Aminohydroxamic Acids Research Articles

An application of triflic anhydride as an acid activator: Synthesis of Nα-protected amino hydroxamic acids

An application of triflic anhydride as an acid activator: Synthesis of Nα-protected amino hydroxamic acids

Water-Soluble Bismuth(III) Polynuclear Tyrosinehydroximate Metallamacrocyclic Complex: Structural Parallels to Lanthanide Metallacrowns.

Recently there has been a great deal of interest and associated research into aspects of the coordination chemistry of lanthanides and bismuth—elements that show intriguing common features. This work focuses on the synthesis and characterization of a novel bismuth(III) polynuclear metallamacrocyclic complex derived from aminohydroxamic acid, in order to compare the coordination ability of Bi3+ with the similarly sized La3+ ions. A polynuclear tyrosinehydroximate Bi(OH)[15-MCCu(II)Tyrha-5](NO3)2 (1) was obtained according to the synthetic routes previously described for water-soluble Ln(III)-Cu(II) 15-MC-5 metallacrowns. Correlations between structural parameters of Bi(III) and Ln(III) complexes were analyzed. DFT calculations confirmed the similarity between molecular structures of the model bismuth(III) and lanthanum(III) tyrosinehydroximate 15-metallacrowns-5. Analysis of the electronic structures revealed, however, stronger donor-acceptor interactions between the central ion and the metallamacrocycle in the case of the lanthanum analogue. Thermochromic properties of 1 were studied.

The synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing versatile chlorinating agent CPI-Cl

The synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing versatile chlorinating agent CPI-Cl

Copper(II) Complexes Based on Aminohydroxamic Acids: Synthesis, Structures, In Vitro Cytotoxicities and DNA/BSA Interactions

Four complexes, [Cu2(glyha)(bpy)2(H2O)]·2ClO4·H2O (1), [Cu2(glyha)(phen)2]·2ClO4 (2), [Cu2(alaha)(bpy)2Cl]·Cl·4H2O (3), and [{Cu2(alaha)(phen)2}{Cu2(alaha)(phen)2(NO3)}]·3NO3 (4) (glyha2− = dianion glycinehydroxamic acid, alaha2− = dianion alaninehydroxamic acid, bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline) have been successfully synthesized and characterized by X-ray single crystal diffraction. The interactions of these complexes with calf thymus DNA (CT-DNA) were studied through UV spectroscopy, fluorescence spectroscopy, and circular dichroism. The results revealed that complexes 1–4 could interact with CT-DNA through intercalation. Interactions of all complexes with bovine serum albumin (BSA) were confirmed by the docking study to quench the intrinsic fluorescence of BSA in a static quenching process. Furthermore, the in vitro cytotoxic effect of the complexes was also examined on four tumor cell lines, including human lung carcinoma cell line (A549), human colon carcinoma cell line (HCT-116), human promyelocytic leukemia cell (HL-60) and cervical cancer cell line (HeLa). All complexes exhibited different antitumor activities.

Water-Soluble Polynuclear Metallamacrocyclic Copper(II) and Lanthanide(III) Complexes Based on Amino Hydroxamic Acids

Data on the synthesis and structure of water-soluble polynuclear copper(II) and lanthanide(III) metallamacrocycles based on amino hydroxamic acids are presented. The structural features of the obtained 15-MC-5 metallacrown aqua complexes and their applicability as NMR contrast agents are considered. Additionally, the applicability as molecular precursors for the synthesis of nano-sized materials was demonstrated for Ce(III) compounds.

Synthesis of Pyrrolo[1,2-a]pyrimidine Enantiomers via Domino Ring-Closure followed by Retro Diels-Alder Protocol

From 2-aminonorbornene hydroxamic acids, a simple and efficient method for the preparation of pyrrolo[1,2-a]pyrimidine enantiomers is reported. The synthesis is based on domino ring-closure followed by microwave-induced retro Diels-Alder (RDA) protocols, where the chirality of the desired products is transferred from norbornene derivatives. The stereochemistry of the synthesized compounds was proven by X-ray crystallography. The absolute configuration of the product is determined by the configuration of the starting amino hydroxamic acid.

ChemInform Abstract: Review: Solution Equilibria of Ternary Complexes Formed from Copper(II), Aliphatic Amines, and Bioligands

AbstractReview: 155 refs.

The mass spectrometric study on aminohydroxamic acids-based metallacrowns.

Electrospray ionization mass spectrometry (MS) has been widely used to detect noncovalent interactions in supramolecular compounds, especially in biological systems. In our work, we present the application of the electrospray ionization MS technique to characterize the metallamacrocycles, known as metallacrowns. This project involves investigations of the aminohydroxamic acids structure and chirality influence on formation of ternary 12-metallacrown-4 complexes. For our experiments, we used a series of β-aminohydroxamic acids and derivatives of histidinehydroxamic acid. A high stability of the studied supramolecular systems in the gas phase was confirmed by MS/MS experiments. We also proposed the fragmentation pathways for the studied compounds. Obtained results reveal that the ternary 12-metallacrown-4 formation process is not selective, and ligands of various structures and chiralities can be incorporated into these systems.

Stoichiometric diversity of Ni(ii) metallacrowns with β-alaninehydroxamic acid in aqueous solution

The complex-formation equilibria of the system Ni(II)/β-alaninehydroxamic acid (β-AlaHA, LH) have been studied in solution by using potentiometry, calorimetry, ESI mass spectrometry and UV-Visible spectrophotometry. A series of mononuclear and polynuclear species have been identified at different pH and for different Ni(II)/ligand ratios. Among the polymetallic species, we have identified the 12-metallacrown-4 (12-MC-4) species [Ni5(LH(-1))4](2+), which is analogous to the previously characterized [Cu5(LH(-1))4](2+) 12-MC-4 complex, and which corresponds to the metallacrown complex predicted by the Metallacrown Structural Paradigm. Besides this species, we have very unexpectedly identified in solution three other polynuclear species, corresponding to the stoichiometries [Ni4(LH(-1))4], [Ni5(LH(-1))5] and [Ni6(LH(-1))6]. A metallacrown with the same stoichiometry as [Ni5(LH(-1))5] containing α-AlaHA as the ligand has been previously reported, while the other two species are new for the speciation systems of Cu(II) or Ni(II) aminohydroxamic acids. Intriguingly, all the three latter stoichiometries correspond to those of vacant 12-MC-4, 15-MC-5 or 18-MC-6 species. The thermodynamic parameters related to their formation in solution are discussed, together with the speciation of the mononuclear complexes, on the basis of the structural and thermodynamic information available on metallacrowns.

Metallacrowns of Ni(ii) with α-aminohydroxamic acids in aqueous solution: beyond a 12-MC-4, an unexpected (vacant?) 15-MC-5

Growing attention has been devoted in the recent years to a class of metallamacrocycles known as metallacrowns (MCs). They are structural analogues of crown ethers where the methylene bridges have been substituted by coordinative bonds formed by a transition metal ion ("ring" metal) and a nitrogen atom. The cavity of the metallacrown can accommodate an additional metal ion ("core" metal) either identical or different from the ring metal, thus forming a homo- or hetero-metallic MC. The most studied ring metal ion is certainly Cu(2+) and the aminohydroxamic acids have proved to be very suitable ligands to form MCs. The behavioural analogies between Cu(2+) and Ni(2+) in forming complexes, along with recent literature data in the solid state, prompted us to investigate the possible MC formation between Ni(2+) and both (S)-α-alaninehydroxamic acid and (S)-valinehydroxamic acid, in aqueous solution. Two metallacrowns, a 12-MC-4 and an unexpected 15-MC-5 have been detected by potentiometry and confirmed by ESI-MS results. Their structures are discussed on the basis of potentiometric, calorimetric, spectroscopic data and DFT calculations. The existence of a vacant 15-MC-5 species in solution can be put forward for the first time, making the present metal/ligand systems very interesting for their potential applications in cation recognition and separation. Finally, the crystal structure of the binary complex K[NiL(2)H(-1)]·5/3 H(2)O of (S)-α-alaninehydroxamic acid (LH) is also reported.

ChemInform Abstract: Hydroxamic and Aminohydroxamic Acids and Their Complexes with Metal Ions

ChemInform Abstract: Hydroxamic and Aminohydroxamic Acids and Their Complexes with Metal Ions

Formation and structure in aqueous solution of complexes between vanadium(V) and aminohydroxamic acids that potentiates vanadium’s insulinomimetic activity: l-glutamic γ-hydroxamic and l-aspartic-β-hydroxamic acids

The full speciation of the vanadium(V) complexation systems with two aminohydroxamic acids, aspartic-β- and glutamic-γ-hydroxamic acid, has been determined using potentiometric and spectroscopic techniques. Formation constants were calculated in a systematic study at different ligand to metal molar ratios and the coordination types are proposed. An almost constant value of the 51V NMR signal in neutral medium can be attributed to two (1:1 and 1:2 metal to ligand ratios) similar structures, both of which can be either protonated or deprotonated. The two ligands have a carboxylic group in the structure and show comparable biological activities. In this work analogous complexation behavior at physiological conditions was found despite the presence of two or three methylenic groups between the amino and hydroxamate groups. The carboxylic groups are quite distant from the hydroxamic groups and are not involved directly in the coordination process. Therefore the coordination structures are related to that found in the vanadium(V)-β-alaninehydroxamic acid in which there is not a carboxylic group.

Pb(II)-binding capability of aminohydroxamic acids: Primary hydroxamic acid derivatives of α-amino acids as possible sequestering agents for Pb(II)

Complexes of aminohydroxamic acids, d,l-α-alaninehydroxamic acid (α-Alaha), sarcosinehydroxamic acid (Sarha), d,l- N-methyl-α-alaninehydroxamic acid ( N-Me-α-Alaha), β-alaninehydroxamic (β-Alaha), l-aspartic acid-β-hydroxamic acid (Asp-β-ha), l-glutamic acid-γ-hydroxamic acid (Glu-γ-ha) and l-histidinehydroxamic acid (Hisha) with lead(II) in aqueous solution were studied by pH-potentiometric, 1H NMR and electrospray ionization mass spectrometric (ESI MS) methods. The results were compared to those of a simple monohydroxamic acid, acetohydroxamic acid and the effects of the amino group, hydroxamate-N, as well as, additional side chain donors on the co-ordination mode and on the stability of the complexes formed were evaluated. It was found that the amino nitrogen atom situating in β- or in γ-position (β-Alaha, Asp-β-ha, Glu-γ-ha) does not co-ordinate to Pb(II), only hydroxamate type chelates are formed before the hydrolytic processes. However, the amino-N in α-position (α-Alaha, Sarha, Hisha) seems to form a stable 5-membered ( N, N)-type chelate together with the deprotonated hydroxamate-N above pH 6. On the other hand, the hydroxamate ( O, O)-type chelate also exists. Since steric reasons do not allow the coordination of these two chelates of a molecule to the same Pb(II) ion, polynuclear complexes with mixed co-ordination modes are formed with the α-derivatives above pH 6. Simple hydroxamate type complexes are formed with N-Me-α-Alaha, where the hydroxamate-N is not able to co-ordinate. The co-ordination of the side chain imidazole of Hisha is not measurable, while a weak interaction of the side chain carboxylates of Asp-β-ha and especially of Glu-γ-ha can be suggested.

O-nucleophilicity of hydroxamate ions in reactions with ethyl 4-nitrophenyl ethylphosphonate, diethyl 4-nitrophenyl phosphate, and 4-nitrophenyl 4-toluenesulfonate

The nucleophilicity of hydroxamate ions toward ethyl 4-nitrophenyl ethylphosphonate, diethyl 4-nitrophenyl phosphate, and 4-nitrophenyl 4-toluenesulfonate in water (µ=1, KCl, 25°C) is described by the Bro nsted equation (βN=0.54, 0.70, and 0.59, respectively). In these reactions, hydroxamate ions act as typical α -nucleophiles; they are more reactive than phenoxide ions with the same basicity by a factor of 300 to 800. In the series of hydroxamate ions, an anomalously high nucleophilicity was revealed for the anions possessing catalytic centers (in terms of general base catalysis), which are capable of providing anchimeric assistance in the transition state. An equation has been proposed, which relates the efficiency of such assistance in anions derived from aminohydroxamic acids to the Δ pKa values characterizing their acidic and basic groups.

Synthesis and Biological Evaluation of New Acinetoferrin Homologues for Use as Iron Transport Probes in Mycobacteria

Four new acinetoferrin homologues were synthesized using a modular synthetic approach. Two linear and two cyclic imide derivatives were generated and evaluated for growth stimulating behavior in Mycobacterium avium subsp paratuberculosis. The yield for the tandem coupling of a functionalized aminohydroxamic acid motif (2 equiv) to a tert-butyl citrate derivative was significantly improved using DCC and N-hydroxysuccinimide. (1)H NMR spectroscopy (CD(3)OD) provided a convenient method for monitoring the final imidization step in TFA using the doublet patterns between 2.5 and 3.06 ppm. New protocols demonstrated that only a 20% growth enhancement was observed with M. avium subsp. paratuberculosis using the imide of acinetoferrin. Last, a siderophore from Streptomyces pilosus, deferrioxamine B, was shown to cross-feed M. avium subsp. paratuberculosis with the same efficiency as the more costly, native chelator, mycobactin J.

Electrochemical behavior of iron(III) complexes with aminohydroxamic acids

The electrochemical reduction of various aminohydroxamate complexes of iron(III), such as alanine-, serine-, lysine-, histidine- and glutamo-γ-hydroxamate, has been investigated in aqueous solution by cyclic voltammetry on hanging mercury drop electrodes to determine the mechanism involved in the electron transfer processes. In all the studied cases the iron(III) complexes, with the exception of histidinehydroxamate, have been found to undergo reversible reductions followed by irreversible chemical reactions (EC mechanism). Rate constants for the irreversible dissociation of iron(II) complexes were calculated. The typical quasi-reversible pattern for the reduction of histidinehydroxamate was attributed to the different coordination mode. The observed differences in redox potentials between the investigated complexes suggest that the electronic effect of the substituent on the carbonyl group, involved in the coordination to the iron center, may modify the donor properties of the oxygen atoms of the hydroxamate moiety. The potentials determined at physiological pH are in the range of biological reducing agents, which makes these compounds potential siderophore models.

Antibacterial activities and characterization of novel inhibitors of LpxC.

Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the alpha-(R)-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae, Serratia marcescens, Morganella morganii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia cepacia. BB-78484 was bactericidal against E. coli, achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.

Effects of side chain amino nitrogen donor atoms on metal complexation of aminohydroxamic acids: New diaminohydroxamates chelating Ni(ii) more strongly than Fe(iii)

Complexes of diaminohydroxamic acids 2,6-diamino-N-hydroxyhexanamide (lysinehydroxamic acid, Lysha), 2,4-diamino-N-hydroxybutanamide (2,4-diaminobutyrohydroxamic acid, Dambha) and 2,3-diamino-N-hydroxypropanamide (2,3-diaminopropionohydroxamic acid, Dampha) with manganese(II), cobalt(II), iron(II), nickel(II), copper(II), zinc(II), iron(III), aluminium(III) and molybdenum(VI) in aqueous solution were studied by pH-potentiometric, UV–visible spectrophotometric and EPR methods. The two latter diaminohydroxamic acids were synthesised as new ligands and characterised. The results were compared to those of a simple α-amino acid derivative, α-alaninehydroxamic acid (α-Alaha) and the effects of the side chain amino group on the co-ordination mode and on the stability of the complexes formed were evaluated. As expected, the side chain amino nitrogen atom of Lysha does not co-ordinate to any of the studied metals but remains free for possible further interactions. The amino groups do not co-ordinate to aluminium(III) or iron(III) at all and the closer the side chain amino group is situated to the α-aminohydroxamic residue the less stable the hydroxamate complex formed in the order of Lysha, Dambha, Dampha, and hydrolytic processes become increasingly dominant. The co-ordination of the side chain amino nitrogen of Dampha and Dambha to nickel(II) and copper(II) was unambiguously observed.

Potentiometric and spectroscopic study of mixed-ligand copper(II) complexes with N, N, N′, N″, N″-pentamethyldiethylenetriamine and α- (or β-) alaninehydroxamic acids in water solution

Stabilities of the mixed-ligand complexes of Cu 2+ ion with N, N, N′, N″, N″-pentamethyldiethylenetriamine [ N, N, N′, N″, N″-pentamethyl-{bis(2-aminoethyl)amine}, Me 5dien] as a primary ligand and α-alaninehydroxamic acid [2-amino- N-hydroxypropanamid, α-Alaha] or β-alaninehydroxamic acid [3-amino- N-hydroxypropanamid, β-Alaha] as a secondary ligand L and their absorption and EPR spectra at various pH values are reported. The visible spectra exhibit a characteristic red shift and a shoulder at lower energies indicating a five-coordinate structure of the formed complexes. The change of the EPR spectral parameters as a function of pH reflects two modes of an equatorial–axial chelation by the aminohydroxamic acid ligand L in the [Cu(Me 5dien)(HL)] 2+ and [Cu(Me 5dien)(L)] + species.

N-Bonding of the hydroxamic function in nickel(II) and copper(II) complexes with 2-(hydroxyimino)propanohydroxamic acid

Potentiometric, spectroscopic and X-ray studies of 2-(hydroxyimino)propanohydroxamic acid (H2L) and its complexes with Ni2+ and Cu2+ showed that the ligand is a strong chelating agent forming a series of stable complex species with remarkably higher formation constants compared to those of either aminohydroxamic acids or oximinocarbonic acids. In the Cu2+–H2L system three dinuclear species [Cu2HL2]+, [Cu2L2] and [Cu2H–1L2]– with different donor atom sets were found to be dominant at pH 3.5–7.5. In both Cu2+ and Ni2+ systems the mononuclear species [MHL2]–, [ML2]2– and [MH–1L2]3– are formed in neutral and alkaline solutions which have, according to the UV-VIS spectral data, square-planar structure with a M{N2(oxime)N2(hydrox)} core. Thus, the ligand studied represents a new example in which the adjacent oxime donor group facilitates the N-bonding of the hydroxamic function. The crystal structures of two complexes, Na2[NiL2]·4H2O 1 and [Cu(phen)(hpa)(H2O)]·4H2O 2 [H2hpa = 2-(hydroxyimino)propanoic acid] have been determined by single-crystal X-ray analysis. In 1 the central atom is situated at the centre of symmetry and in square-planar surroundings of four nitrogen atoms belonging to the deprotonated oxime and hydroxamic groups. The trans-disposed ligands are additionally linked by short intramolecular hydrogen bonds featuring the oxime and hydroxamic oxygen atoms. Complex 2 was crystallised from an alkaline solution containing [Cu(phen)Cl2] and H2L and formed as a result of ligand hydrolysis. The copper(II) ion is in distorted square-pyramidal surrounding, the basal plane being formed by two nitrogen atoms of 1,10-phenanthroline, an oxime nitrogen and a carboxylic oxygen atom of the dianion hpa and the water molecule occupies the apical position. Both organic ligands are co-ordinated in a bidentate chelate mode.