Hydroxamic Group Research Articles

Exploration of the labeling of [11C]tubastatin A at the hydroxamic acid site with [11C]carbon monoxide.

We aimed to label tubastatin A (1) with carbon-11 (t1/2 = 20.4 min) in the hydroxamic acid site to provide a potential radiotracer for imaging histone deacetylase 6 in vivo with positron emission tomography. Initial attempts at a one-pot Pd-mediated insertion of [(11)C]carbon monoxide between the aryl iodide (2) and hydroxylamine gave low radiochemical yields (<5%) of [(11) C]1. Labeling was achieved in useful radiochemical yields (16.1 ± 5.6%, n = 4) through a two-step process based on Pd-mediated insertion of [(11)C]carbon monoxide between the aryl iodide (2) and p-nitrophenol to give the [(11)C]p-nitrophenyl ester ([(11)C]5), followed by ultrasound-assisted hydroxyaminolysis of the activated ester with excess hydroxylamine in a DMSO/THF mixture in the presence of a strong phosphazene base P1-t-Bu. However, success in labeling the hydroxamic acid group of [(11)C]tubastatin A was not transferable to the labeling of three other model hydroxamic acids.

Why Hydroxamates May Not Be the Best Histone Deacetylase Inhibitors--What Some May Have Forgotten or Would Rather Forget?

Hydroxamate-based histone deacetylase inhibitors (HDACIs) have been approved as therapeutic agents by the US Food and Drug Administration for use in oncology applications. While the potential utility of such HDACIs in other areas of medicinal chemistry is tremendous, there are significant concerns that "pan-HDAC inhibitors" may be too broadly acting and/or toxic for clinical use beyond oncology. In addition to the isozyme selectivity challenge, the potential mutagenicity of hydroxamate-containing HDAC inhibitors represents a major hindrance in their application to other therapeutic areas. Herein we report on the mutagenicity of known hydroxamates, discuss the mechanisms responsible for their genotoxicity, and review some of the current alternatives to hydroxamates. We conclude that the hydroxamate group, while providing high-potency HDACIs, is not necessarily the best zinc-binding group for HDACI drug discovery.

A Metal Organic Framework with Spherical Protein Nodes: Rational Chemical Design of 3D Protein Crystals.

We describe here the construction of a three-dimensional, porous, crystalline framework formed by spherical protein nodes that assemble into a prescribed lattice arrangement through metal-organic linker-directed interactions. The octahedral iron storage enzyme, ferritin, was engineered in its C3 symmetric pores with tripodal Zn coordination sites. Dynamic light scattering and crystallographic studies established that this Zn-ferritin construct could robustly self-assemble into the desired bcc-type crystals upon coordination of a ditopic linker bearing hydroxamic acid functional groups. This system represents the first example of a ternary protein-metal-organic crystalline framework whose formation is fully dependent on each of its three components.

Impact of the uranium (VI) speciation in mineralised urines on its extraction by calix[6]arene bearing hydroxamic groups used in chromatography columns

Actinides determination in urine samples is part of the analyses performed to monitor internal contamination in case of an accident or a terrorist attack involving nuclear matter. Mineralisation is the first step of any of these analyses. It aims at reducing the sample volume and at destroying all organic compounds present. The mineralisation protocol is usually based on a wet ashing step, followed by actinides co-precipitation and a furnace ashing step, before redissolution and the quantification of the actinides by the appropriate techniques. Amongst the existing methods to perform the actinides co-precipitation, alkali-earth (typically calcium) precipitation is widely used. In the present work, the extraction of uranium(VI), plutonium(IV) and americium(III) from the redissolution solutions (called “mineralised urines”) on calix[6]arene columns bearing hydroxamic groups was investigated as such an extraction is a necessary step before their determination by ICP–MS or alpha spectrometry. Difficulties were encountered in the transfer of uranium(VI) from raw to mineralised urines, with yield of transfer ranging between 0% and 85%, compared to about 90% for Pu and Am, depending on the starting raw urines. To understand the origin of such a difficulty, the speciation of uranium (VI) in mineralised urines was investigated by computer simulation using the MEDUSA software and the associated HYDRA database, compiled with recently published data. These calculations showed that the presence of phosphates in the “mineralised urines” leads to the formation of strong uranyl-phosphate complexes (such as UO2HPO4) which compete with the uranium (VI) extraction by the calix[6]arene bearing hydroxamic groups. The extraction constant of uranium (VI) by calix[6]arene bearing hydroxamic groups was determined in a 0.04molL−1 sodium nitrate solution (logK=4.86±0.03) and implemented in an extraction model taking into account the speciation in the aqueous phase. This model allowed to simulate satisfactorily the experimental uranium extraction data and to support the preliminary conclusions about the role of the phosphates present in mineralised urines. These calculations also showed that the phosphate/calcium ratio is a key parameter as far as the efficiency of the uranium (VI) extraction by the calix[6]arene columns is concerned. It predicted that the addition of CaCl2 in mineralised urines would release uranium (VI) from phosphates by forming calcium (II)-phosphate complexes and thus facilitate the uranium (VI) extraction on calix[6]arene columns. These predictions were confirmed experimentally as the addition of 0.1molL−1 CaCl2 to a mineralised urine containing naturally a high concentration of phosphate (typically 0.04molL−1) significantly increased the percentage of uranium (VI) extraction on the calix[6]arene columns.

Synthesis of modified polyacrylamide with high content of hydroxamate groups and settling performance of red mud

Hydroxamated polyacrylamide (HPAM) was synthesized from polyacrylamide (PAM) with high relative molecular mass under the optimum reaction conditions (pH 12 and a molar ratio of hydroxylamine to amide groups of 1.5 at 50 °C for 12 h). The hydroxamate groups of HPAM were verified by Fourier transform infrared spectrum (FT-IR). 46% (molar fration) hydroxamate groups and 23% (molar fraction) carbonyl groups on HPAM were determined by conductometric titration combined with Kjeldahl’s microanalysis method. The settling performance achieved at different flocculant dosages was investigated with high goethite-containing red mud slurry of simulated Bayer process synthesized in laboratory. It turns out that the settling performance of high goethite-containing red mud was better with HPAM. The average settling rate of red mud in the first 5 min and the turbidity of supernatant after settling for 30 min are 2.36 m/h and 507 NTU, respectively, at a flocculant dosage of 120 g/t, which is similar to that achieved with Hx-600.

Effects of metalloprotease anthrax lethal factor on its peptide-based inhibitor R9LF-1.

The metalloprotease lethal factor (LF) from Bacillus anthracis plays a vital role in anthrax toxin action, and thus becomes a target for anti-anthrax therapy. Following the guidelines based on existing metalloprotease inhibitors, we designed a 'first-generation' LF inhibitor R9LF-1. This inhibitor was shown to be very stable by itself in a wide range of pH and temperature and able to inhibit LF activity in vitro. However, as we reported previously in the presence of LF, this inhibitor was degraded to a small molecular weight species, resulting in a significantly decreased ability to protect MAPKK from cleavage by LF as well as to protect murine macrophages from lethal toxin. In order to elucidate this unusual phenomenon to build solid basis for high-efficiency LF inhibitor development, we performed extensive research to study the effect of LF on its peptide-based inhibitor. Effects of temperature and incubation period of time on generation of the smaller peptide (short version R9LF-1) by LF as well as its catalytic domain were analyzed. We found that LF degraded R9LF-1 with maximum efficiency in the pH range of 7.0-8.5, which correlates well with the range of LF enzymatic activity with its native substrate. The degradation showed a deviation from normal hyperbolic kinetics but a similarity to the kinetics profile of an enzyme-catalyzed reaction with positive cooperativity. The short version R9LF-1 had decreased inhibitory activity toward LF; surprisingly, BIAcore results suggested a better affinity for its binding to LF. In addition, R9LF-1 was not hydrolyzed by other common proteases, such as chymotrypsin and pepsin, suggesting hydrolysis of the bond between amino acid and hydroxamate groups is unique to LF. This study calls for caution when designing peptide-based LF inhibitors and when interpreting effects of these types of inhibitors.

Flocculation performance and mechanism of hydroxamate flocculants on synthetic hematite or goethite suspension

Suitable amounts of Al(OH)3, NaOH and synthetic hematite or goethite were taken to be digested under the simulated condition of the Bayer process and subsequently diluted with simulative Bayer red mud lotion, then the synthetic hematite or goethite suspension was obtained. The flocculation effect of self-made modified poly(acrylic acids) flocculants containing hydroxamic acid groups (abbreviated as HPAA) on the synthetic hematite or goethite suspension was studied. The experimental results show that with the increase of the dosages of added flocculants, the average settling rate of the synthetic hematite or goethite suspension in the first 1 min speeds up, the supernatant solids decrease. It could also be found that there is generally a decrease in the average settling rate of the synthetic hematite or goethite suspension in the first 1 min with increasing solid content of the suspension. When the solid content of hematite or goethite of the suspension is 50 g/L with 240 g/t dosage of HPAA, HPAA has a better flocculation effect on the synthetic goethite suspension than on the synthetic hematite suspension. The adsorption mechanism of HPAA on the surface of hematite or goethite was investigated by Fourier transform infrared spectroscopy(FT-IR) and X-ray photoelectron spectroscopy(XPS). All the results suggest that HPAA is adsorbed on the hematite or goethite surface by a chemisorption, and it has a stronger adsorption on the goethite surface than on the hematite surface.

Hybrids from Farnesylthiosalicylic Acid and Hydroxamic Acid as Dual Ras-Related Signaling and Histone Deacetylase (HDAC) Inhibitors: Design, Synthesis and Biological Evaluation.

A novel series of hybrids was designed and synthesized by combining key elements from farnesylthiosalicylic acid (FTS) and hydroxamic acid. Several 3,7,11-trimethyldodeca-2,6,10-trien-1-yl) thio)benzamide derivatives, particularly those with branched and linear aliphatic linkers between the hydroxamic zinc binding group (ZBG) and the benzamide core, not only displayed significant antitumor activities against six human cancer cells but also exhibited histone deacetylase (HDAC) inhibitory effects in vitro. Among them, N-(4-(hydroxyamino)-4-oxobutyl)-2-(((2E,6E)-3,7,11-trimethyldodeca-2,6, 10-trien-1-yl)thio)benzamide (8 d) was the most potent, with IC50 values of 4.9-7.6 μM; these activities are eight- to sixteen-fold more potent than FTS and comparable to that of suberoylanilide hydroxamic acid (SAHA). Derivative 8 d induced cell cycle arrest in the G0/G1 phase, inhibited the acetylation of histone H3 and α-tubulin, and blocked Ras-related signaling pathways in a dose-dependent manner. The improved tumor growth inhibition and cell-cycle arrest in vitro might result from the dual inhibition. These findings suggest dual inhibitors of Ras-related signaling pathway and HDAC hold promise as therapeutic agents for the treatment of cancer.

Design and Evaluation of Tumor-Specific Dendrimer Epigenetic Therapeutics.

Histone deacetylase inhibitors (HDACi) are promising therapeutics for cancer. HDACi alter the epigenetic state of tumors and provide a unique approach to treat cancer. Although studies with HDACi have shown promise in some cancers, variable efficacy and off-target effects have limited their use. To overcome some of the challenges of traditional HDACi, we sought to use a tumor-specific dendrimer scaffold to deliver HDACi directly to cancer cells. Here we report the design and evaluation of tumor-specific dendrimer–HDACi conjugates. The HDACi was conjugated to the dendrimer using an ester linkage through its hydroxamic acid group, inactivating the HDACi until it is released from the dendrimer. Using a cancer cell model, we demonstrate the functionality of the tumor-specific dendrimer–HDACi conjugates. Furthermore, we demonstrate that unlike traditional HDACi, dendrimer–HDACi conjugates do not affect tumor-associated macrophages, a recently recognized mechanism through which drug resistance emerges. We anticipate that this new class of cell-specific epigenetic therapeutics will have tremendous potential in the treatment of cancer.

New matrix metalloproteinase inhibitors based on γ-fluorinated α-aminocarboxylic and α-aminohydroxamic acids

Matrix metalloproteinases (MMPs) are involved in a number of physiological as well as pathological processes such as atherosclerosis and tumorigenesis, where an up-regulation of MMPs is predominant. Fluorinated analogues of the hydroxamate-based non-peptidic broad-spectrum MMP inhibitor (MMPI) CGS 27023A were synthesized and inhibition potencies for MMP-2 and MMP-9 in the nanomolar range were measured using fluorimetric in vitro assays. The inhibition potencies of the herein reported fluorinated MMPIs were comparable or even superior in some cases to their non-fluorinated analogues. In contrast to the lead structure, both enantiomers of fluorinated MMPs were almost equally potent. Modelling studies suggest that the core α-amino hydroxamic acid residues appear to influence the relative potencies via specific inhibitor-peptidase interactions, including short fluorine–hydrogen contacts, within the enzyme’s pockets. The binding of the essential hydroxamate group to the zinc ion is rather unaffected by the rest of the molecule. In contrast, the corresponding α-aminocarboxylic acid derivatives are 103 times less potent or were even inactive.

A novel surfactant N-(6-(hydroxyamino)-6-oxohexyl)octanamide: Synthesis and flotation mechanisms to wolframite

In this paper, a novel surfactant N-(6-(hydroxyamino)-6-oxohexyl)octanamide (NHOO) was prepared and its flotation performances and adsorption mechanism for wolframite were first investigated by FTIR spectra, flotation tests, zeta potential and adsorption quantity measurements. The flotation results showed that NHOO was a stronger collector than the conventional hydroxamic acid collectors such as benzoyl hydroxamic acid (BHA) and octyl hydroxamic acid (OHA). The adsorption data demonstrated that the adsorption affinity of NHOO to wolframite was far stronger than that of BHA or OHA, and the preferable pH ranges for NHOO adsorption on wolframite surfaces were below 6.69 or above 9.35. The results of FTIR spectra and zeta potential illustrated that NHOO might adsorb on wolframite mainly through hydrogen bonding and electrostatic attraction by its amide C(O)H2N+ group at pH<6.69 or coordination bonding by its hydroxamic C(O)NHO− group at pH>9.35. In the pH range between 6.69 and 9.35, NHOO might exist in zwitterion species which was formed through intramolecular electrostatic attraction between its positive amide and negative hydroxamic groups, resulting in mildly weakening interaction force and collecting power to wolframite. NHOO’s unique properties, such as double reactive centers to mineral surfaces, double hydrophobic groups, and self-adapting adsorption manner and hydrophobic geometry to pulp pH values, made it a superior collector for wolframite flotation.

Different binding modes of Cu and Pb vs. Cd, Ni, and Zn with the trihydroxamate siderophore desferrioxamine B at seawater ionic strength

The solution speciation in seawater of divalent trace metals (Cd, Cu, Ni, Pb, Zn) is dominated by strong, ostensibly metal-specific organic ligands that may play important roles in microbial metal acquisition and/or detoxification processes. We compare the effective stabilities of these metal–organic complexes to the stabilities of their complexes with a model siderophore, desferrioxamine B (DFOB). While metal–DFOB complexation has been studied in various dilute but often moderately coordinating media, for the purpose of this investigation we measured the stability constants in a non-coordinating background electrolyte at seawater ionic strength (0.7M NaClO4). Potentiometric titrations of single metals (M) were performed in the presence of ligand (L) at different M:L molar ratios, whereupon the stability constants of multiple complexes were simultaneously determined by non-linear regression of the titration curves with FITEQL, using the optimal binding mode for each metal.Cadmium, Ni, and Zn, like trivalent Fe, sequentially form a bi-, tetra-, and hexadentate complex with DFOB as pH increases, consistent with their coordination number of 6 and regular octahedral geometry. Copper has a Jahn–Teller-distorted square-bipyramidal geometry whereas the geometry of Pb is cryptic, involving a range of bond lengths. Supported by a thermodynamic argument, our data suggest that this impedes binding of the third hydroxamate group and that the hexadentate Cu–DFOB and Pb–DFOB complex identified in earlier reports may instead be a deprotonated tetradentate complex. Absence of the hexadentate complex promotes the formation of a dinuclear (bidentate–tetradentate) complex, M2HL2+, albeit not for Pb in 0.7M NaCl, evidently due to extensive complexation with chloride.Stabilities of the hexadentate Ni–DFOB, Zn–DFOB, and the tetradentate Pb–DFOB complex are nearly equal, yet about 2 orders of magnitude higher and 4 orders of magnitude lower than those of the hexadentate Cd–DFOB and tetradentate Cu–DFOB complex, respectively. Linear free-energy relations defined by the rare earth elements are able to predict stabilities of the Cd, Zn, and one of the Pb complexes, but underestimate those of the Ni and Cu complexes. The comparison with metal-specific organic ligands detected in seawater yields fair agreement for three of the five metals, implying that they could be siderophore-like. The Cd- and Ni-specific ligands are much stronger and may contain quite different functional groups. Calculations with MINEQL incorporating our new stability constants indicate that very high DFOB concentrations would be required to match the extent of metal–organic complexation observed in seawater, however DFOB may well represent a much broader class of structurally related ligands.

Synthesis and Biological Activity of 4H-Thieno[3,2-c]Chromene Derivatives

The formyl group of 4H-thieno[3,2-c]chromene-2-carbaldehyde was transformed into the respective nitrile, amide, ester, carboxylic, hydroxamic, or hydroxy group. Electrophilic substitution in 4H-thieno[3,2-c]chromene-2-carbaldehyde was shown to occur at the ɋ-8 atom, while oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol led to 4-methoxy-4H-thieno[3,2-c]chromene2-carbaldehyde. The latter compound was found to possess high antiulcer activity.

A QSAR study on the inhibition mechanism of matrix metalloproteinase-12 by arylsulfone analogs based on molecular orbital calculations.

A binding mechanism between human matrix metalloproteinase-12 (MMP-12) and eight arylsulfone analogs having two types of carboxylic and hydroxamic acids as the most representative zinc binding group is investigated using a quantitative structure-activity relationship (QSAR) analysis based on a linear expression by representative energy terms (LERE). The LERE-QSAR analysis quantitatively reveals that the variation in the observed (experimental) inhibitory potency among the arylsulfone analogs is decisively governed by those in the intrinsic binding and dispersion interaction energies. The results show that the LERE-QSAR analysis not only can excellently reproduce the observed overall free-energy change but also can determine the contributions of representative free-energy changes. An inter-fragment interaction energy difference (IFIED) analysis based on the fragment molecular orbital (FMO) method (FMO-IFIED) leads to the identification of key residues governing the variation in the inhibitory potency as well as to the understanding of the difference between the interactions of the carboxylic and hydroxamic acid zinc binding groups. The current results that have led to the optimization of the inhibitory potency of arylsulfone analogs toward MMP-12 to be used in the treatment of chronic obstructive pulmonary disease may be useful for the development of a new potent MMP-12 inhibitor.

Molecular Pac-Man and Tacos: layered Cu(II) cages from ligands with high binding site concentrations.

The in situ formation and subsequent Cu(ii) ligation of the polydentate pro-ligands o-[(E)-(2-hydroxy-3-methoxyphenyl)methylideneamino]benzohydroxamic acid (L1H3), o-[(E)-(2-hydroxy-3-methoxy-5-bromophenyl)methylideneamino]benzohydroxamic acid (L2H3) and o-[(E)-(2-hydroxyphenyl)methylideneamino]benzohydroxamic acid (L3H3), leads to the self-assembly of the cages [Cu(ii)10(L1)4(2-aph)2(H2O)2](ClO4)4·5MeOH (), [Cu(ii)14(L1)8(MeOH)2.5(H2O)7.5](NO3)4·3MeOH·7H2O (), [Cu(ii)14(L2)8(MeOH)4(H2O)6](NO3)4·6H2O (), [Cu(ii)14(L3)8(MeOH)6(H2O)2](NO3)4·4MeOH·8H2O () and [Cu(ii)30O(OH)4(OMe)2(L1)16(MeOH)4(H2O)2](ClO4)4·2MeOH·30H2O (). Each member comprises a highly unusual topology derived from off-set, stacked, near planar layers of polynuclear subunits connected through long Cu(ii)-O contacts. The exact topology observed is dependent on the specific reaction conditions and methodologies employed. Dc magnetic susceptibility studies on , , and reveals strong antiferromagnetic exchange between the Cu(ii) centres in all siblings. We also present the 1D coordination polymer {[Cu(ii)(L4)]·H2O}n () comprising the pseudo macrocyclic ligand [[2-[(E)-(2-hydroxy-3-methoxy-phenyl)methyleneamino]benzoyl]amino]ethanimidate (L4H2), which is formed upon the incorporation of an MeCN unit at the hydroxamate group of precursor ligand L1H3.

Plasmid-Encoded Iron Uptake Systems.

Plasmids confer genetic information that benefits the bacterial cells containing them. In pathogenic bacteria, plasmids often harbor virulence determinants that enhance the pathogenicity of the bacterium. The ability to acquire iron in environments where it is limited, for instance the eukaryotic host, is a critical factor for bacterial growth. To acquire iron, bacteria have evolved specific iron uptake mechanisms. These systems are often chromosomally encoded, while those that are plasmid-encoded are rare. Two main plasmid types, ColV and pJM1, have been shown to harbor determinants that increase virulence by providing the cell with essential iron for growth. It is clear that these two plasmid groups evolved independently from each other since they do not share similarities either in the plasmid backbones or in the iron uptake systems they harbor. The siderophores aerobactin and salmochelin that are found on ColV plasmids fall in the hydroxamate and catechol group, respectively, whereas both functional groups are present in the anguibactin siderophore, the only iron uptake system found on pJM1-type plasmids. Besides siderophore-mediated iron uptake, ColV plasmids carry additional genes involved in iron metabolism. These systems include ABC transporters, hemolysins, and a hemoglobin protease. ColV- and pJM1-like plasmids have been shown to confer virulence to their bacterial host, and this trait can be completely ascribed to their encoded iron uptake systems.

Suberoylanilide hydroxamic acid radiosensitizes tumor hypoxic cells in vitro through the oxidation of nitroxyl to nitric oxide

The pharmacological effects of hydroxamic acids are partially attributed to their ability to serve as HNO and/or NO donors under oxidative stress. Previously, it was concluded that oxidation of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) by the metmyoglobin/H2O2 reaction system releases NO, which was based on spin trapping of NO and accumulation of nitrite. Reinvestigation of this system demonstrates the accumulation of N2O, which is a marker of HNO formation, at similar rates under normoxia and anoxia. In addition, the yields of nitrite that accumulated in the absence and the presence of O2 did not differ, implying that the source of nitrite is other than autoxidation of NO. In this system metmyoglobin is instantaneously and continuously converted into compound II, leading to one-electron oxidation of SAHA to its respective transient nitroxide radical. Studies using pulse radiolysis show that one-electron oxidation of SAHA (pKa=9.56±0.04) yields the respective nitroxide radical (pKa=9.1±0.2), which under all experimental conditions decomposes bimolecularly to yield HNO. The proposed mechanism suggests that compound I oxidizes SAHA to the respective nitroxide radical, which decomposes bimolecularly in competition with its oxidation by compound II to form HNO. Compound II also oxidizes HNO to NO and NO to nitrite. Given that NO, but not HNO, is an efficient hypoxic cell radiosensitizer, we hypothesized that under an oxidizing environment SAHA might act as a NO donor and radiosensitize hypoxic cells. Preincubation of A549 and HT29 cells with 2.5μM SAHA for 24h resulted in a sensitizer enhancement ratio at 0.01 survival levels (SER0.01) of 1.33 and 1.59, respectively. Preincubation of A549 cells with oxidized SAHA had hardly any effect and, with 2mM valproic acid, which lacks the hydroxamate group, resulted in SER0.01=1.17. Preincubation of HT29 cells with SAHA and Tempol, which readily oxidizes HNO to NO, enhanced the radiosensitizing effect of SAHA. Pretreatment with SAHA blocked A549 cells at the G1 stage of the cell cycle and upregulated γ-H2AX after irradiation. Overall, we conclude that SAHA enhances tumor radioresponse by multiple mechanisms that might also involve its ability to serve as a NO donor under oxidizing environments.

Rodriguesic Acids, Modified Diketopiperazines from the Gastropod MolluscPleurobranchus areolatus

In the present investigation, two specimens of the nudipleuran mollusc Pleurobranchus areolatus have shown to accumulate oxidized rodriguesin A derivatives. Rodriguesic acid presents a carboxylic acid replacing the terminal methyl group of the alkyl chain of rodriguesin A. A hydroxamate group was also present on the diketopiperazine moiety of a rodriguesic acid derivative. The structures of both rodriguesic acid and of rodriguesic acid hydroxamate have been established by analysis of spectroscopic data, including their absolute configuration. Two methyl esters of the rodriguesic acids have been isolated as major compounds, but were considered to be isolation artifacts.

Synthesis and structural characterization of dioxomolybdenum and dioxotungsten hydroxamato complexes and their function in the protection of radiation induced DNA damage

The synthesis and structural characterization of two novel dioxomolybdenum(VI) (1) and dioxotungsten(VI) (2) complexes with 2-phenylacetylhydroxamic acid (PAHH) [M(O)2(PAH)2] [M = Mo, W] have been accomplished. The dioxomolybdenum(VI) and dioxotungsten(VI) moiety is coordinated by the hydroxamate group (-CONHO(-)) of the 2-phenylacetylhydroxamate (PAH) ligand in a bi-dentate fashion. In both the complexes the PAHH ligand is coordinated through oxygen atoms forming a five membered chelate. The hydrogen atom of N-H of the hydroxamate group is engaged in intermolecular H-bonding with the carbonyl oxygen of another coordinated hydroxamate ligand, thereby forming an extended 1D chain. The ligand as well as both the complexes exhibit the ability to protect from radiation induced damage both in CTDNA as well as in pUC19 plasmid DNA. As the damage to DNA is caused by the radicals generated during radiolysis, its scavenging imparts protection from the damage to DNA. To understand the mechanism of protection, binding affinities of the ligand and the complex with DNA were determined using absorption and emission spectral studies and viscosity measurements, whereby the results indicate that both the complexes and the hydroxamate ligand interact with calf thymus DNA in the minor groove. The intrinsic binding constants, obtained from UV-vis studies, are 7.2 × 10(3) M(-1), 5.2 × 10(4) M(-1) and 1.2 × 10(4) M(-1) for the ligand and complexes 1 and 2 respectively. The Stern-Volmer quenching constants obtained from a luminescence study for both the complexes are 5.6 × 10(4) M(-1) and 1.6 × 10(4) M(-1) respectively. The dioxomolybdenum(VI) complex is found to be a more potent radioprotector compared to the dioxotungsten(VI) complex and the ligand. Radical scavenging chemical studies suggest that the complexes have a greater ability to scavenge both the hydroxyl as well as the superoxide radicals compared to the ligand. The free radical scavenging ability of the ligand and the complexes was further established by EPR spectroscopy using a stable free radical, the DPPH, as a probe. The experimental results of DNA binding are further supported by molecular docking studies.

Copper(ii) complexes of 3- and 4-picolinehydroxamic acids: from mononuclear compounds to 1D- and 2D-coordination polymers

A series of copper(II) complexes with 3- and 4-picolinehydroxamic acids has been synthesized and characterized by a variety of spectroscopic methods, X-ray structure analysis and magnetic susceptibility measurements. The ligands show the tendency to form 1D- and 2D-polymeric structures with copper(II) ions due to the chelating-and-bridging binding mode involving the (O,O′)-hydroxamate chelate formation combined with N-coordination of the pyridine moiety. In some cases the (O, μ2-O′) chelating-and-bridging modes are realized, in which either amide or hydroxamic oxygen atoms play a μ2-bridging role. Molecular and crystal structures of two discrete complexes: mononuclear [Cu(3-HPicHA)2(ClO4)2] (1) and binuclear [{Cu(4-HPicHA)(bpy)(ClO4)}2](ClO4)2 (4a), and five coordination polymers catena-[Cu(3-PicHA)(phen)]n(ClO4)n (7), catena-[Cu(4-PicHA)(bpy)]n(OH)n·3.25nH2O (8), catena-[Cu(4-PicHA)(DMSO)2]2n(ClO4)2n (9), [Cu(3-PicHA)(DMSO)(ClO4)]nm·nmDMSO (10), and [{Cu(4-PicHA)(phen)}2]n(ClO4)2n (11) were determined by single crystal X-ray analysis. In structures 1 and 4a the hydroxamate ligands exist in a zwitterionic form with the O-deprotonated hydroxamate groups and protonated pyridine rings. The following types of coordination polymers have been structurally characterized: (i) single-stranded zigzag-shaped 1D polymers (7 and 8); (ii) double-stranded 1D polymer comprising binuclear subunits formed on account of μ2(O)-carbonyl oxygen bridging coordination to the axial position of the copper(II) ion (9); (iii) 2D netted coordination polymers of two different types comprising μ2(O)-bridged binuclear subunits (10 and 11). Magnetic susceptibility measurements (2–300 K) of powdered samples revealed the presence of moderate antiferromagnetic interaction in the binuclear complex 4a (2J = −7.164(6) cm−1), while the coordination polymers exhibit weak antiferromagnetic interaction with a cryomagnetic behaviour obeying the Curie–Weiss law.