycoscaffold is of interest as it opens up an easy way to modulate the pFe.

Synthesis and Iron Sequestration Equilibria of Novel Exocyclic 3-Hydroxy-2-pyridinone Donor Group Siderophore Mimics

The synthesis of a novel class of exocyclic bis- and tris-3,2-hydroxypyridinone (HOPO) chelators built on N(2) and N(3) aza-macrocyclic scaffolds and the thermodynamic solution characterization of their complexes with Fe(III) are described. The chelators for this study were prepared by reaction of either piperazine or N,N',N''-1,4,7-triazacyclononane with a novel electrophilic HOPO iminium salt in good yields. Subsequent removal of the benzyl protecting groups using HBr/acetic acid gave bis-HOPO chelators N(2)(etLH)(2) and N(2)(prLH)(2), and tris-HOPO chelator N(3)(etLH)(3) in excellent yields. Solution thermodynamic characterization of their complexes with Fe(III) was accomplished using spectrophotometric, potentiometric, and electrospray ionization-mass spectrometry (ESI-MS) methods. The pK(a)'s of N(2)(etLH)(2), N(2)(prLH)(2), and N(3)(etLH)(3), were determined spectrophotometrically and potentiometrically. The Fe(III) complex stability constants for the tetradentate N(2)(etLH)(2) and N(2)(prLH)(2), and hexadentate N(3)(etLH)(3), were measured by spectrophotometric and potentiometric titration, and by competition with ethylenediaminetetraacetic acid (EDTA). N(3)(etLH)(3) forms a 1:1 complex with Fe(III) with log β(110) = 27.34 ± 0.04. N(2)(prLH)(2) forms a 3:2 L:Fe complex with Fe(III) where log β(230) = 60.46 ± 0.04 and log β(110) = 20.39 ± 0.02. While N(2)(etLH)(2) also forms a 3:2 L:Fe complex with Fe(III), solubility problems precluded determining log β(230); log β(110) was found to be 20.45 ± 0.04. The pFe values of 26.5 for N(3)(etLH)(3) and 24.78 for N(2)(prLH)(2) are comparable to other siderophore molecules used in the treatment of iron overload, suggesting that these hydroxypyridinone ligands may be useful in the development of new chelation therapy agents.

Amido‐3‐hydroxypyridin‐4‐ones as Iron(III) Ligands

The synthesis and physicochemical properties of a range of 2- and 6-amido-3-hydroxypyridin-4-ones are described. All the amido-substituted 3-hydroxypyridin-4-ones have lower pK(a) values than 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone). This is due to the inductive effect of the amido group. Furthermore, the pK(a) values of the 3-hydroxy group in 1-nonsubstituted pyridinones are dramatically lower than those of the corresponding 1-alkyl analogues, indicating that a strong hydrogen bond exists between the 2-amido function and the 3-oxygen anion, which stabilises the anion. As a result of the decreased competition with protons, the pFe(3+) values of this group of molecules are higher than that of deferiprone. The distribution coefficients of these molecules are also increased despite the lack of a hydrophobic 1-alkyl substituent and this is ascribed to the intramolecular hydrogen bond. X-ray diffraction studies confirm the existence of the intramolecular hydrogen bond.

Comparação de valores de PFE em uma amostra da população da cidade de São Carlos, São Paulo, com valores de referência

To compare the reference values for PEF suggested by other authors in 1963, 1989 and 2001 (for populations in the USA, England and Cuba, respectively) with those obtained from a population sample in the city of São Carlos, Brazil, and to determine whether there is concordance among them. A total of 243 volunteers (123 females and 120 males; 20-70 years of age) participated in the study. The PEF measurements were performed with the volunteer standing, using a nose clip, by means of a portable peak flow meter. These measurements were compared with the reference values using the Friedman test and Dunn's post-hoc test (p < 0.05). Significant differences were found in all age groups from both genders regarding the values predicted in 1989; the same occurred in the 20-30 and 31-40 age groups (both genders), as well as in the 61-70 age group (females only), regarding those predicted in 2001, as well as in the 20-30 age group (males only) regarding those predicted in 1963. The values predicted in 1963 are appropriate for a population of individuals with the same characteristics as the study sample, except for males in the 20-30 age group. Our study is relevant due to the fact that our sample was larger than that evaluated in the 1963 study. The majority of the values predicted in 1989 and 2001 overestimated the PFE values obtained in our study, proving to be inappropriate for the population studied.

Potentiometric, spectrophotometric and calorimetric study on iron(III) and copper(II) complexes with 1,2-dimethyl-3-hydroxy-4-pyridinone

The iron(III)–1,2-dimethyl-3-hydroxy-4-pyridinone (Deferiprone) system is carefully characterized by a combined potentiometric–spectrophotometric procedure at 25 and 37°C at different ionic strengths, and by thermochemical and quantum-chemical studies. The main purpose of this work was to determine how the temperature dependence of both complex-formation and protonation constants can affect the pFe values on going from 25°C (pFe is normally calculated using 25°C stability constants) to the physiological temperature of 37°C at which chelating agents are active in vivo. The copper(II)–Deferiprone system is also studied and the iron(III)–Deferiprone distribution diagrams in presence of variable copper(II) amounts are shown so as to explain possible side effects due to a competing metal ion during the chelating therapy of iron overload.

Design of Iron chelators: Syntheses and iron (III) complexing abilities of tripodal tris-bidentate ligands

The interest in synthetic siderophore mimics includes therapeutic applications (iron chelation therapy), the design of more effective agents to deliver Fe to plants and the development of new chemical tools in order to study iron metabolism and iron assimilation processes in living systems. The design of ligands needs a rational approach for the understanding of the metal ion complexing abilities. The octahedral arrangement of donor atoms is the most favourable geometry, allowing the maximum possible distance between their formal or partial negative charges. Hexadentate chelators, usually of the tris-bidentate type, can accommodate the metal coordination sphere and are well-suited to obtain high pFe values. The first part of this review is dedicated to selected synthetic routes, taking into account (i) the nature of the chelating subunits, connecting groups and spacers, (ii) the water-solubility and hydrophilic/lipophilic balance, (iii) the chirality and (iv) the possibility of grafting probes or vectors. In the second part, we discuss the role of the molecular design on complexing abilities (thermodynamics and kinetics). The bidentate 8-hydroxyquinoline moiety offers an alternative to the usual coordinating hydroxamic acids, catechols and/or alpha-hydroxycarboxylic acids groups encountered in natural siderophores. The promizing results obtained with the tris-hydroxyquinoline-based ligand O-TRENSOX are summarized. O-TRENSOX exhibits a high and selective affinity for Fe(III) complexation. Its efficiency in delivering Fe to plants, iron mobilization, cell protection, and antiproliferative effects has been evidenced. Other chelators derived from O-TRENSOX (mixed catechol/8-hydroxyquinoline ligands, lipophilic ligands) are also described. Some results question the relevance of partition coefficients to foresee the activity of iron chelators. The development of probes (fluorescent, radioactive, spin labelled) based on the O-TRENSOX backbone is in progress in order to get insights in the complicated iron metabolism processes.

Speciation Studies of Iron (III) with (Poly)phosphonate Ligands: The Case of EDTMP (EthylenediamineTetramethylene Phosphonic Acid)

The complex formation equilibrium of ethylenediaminetetramethylenephosphonic acid (EDTMP, H8L) with iron (III) has been studied potentiometrically at 25°C and an ionic strength of 0.2 M (NaCl). The successive protonation constants of ligand EDTMP and the complex formation constants were determined with the PSEQUAD program. Keeping in view the biological studies, the speciation in the system Fe (III)—EDTMP was calculated and drawn with the HySS computer program, and pFe values are compared.

Avaliação da função respiratória em indivíduos submetidos à abdominoplastia

OBJETIVO: Avaliar a função respiratória em indivíduos submetidos à abdominoplastia, através de parâmetros espirométricos. MÉTODO: Estudo prospectivo de 33 mulheres hígidas e não tabagistas, submetidas à abdominoplastia, e com resultados normais para as radiografias de tórax realizadas antes e quatro dias após a operação. Foram realizadas provas espirométricas no pré-operatório, no quarto, 15o e no 30o dias de pós-operatório. RESULTADOS: Provas espirométricas evidenciaram que, exceto pela relação VFE1/CVF e FEF 25-75%/CVF, todos os demais parâmetros avaliados (CVF, VEF1, FEF 25-75% e PFE) se apresentaram significativamente diminuídos no 4o PO em relação aos valores pré-operatórios. Os valores de CVF e PFE se mostraram normalizados à avaliação realizada no 30o PO. Já os valores de VEF1 ainda se revelaram significativamente inferiores aos valores pré-operatórios mesmo na última avaliação. CONCLUSÕES: Ocorreu diminuição da função respiratória no 4º dia de pós-operatório com normalização até o 30º dia de pós-operatório.

Synthesis and Antiviral Evaluation of Cyclic and Acyclic 2-Methyl-3-hydroxy-4-pyridinone Nucleoside Derivatives

A series of cyclic and acyclic nucleoside analogues derived from 3-hydroxy-4-pyridinone were synthesized using the Vorbrüggen reaction. Iron chelation studies, and antiviral evaluation against a broad panel of viruses, were performed. The pK(a) value of ligand 25 and the stability constant of the corresponding iron(III) complex were compared to those of deferiprone. The pFe(3+) values were found to be similar. Some compounds showed moderate activity against both wild-type HSV-1 and HSV-2, as well as against a thymidine kinase deficient strain of HSV-1. These results suggest a novel mode of action for this group of nucleoside analogues.

Complex Formation of ICL670 and Related Ligands with FeIII and FeII

AbstractThe pFe values of the two ligands H3Lx and H3Ly in section 2.3 on page 4183 of the original article[1] are incorrect; the corresponding sentence with the correct values should read as follows: In general, the iron binding properties of H3Lx and H3Ly are indeed closely related: the pFe values[30] for H3Lx and H3Ly (total [L] = 10 μM, total [Fe] = 1 μM, pH = 7.4, H2O, I = 0.1 M) are 23.5 and 22.6, respectively.

Effect of the tether on the Mg(ii), Ca(ii), Cu(ii) and Fe(iii) stability constants and pM values of chelating agents related to EDDHA

The effect of the length and the structure of the tether on the chelating ability of EDDHA-like chelates have not been established. In this work, PDDHA (propylenediamine-N,N'-bis(o-hydroxyphenyl)acetic acid), BDDHA (butylenediamine-N,N'-bis(o-hydroxyphenyl)acetic acid) and XDDHA (p-xylylenediamine-N,N'-bis(o-hydroxyphenyl)acetic acid) have been obtained and their chemical behaviour has been studied and compared with that of EDDHA following our methodology. The purity of the chelating agents, and their protonation, Ca(II), Mg(II), Fe(III) and Cu(II) stability constants and pM values have been determined. The stability constants and pM values indicate that EDDHA forms the most stable chelates followed by PDDHA. However, the differences among the pFe values are small when a nutrient solution is used, and in these conditions the XDDHA/Fe(III) chelate is the most stable. The results obtained in this work indicate that all the chelating agents studied can be used as iron chlorosis correctors and they can be applied to soil/plant systems.