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The hydroxamic acid functionality is present in various medicinal agents and has attracted special interest for synthetic transformations in both organic and medicinal chemistry. The N−O bond cleavage of hydroxamic acid derivatives provides an interesting transformation for the generation of various products. We demonstrate, herein, that O‐benzyl‐type protected hydroxamic acids may undergo photochemical N−O bond cleavage, in the presence or absence of a catalyst, leading to amides. Although some O‐benzyl protected aromatic hydroxamates may be photochemically converted to amides in the presence of a base and anthracene as the catalyst, employing O‐2‐nitrobenzyl group allowed the smooth conversion of both aliphatic and aromatic hydroxamates to primary or secondary amides in good to excellent yields in the presence of an amine, bypassing the need of a catalyst. DFT and UV‐Vis studies supported the effective generation of an electron donor‐acceptor (EDA) complex between O‐2‐nitrobenzyl hydroxamates and amines, which enabled the successful product formation under these photochemical conditions. An extensive substrate scope was demonstrated, showcasing that both aliphatic and aromatic hydroxamates are compatible with this protocol, affording a wide variety of primary and secondary amides. [ABSTRACT FROM AUTHOR]

Despite their early discovery, the bioactivity of acidic cannabinoids was long overlooked. Issues of stability and a pharmacological focus on Δ9-THC and its biological profile combined to relegate the non-narcotic native form of phytocannabinoids to a sort of investigational limbo. Recent studies have disclosed an attractive bioactivity profile for specific acidic phytocannabinoids but concerns about their limited stability have remained substantially unaddressed. To solve this issue, we have developed the hydroxamate derivatives of Δ8-tetrahydrocannabinolic acid-A (Δ8-THCA-AH, 6) and cannabidiolic acid (CBDAH, 5) as novel acidic cannabinoid bioisosteres, and we report here their synthesis and bioactivity profile against specific cannabinoid targets, as well as promising in vivo activity in a murine model of polycystic ovary syndrome (PCOS) associated with obesity. [ABSTRACT FROM AUTHOR]

Simple Summary: Protein lysine acetylation is, with phosphorylation, the most common regulatory post-translational modification of proteins. Histone deacetylases (HDAC) catalyze the removal of acetyl groups from histone and non-histone proteins, participating in the modulation of several pathways. Histone deacetylase 6 is perhaps the most complex among histone deacetylases, comprising two catalytic domains, an N-terminal microtubule-binding domain and a C-terminal ubiquitin–binding domain. Interfering with its catalytic activity by using small synthetic molecules has been shown to be beneficial in the treatment of cancer, and neurological and immunological disorders. Thus, the development of potent and selective inhibitors of HDAC6 is an active field of medicinal chemistry. We shall here discuss the importance of monitoring the kinetics of onset and relief of inhibition to contribute important information on inhibition mechanisms during drug design/development campaigns using selected HDAC6 inhibitors as examples. Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique among HDAC as it contains two catalytic domains, an N-terminal microtubule binding region and a C-terminal ubiquitin binding domain. Most of its known biological roles are related to its protein lysine deacetylase activity in the cytoplasm. The design of specific inhibitors is the focus of a large number of medicinal chemistry programs in the academy and industry because lowering HDAC6 activity has been demonstrated to be beneficial for the treatment of several diseases, including cancer, and neurological and immunological disorders. Here, we show how re-evaluation of the mechanism of action of selected HDAC6 inhibitors, by monitoring the time-dependence of the onset and relief of the inhibition, revealed instances of slow-binding/slow-release inhibition. The same approach, in conjunction with X-ray crystallography, in silico modeling and mass spectrometry, helped to propose a model of inhibition of HDAC6 by a novel difluoromethyloxadiazole-based compound that was found to be a slow-binding substrate analog of HDAC6, giving rise to a tightly bound, long-lived inhibitory derivative. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique among HDAC as it contains two catalytic domains, an N-terminal microtubule binding region and a C-terminal ubiquitin binding domain. Most of its known biological roles are related to its protein lysine deacetylase activity in the cytoplasm. The design of specific inhibitors is the focus of a large number of medicinal chemistry programs in the academy and industry because lowering HDAC6 activity has been demonstrated to be beneficial for the treatment of several diseases, including cancer, and neurological and immunological disorders. Here, we show how re-evaluation of the mechanism of action of selected HDAC6 inhibitors, by monitoring the time-dependence of the onset and relief of the inhibition, revealed instances of slow-binding/slow-release inhibition. The same approach, in conjunction with X-ray crystallography, in silico modeling and mass spectrometry, helped to propose a model of inhibition of HDAC6 by a novel difluoromethyloxadiazole-based compound that was found to be a slow-binding substrate analog of HDAC6, giving rise to a tightly bound, long-lived inhibitory derivative.

In this study, a strain of Anabaena flos-aquae UTEX 1444 was cultivated in six different concentrations of iron (III). Cultures were extracted with organic solvents and analyzed using our dereplication strategy, based on the combined use of high-resolution tandem mass spectrometry and molecular networking. The analysis showed the presence of the siderophores' family, named synechobactins, only in the zero iron (III) treatment culture. Seven unknown synechobactin variants were present in the extract, and their structures have been determined by a careful HRMS/MS analysis. This study unveils the capability of Anabaena flos-aquae UTEX 1444 to produce a large array of siderophores and may be a suitable model organism for a sustainable scale-up exploitation of such bioactive molecules, for the bioremediation of contaminated ecosystems, as well as in drug discovery. [ABSTRACT FROM AUTHOR]

Bacterial resistance caused by metallo‐β‐lactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O‐aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase‐1 (IMP‐1) and New Delhi metallo‐β‐lactamase‐1, exhibiting an IC50 value in the range of 0.10–18.42 and 0.23–22.33 μM, respectively. The hydroxamate 5 was found to be the most potent inhibitor, with an IC50 of 0.1 and 0.23 μM using meropenem and cefazolin as substrates. ICP‐MS analysis showed that 5 did not coordinate to the Zn(II) ions at the active site of IMP‐1, while the rapid dilution, thermal shift and MALDI‐TOF assays revealed that the hydroxamate formed a covalent bond with the enzyme. Cytotoxicity assays indicated that the hydroxamates have low toxicity in MCF‐7 cells. This work provided a potent scaffold for the development of MβLs inhibitors. [ABSTRACT FROM AUTHOR]

An improved, one‐pot two‐step process is described to convert carboxylic acid to amides, dipeptides, esters, and hydroxamates using Oxyma and thionyl chloride. The addition of Oxyma to thionyl chloride in the presence of Hunig's base results in a mixture of probably Oxyma‐sulfinyl chloride and sulfinyl diOxyma, two new intermediates, which successfully converts the carboxylic acid into its Oxyma ester. Adding a nucleophile to the generated Oxyma ester leads to corresponding amide, ester, or hydroxamic acid formation at room temperature. The procedure is mild and well tolerant to various carboxylic acids, including N‐protected amino acids and different nucleophiles such as methyl esters of amino acids and alcohols. 32 examples with moderate to good yield (67–86 %) are reported. A rigorous mechanism investigation is performed using 1H and 13C‐NMR. By‐product Oxyma can be recovered and recycled. Thionyl chloride has been used for such coupling reactions in industries and academia for a few hundred years to date. Nevertheless, minimum racemization, side reaction, and waste generation make the addition of Oxyma (this methodology) a valuable improvement. [ABSTRACT FROM AUTHOR]

An improved, one‐pot two‐step process is described to convert carboxylic acid to amides, dipeptides, esters, and hydroxamates using Oxyma and thionyl chloride. The addition of Oxyma to thionyl chloride in the presence of Hunig's base results in a mixture of probably Oxyma‐sulfinyl chloride and sulfinyl diOxyma, two new intermediates, which successfully converts the carboxylic acid into its Oxyma ester. Adding a nucleophile to the generated Oxyma ester leads to corresponding amide, ester, or hydroxamic acid formation at room temperature. The procedure is mild and well tolerant to various carboxylic acids, including N‐protected amino acids and different nucleophiles such as methyl esters of amino acids and alcohols. 32 examples with moderate to good yield (67–86 %) are reported. A rigorous mechanism investigation is performed using 1H and 13C‐NMR. By‐product Oxyma can be recovered and recycled. Thionyl chloride has been used for such coupling reactions in industries and academia for a few hundred years to date. Nevertheless, minimum racemization, side reaction, and waste generation make the addition of Oxyma (this methodology) a valuable improvement. [ABSTRACT FROM AUTHOR]

An alternate synthetic route to the important anticancer drug suberoylanilide hydroxamic acid (SAHA) from its α,ß-didehydro derivative is described. The didehydro derivative is obtained through a cross metathesis reaction between a suitable terminal alkene and N-benzyloxyacrylamide. Some of the didehydro derivatives of SAHA were preliminarily evaluated for anticancer activity towards HeLa cells. The administration of the analogues caused a significant decrease in the proliferation of HeLa cells. Furthermore, one of the analogues showed a maximum cytotoxicity with a minimum GI50 value of 2.5 µg/mL and the generation of reactive oxygen species (ROS) as some apoptotic features.

Three new isotypic heteropolynuclear complexes, namely pentaaquacarbonatopentakis(glycinehydroxamato)nitratopentacopper(II)lanthanide(III) x-hydrate, [LnCu5(GlyHA)5(CO3)(NO3)(H2O)5]·xH2O (GlyHA2− is glycinehydroxamate, N-hydroxyglycinamidate or aminoacetohydroxamate, C2H4N2O22−), with lanthanide(III) (LnIII) = gadolinium (Gd, 1, x = 3.5), dysprosium (Dy, 2, x = 3.28) and holmium (Ho, 3, x = 3.445), within a 15-metallacrown-5 class were obtained on reaction of lanthanide(III) nitrate, copper(II) acetate and sodium glycinehydroxamate. Complexes 1–3 contain five copper(II) ions and five bridging GlyHA2− anions, forming a [CuGlyHA]5 metallamacrocyclic core. The LnIII ions are coordinated to the metallamacrocycle through five O-donor hydroxamates. The electroneutrality of complexes 1–3 is achieved by a bidentate carbonate anion coordinated to the LnIII ion and a monodentate nitrate anion coordinated apically to one of the copper(II) ions of the metallamacrocycle. The lattice parameters of complexes 1–3 are similar to those previously reported for an EuIII–CuII 15-metallacrown-5 complex with glycinehydroxamate of proposed composition [EuCu5(GlyHA)5(OH)(NO3)2(H2O)4]·3.5H2O [Stemmler et al. (1999). Inorg. Chem. 38, 2807–2817]. High-quality X-ray data obtained for 1–3 have allowed a re-evaluation of the X-ray data solution proposed earlier for the EuCu5 complex and suggest that the formula is actually [EuCu5(GlyHA)5(CO3)(NO3)(H2O)5]·3.5H2O.

In this study, a strain of Anabaena flos-aquae UTEX 1444 was cultivated in six different concentrations of iron (III). Cultures were extracted with organic solvents and analyzed using our dereplication strategy, based on the combined use of high-resolution tandem mass spectrometry and molecular networking. The analysis showed the presence of the siderophores’ family, named synechobactins, only in the zero iron (III) treatment culture. Seven unknown synechobactin variants were present in the extract, and their structures have been determined by a careful HRMS/MS analysis. This study unveils the capability of Anabaena flos-aquae UTEX 1444 to produce a large array of siderophores and may be a suitable model organism for a sustainable scale-up exploitation of such bioactive molecules, for the bioremediation of contaminated ecosystems, as well as in drug discovery.

An alternative synthesis of α,ß-unsaturated hydroxamates via cross metathesis between a class-I olefin and N-benzyloxyacrylamide is reported. The reaction proceeds better in the presence of Grubbs’ second generation catalyst within short time and in good yields (57–85%) with a range of substrates. Subsequent hydrogenation of each of the CM products delivers the title compounds in moderate to very good yield (70–89%). An important demonstration of the protocol is the preparation of the unusual amino acid component of the bioactive cyclic peptide Chap-31.

Reaction of copper(II) nitrate with pivaloylhydroxamic acid yielded the title compound, [Cu(pivHA)2] (where pivHA− is pivaloyl hydroxamate, C5H10NO2). The centrosymmetric mononuclear complex consists of a CuII ion, which is located on a center of inversion, with two coordinated pivaloyl hydroxamate monoanions. The CuII ion has a square-planar coordination environment consisting of four O atoms – two carbonyl O atoms and two hydroxamate O atoms from two hydroxamate pivHA− ligands. The pivHA− anions are coordinated to copper(II) in a trans-mode, forming two five-membered O,O′-chelate rings.

In this work, we designed, developed, characterized, and investigated a new chelator and its bifunctional derivative for 89Zr labeling and PET-imaging. In a preliminary study, we synthesized two hexadentate chelators named AAZTHAS and AAZTHAG, based on the seven-membered heterocycle AMPED (6-amino-6-methylperhydro-1,4-diazepine) with the aim to increase the rigidity of the 89Zr complex by using N-methyl-N-(hydroxy)succinamide or N-methyl-N-(hydroxy)glutaramide pendant arms attached to the cyclic structure. N-methylhydroxamate groups are the donor groups chosen to efficiently coordinate 89Zr. After in vitro stability tests, we selected the chelator with longer arms, AAZTHAG, as the best complexing agent for 89Zr presenting a stability of 86.4 ± 5.5% in human serum (HS) for at least 72 h. Small animal PET/CT static scans acquired at different time points (up to 24 h) and ex vivo organ distribution studies were then carried out in healthy nude mice (n = 3) to investigate the stability and biodistribution in vivo of this new 89Zr-based complex. High stability in vivo, with low accumulation of free 89Zr in bones and kidneys, was measured. Furthermore, an activated ester functionalized version of AAZTHAG was synthesized to allow the conjugation with biomolecules such as antibodies. The bifunctional chelator was then conjugated to the human anti-HER2 monoclonal antibody Trastuzumab (Tz) as a proof of principle test of conjugation to biologically active molecules. The final 89Zr labeled compound was characterized via radio-HPLC and SDS-PAGE followed by autoradiography, and its stability in different solutions was assessed for at least 4 days.

Three new isotypic heteropolynuclear complexes, namely pentaaquacarbonatopentakis(glycinehydroxamato)nitratopentacopper(II)lanthanide(III) x-hydrate, [LnCu5(GlyHA)5(CO3)(NO3)(H2O)5]·xH2O (GlyHA2- is glycinehydroxamate, N-hydroxyglycinamidate or aminoacetohydroxamate, C2H4N2O22-), with lanthanide(III) (LnIII) = gadolinium (Gd, 1, x = 3.5), dysprosium (Dy, 2, x = 3.28) and holmium (Ho, 3, x = 3.445), within a 15-metallacrown-5 class were obtained on reaction of lanthanide(III) nitrate, copper(II) acetate and sodium glycinehydroxamate. Complexes 1-3 contain five copper(II) ions and five bridging GlyHA2- anions, forming a [CuGlyHA]5 metallamacrocyclic core. The LnIII ions are coordinated to the metallamacrocycle through five O-donor hydroxamates. The electroneutrality of complexes 1-3 is achieved by a bidentate carbonate anion coordinated to the LnIII ion and a monodentate nitrate anion coordinated apically to one of the copper(II) ions of the metallamacrocycle. The lattice parameters of complexes 1-3 are similar to those previously reported for an EuIII-CuII 15-metallacrown-5 complex with glycinehydroxamate of proposed composition [EuCu5(GlyHA)5(OH)(NO3)2(H2O)4]·3.5H2O [Stemmler et al. (1999). Inorg. Chem. 38, 2807-2817]. High-quality X-ray data obtained for 1-3 have allowed a re-evaluation of the X-ray data solution proposed earlier for the EuCu5 complex and suggest that the formula is actually [EuCu5(GlyHA)5(CO3)(NO3)(H2O)5]·3.5H2O. [ABSTRACT FROM AUTHOR]

ADAM8 as a membrane-anchored metalloproteinase-disintegrin is upregulated under pathological conditions such as inflammation and cancer. As active sheddase, ADAM8 can cleave several membrane proteins, among them the low-affinity receptor FcεRII CD23. Hydroxamate-based inhibitors are routinely used to define relevant proteinases involved in ectodomain shedding of membrane proteins. However, for ADAM proteinases, common hydroxamates have variable profiles in their inhibition properties, commonly known for ADAM proteinases 9, 10 and 17. Here, we determined the inhibitor profile of human ADAM8 for eight ADAM/MMP inhibitors by in vitro assays using recombinant ADAM8 as well as the in vivo inhibition in cell-based assays using HEK293 cells to monitor the release of soluble CD23 by ADAM8. ADAM8 activity is inhibited by BB94 (Batimastat), GW280264, FC387 and FC143 (two ADAM17 inhibitors), made weaker by GM6001, TAPI2 and BB2516 (Marimastat), while no inhibition was observed for GI254023, an ADAM10 specific inhibitor. Modeling of inhibitor FC143 bound to the catalytic sites of ADAM8 and ADAM17 reveals similar geometries in the pharmacophoric regions of both proteinases, which is different in ADAM10 due to replacement in the S1 position of T300 (ADAM8) and T347 (ADAM17) by V327 (ADAM10). We conclude that ADAM8 inhibitors require maximum selectivity over ADAM17 to achieve specific ADAM8 inhibition. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective, safe, affordable, and administered via the oral route. Histone deacetylases (HDACs) are involved in silencing critical regulatory pathways, including pro-apoptotic programs, and represent potential therapeutic targets for pharmacological interventions. O -alkyl hydroxamates have traditionally been considered to exert no effect on mammal HDACs. The aim of this study was to evaluate the effect of MDG, a SAHA derivative of the O -alkyl hydroxamate family with no activity on human histone deacetylase enzymes, on the visceral leishmaniasis causative agents and in a murine model of the disease. The effects of vorinostat, tubacin and valproic acid (well-known mammal HDAC inhibitors) on the parasite were also evaluated. MDG was found to be highly active against Leishmania infantum and L. donovani intracellular amastigotes in vitro but not against the promastigote stage. In contrast, vorinostat, tubacin and valproic acid showed no activity against the parasite. Assays investigating hERG and Cav1.2 channels in vitro found no evidence of MDG-driven cardiotoxicity. MDG showed neither hepatotoxicity nor mutagenicity, nor did it exert activity on cytochrome P450 enzymes. MDG was adsorbed onto gold nanoparticles for the in vivo experiments, performed on infected Balb/c mice. MDG was effective at reducing the parasite load in major target tissues (bone marrow, spleen and liver) in more than 70% at 25 mg/kg through both the oral and intraperitoneal route, proving more active than the reference compounds (meglumine antimoniate, MA) without showing toxicity. In addition, the combination of MDG and MA was very effective. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Two new siderophores containing phenylacetate motif were characterized. • The putative biosynthetic gene cluster was identified. • Precursor-directed biosynthesis showed natural flexibility for unnatural precursors. Abstract Two new siderophores belonging to the hydroxamate class, Legonoxamine A (1) and B (2) have been isolated from the soil bacterium, Streptomyces sp. MA37, together with one known compound, desferrioxamine B (3). Their structures were elucidated based on spectroscopic methods including 1D, 2D NMR, MS, as well as by comparison with the relevant literatures. To our knowledge, this is the first report describing a siderophore containing the N -hydroxyl phenylacetyl cadaverine (HPAC) moiety in the structure. Based on bioinformatics analysis and previous knowledge of the biosynthesis of the hydroxamate-type siderophore, the biosynthetic gene cluster (lgo) responsible for the production of 1 – 3 was identified in the annotated genome of the producing strain. The supplementation of phenylacetate and benzoate analogues with meta substitution into the cultures of Streptomyces sp. MA37 resulted in the production of new legonoxamine A derivatives as observed in LC-HR-ESIMS, suggesting that the legonoxamine biosynthetic pathway has a good degree of natural flexibility of accepting unnatural precursors with different functional groups. [ABSTRACT FROM AUTHOR]

Reaction of copper(II) nitrate with pivaloyl­hydroxamic acid yielded the title compound, [Cu(pivHA)2] (where pivHA- is pivaloyl hydroxamate, C5H10NO2). The centrosymmetric mononuclear complex consists of a CuII ion, which is located on a center of inversion, with two coordinated pivaloyl hydroxamate monoanions. The CuII ion has a square-planar coordination environment consisting of four O atoms - two carbonyl O atoms and two hydroxamate O atoms from two hydroxamate pivHA- ligands. The pivHA- anions are coordinated to copper(II) in a trans-mode, forming two five-membered O,O′-chelate rings. [ABSTRACT FROM AUTHOR]

Many elements are scarcely soluble in aqueous conditions found in high pH environments, such as calcareous grassland soils, unless complexed to strong binding organic ligands. To overcome this limitation, some plants and microbes produce chelators that solubilize micronutrient metals such as Fe, Ni, Cu, and Zn from mineral phases. These complexes are taken up by organisms via specific membrane receptors, thereby differentially impacting the bioavailability of these metals to the plant and microbial community. Although the importance of these chelation strategies for individual organisms has been well established, little is known about which pathways coexist within rhizosphere microbiomes or how they interact and compete for metal binding. Identifying these metallophores within natural ecosystems has remained a formidable analytical challenge due to the vast diversity of compounds and poorly defined metabolic processes in complex soil matrices. Herein, we employed recently developed liquid chromatography (LC) mass spectrometry (MS) methods to characterize the speciation of water-soluble dissolved trace elements (Fe, Ni, Cu, and Zn) of soils from native tallgrass prairies in Kansas and Iowa. Both plant and fungal metallophores were identified, revealing compound-specific patterns of chelation to biologically essential metals. Numerous metabolites typically implicated in plant Fe acquisition and homeostasis, including mugineic acids, deoxymugineic acid, nicotianamine, and hydroxynicotianamines, dominated the speciation of divalent metals such as Ni, Cu, and Zn (2–90 pmol/g soil). In contrast, the fungal siderophore ferricrocin was specific for trivalent Fe (7–32 pmol/g soil). These results define biochemical pathways that underpin the regulation of metals in the grassland rhizosphere. They also raise new questions about the competition of these compounds for metal binding and their bioavailability to different members of the rhizosphere population. Small structural modifications result in significant differences in metal ligand selectivity, and likely impact metal uptake within the rhizosphere of grassland soils. [ABSTRACT FROM AUTHOR]

We report a new method of crystal growth and synthesis based on liquid-liquid partitioning that allows for isolation and in-depth characterization of molybdenyl bis(formohydroxamate), Mo-FHA , molybdenyl bis(acetohydroxamate), Mo-AHA , and molybdenyl deferoxamine, Mo-DFO , for the first time. This novel approach affords shorter crystal growth time (hourly timeframe) without sacrificing crystal size or integrity when other methods of crystallization were unsuccessful. All three Mo complexes are characterized in solution via FTIR, NMR, UV–vis, and EXAFS spectroscopy. Mo-AHA and Mo-FHA structures are resolved by single crystal X-ray diffraction. Using the molybdenyl hydroxamate structural information, the speciation of Mo in a siderophore complex (Mo-DFO) is determined via complimentary spectroscopic methods and confirmed by DFT calculations. ESI-MS verifies that a complex of 1:1 molybdenum to deferoxamine is present in solution. Additionally, the Mo solution speciation in the precursor organic phase, MoO 2 (NO 3 ) 2 HEH[EHP] 2 (where HEH[EHP] is 2-ethylhexylphosphonic acid mono-2-ethylhexyl ester), is characterized by FTIR and EXAFS spectroscopy as well as DFT calculations. [ABSTRACT FROM AUTHOR]

A series of amino acid-derived monohydroxamate compounds A1 – A7 was synthesized and characterized for their coordination properties of Fe(III). The series varies in their skeletal lengths and compositions; some compounds lack external substituents, others are substituted with external functional amino or carboxylic groups, or alternatively inert methyl. Undertaken investigations allowed the determination of stoichiometry, stability constants and spectroscopic parameters of formed ferric complexes. Incorporation of an external functional group with a dissociable proton affects the coordination behavior; the presence of carboxylic or amino groups hampers the formation of mono-, di- and trihydroxamate ferric complexes of presented compounds. The differences in Fe(III) affinity of the monohydroxamates vs trihydroxamates was reflected by the stability constants and pFe, indicating the superior stability of hexadentate complexes. [ABSTRACT FROM AUTHOR]

Copper oxide minerals, such as malachite, do not often respond well to traditional copper sulphide collectors, and require alternative flotation schemes. Hydroxamic acid collectors have been suggested as a means to directly float malachite; however, there is limited information on the effect of reagent structure on the performance of these collectors. This paper investigated the effect of five alkyl hydroxamates and two aromatic hydroxamates on the flotation of a synthetic ore composed of pure, fully liberated, malachite and quartz. Zeta potential measurements were used to aid in understanding reagent adsorption onto the surface of the two minerals. The collectors were then evaluated using bench scale flotation results. While zeta potential measurements suggested that all the collectors investigated selectively adsorb onto the surface of malachite, only benzohydroxamic acid and C 8 alkyl hydroxamates were effective collectors in the flotation of malachite. Benzohydroxamic acid was the most selective; however, significantly lower dosages of C 8 alkyl hydroxamates were required to obtain similar malachite recoveries, with minimal increases in quartz recovery. Benzo- and octylhydroxamic acid were further examined for the flotation of fine (−38 μm) particles. For fine particle flotation experiments the effect of temperature was also investigated as a means to improve the flotation performance. [ABSTRACT FROM AUTHOR]

Many studies have indicated that histone deacetylase (HDAC) inhibitors are promising agents for the treatment of cancer. With the aim to search for novel potent HDAC inhibitors, we designed and synthesized two series of hydroxamates and 2-aminobenzamides compounds as HDAC inhibitors and antitumor agents. Those compounds were investigated for their HDAC enzymatic inhibitory activities and in vitro anti-proliferation activities against diverse cancer cell line (A549, HepG2, MGC80-3 and HCT116). Most of the synthesized compounds displayed potent HDAC inhibitory activity and antiproliferative activity. In particular, Compound 12a, N -(2-aminophenyl)-4-[(4-fluorophenoxy)methyl]benzamide, was shown to have the most HDAC inhibitory activity (70.6% inhibition at 5 μM) and antitumor activity with IC50 value of as low as 3.84 μM against HepG2 human liver hepatocellular carcinoma cell line, more than 4.8–fold lower than CS055 and 5.9–fold lower than CI994. HDAC isoform selectivity assay indicated 12a is a potent HDAC2 inhibitor. Docking study of 12a suggested that it bound tightly to the binding pocket of HDAC2. Further investigation showed that 12a could inhibit the migration and colony formation of A549 cancer cells. Furthermore, 12a remarkably induced apoptosis and G2/M phase cell cycle arrest in A549 cancer cells. Those results indicated that compound 12a could be a promising candidate for treatment of cancer. [ABSTRACT FROM AUTHOR]

Among the key environmental factors influencing the fate and transport of radionuclides in the environment is natural organic matter (NOM). While this has been known for decades, there still remains great uncertainty in predicting NOM-radionuclide interactions because of lack of understanding of radionuclide interactions with the specific organic moieties within NOM. Furthermore, radionuclide-NOM studies conducted using modelled organic compounds or elevated radionuclide concentrations provide compromised information related to true environmental conditions. Thus, sensitive techniques are required not only for the detection of radionuclides, and their different species, at ambient and/or far-field concentrations, but also for potential trace organic compounds that are chemically binding these radionuclides. GC-MS and AMS techniques developed in our lab are reviewed here that aim to assess how two radionuclides, iodine and plutonium, form strong bonds with NOM by entirely different mechanisms; iodine tends to bind to aromatic functionalities, whereas plutonium binds to N-containing hydroxamate siderophores at ambient concentrations. While low-level measurements are a prerequisite for assessing iodine and plutonium migration at nuclear waste sites and as environmental tracers, it is necessary to determine their in-situ speciation, which ultimately controls their mobility and transport in natural environments. More importantly, advanced molecular-level instrumentation (e.g., nuclear magnetic resonance (NMR) and Fourier-transform ion cyclotron resonance coupled with electrospray ionization (ESI-FTICRMS) were applied to resolve either directly or indirectly the molecular environments in which the radionuclides are associated with the NOM. [ABSTRACT FROM AUTHOR]

A set of 12 novel hydroxamate compounds (NHCs), structurally designed as inhibitors of histone deacetylase (HDAC) enzyme, were synthesized at our facility. These were adamantane derivatives with N-hydroxyacetamide as pharmacophore, and each of these compounds was tested for potentiating activity on fluconazole. The concentration of fluconazole which completely inhibited (concentration of complete inhibition [CCI]) the growth of Candida albicans ATCC 90028 and C. albicans ATCC 64550 was determined by micro-dilution method in the absence and presence of NHCs. The CCI of fluconazole without the NHC combination was 64 µg/ml and 1024 µg/ml against C. albicans ATCC 90028 and C. albicans ATCC 64550, respectively. The majority of the NHCs potentiated the fluconazole activity markedly as CCI of fluconazole against C. albicans ATCC 90028 reduced to 0.25 µg/ml. Similarly, CCI of fluconazole against C. albicans ATCC 64550 reduced to 4-8 µg/ml in combination with majority of NHCs while the best activity was displayed by the compound 1 with a reduction of CCI to 0.5 µg/ml. The study results revealed the potential usage of hydroxamate derivatives, structurally designed as HDAC inhibitors to enhance the activity of fluconazole against C. albicans. [ABSTRACT FROM AUTHOR]

The betulinic acid-derived hydroxamates 5 – 18 , the amides 19 – 24 , and betulin-derived bis-carbamates 25 – 28 as well as the carbamates 31 – 40 and 44 – 48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3- O -acetyl hydroxamic acid 5 EC 50 values as low as EC 50 = 1.3 μM were found, N , O -bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC 50 = 16–20 μM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC 50 = 5.9 μM for A2780 human ovarian carcinoma cells and EC 50 > 30 μM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19 – 24 and of betulin derived bis-carbamates 25 – 28 was low, except for N -ethyl substituted 25 . Hexyl substituted 39 showed EC 50 = 5.6 μM (518A2 cells) while for mouse fibroblasts EC 50 > 30 was determined. [ABSTRACT FROM AUTHOR]

The continuous development of drug resistance by Plasmodium falciparum , the agent responsible for the most severe forms of malaria, creates the need for the development of novel drugs to fight this disease. Fosmidomycin is an effective antimalarial and potent antibiotic, known to act by inhibiting the enzyme 1-deoxy- d -xylulose-5-phosphate reductoisomerase (DXR), essential for the synthesis of isoprenoids in eubacteria and plasmodia, but not in humans. In this study, novel constrained cyclic prodrug analogues of fosmidomycin were synthesized. One, in which the hydroxamate function is incorporated into a six-membered ring, was found have higher antimalarial activity than fosmidomycin against the chloroquine and mefloquine resistant P. falciparum Dd2 strain. In addition, it showed very low cytotoxicity against cultured human cells. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effect of adding a matrix metalloproteinase (MMP) inhibitor (BB94, Batimastat) to the primer of a three-step etch and rinse adhesive system on caries-affected dentin (CaD) MMP activity, and to assess the effect of such an inclusion on the chemical content of the CaD-adhesive interface. Methods Caries-infected dentin (CiD) was excavated selectively from freshly extracted human carious teeth using a chemo-mechanical agent. Each tooth was sectioned into three slabs through the CaD retained cavity. These were treated with either Optibond FL “OB” (Kerr, Orange, USA) without MMP inhibitor, or with 500 μM BB94 prior to the application of OB primer and bond, or with OB primer that contained 5 μM BB94. In situ zymography and Raman micro-spectroscopy were used to investigate MMP activity and the changes in the chemical content at the CaD/adhesive interface, respectively. Results Data showed the use of OB adhesive with BB94 resulted in immediate interfacial MMP inhibition, by direct application (93.3%) and by means of a drug delivery system (80%), as demonstrated by in situ zymography. Raman imaging revealed 33% higher resin infiltration into MMP-inhibited adhesive interfaces (SE 3.88). Significance Through competitive inhibition by batimastat (BB94), a proportion of the MMPs found in CaD were inhibited immediately and irreversibly. Such a competitive mechanism brings the adhesive primer close to the collagen matrix and enhances the dental adhesive wettability, which is a proposed mechanism to explain the presence of more resin within the hybrid layer. [ABSTRACT FROM AUTHOR]

Siderophore-producing bacteria/actinobacteria and fungi were isolated from O- (organic), E- (eluvial), B- (upper illuvial), and C- (parent material) horizons of podzol soil. Siderophores were isolated and hydroxamate type siderophores were detected and quantitated by high-performance liquid chromatography coupled to electrospray ionization mass spectrometry. The molecular identification of siderophore-producing isolates showed that there was a high diversity of fungal and bacterial/actinobacterial species throughout the soil profile. The isolated bacteria/actinobacteria showed different abilities in the production of ferrioxamines (E, B, G and D). Moreover, the isolated fungal species showed great variety in the production of ferrichromes, coprogens and fusarinines. [ABSTRACT FROM AUTHOR]

Introduction Hepatocellular carcinoma (HCC) is the most abundant tumour of the liver with rising patient numbers in the Western world countries. Despite newly approved drugs like protein kinase inhibitors the survival rate is still poor. Methods In order to identify potential new drugs for the treatment of HCC we investigated the real-time cell viability, apoptosis induction (sub-G1 cells), and HDAC (histone deacetylase) activity of two hepatocellular cancer cell lines HepG2 and Hep3B treated with new imidazole-tethered hydroxamates. Results The tested cinnamyl hydroxamates exhibited significant antiproliferative and cytotoxic activity in HCC cells as apparent from high sub-G1 cell levels in flow cytometric cell cycle analyses. In Hep3B cells HDAC inhibition was observed comparable in magnitude to that induced by the clinically applied HDAC inhibitor SAHA (Zolinza, Vorinostat). Conclusions The new imidazolyl hydroxamic acids lend themselves as a possible alternative to SAHA in the therapy of HCC. Even more so since similar 4,5-diarylimidazoles lacking only the hydroxamate functionality were previously shown in animal studies to be well tolerated and orally applicable. [ABSTRACT FROM AUTHOR]

The influence of lead nitrate on rare earth flotation in the presence of hydroxamates as collectors has been investigated by a combination of micro-flotation tests and time of flight secondary ion mass spectrometry (ToF-SIMS) surface chemical analysis. Micro-flotation tests identified a link between lead nitrate dose and an improved grade of REE minerals for concentrates. The testing also identified differences in the flotation behaviour of light rare earth (LREEs, La or Ce bearing minerals) and Y and Zr bearing minerals. TOF-SIMS analyses evaluated the variability in surface components on undifferentiated REE grains from the concentrates and tails samples in response to the varied lead nitrate dosing in micro-flotation tests. The surface analyses showed that both the REE grains and gangue phases reporting to the concentrate have higher relative surface proportions of both Pb and collectors as compared to those reporting to the tails. It is noted that the lead does not appear to be associated with an increase in collector adsorption, so the grade of REE can go up is not by selective adsorption of collectors. The significantly higher intensity of Pb species identified on the surface of the concentrate would suggest that lead addition can actually reverse the surface charge making it efficient for collectors to adsorb onto surfaces that they could not easily close to. It is also possible PbOH + potentially acting as a point activator. [ABSTRACT FROM AUTHOR]

[Display omitted] • The main protease (Mpro) of SARS-CoV-2 is promising target for antiviral drugs to combat COVID-19; • The hydroxamates and thiosemicarbazones effectively inhibited Mpro with an IC 50 in range of 0.12–34.22 μM; • The hydroxamates irreversibly, but thiosemicarbazones reversibly and competitively bind to Mpro. The emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (Mpro) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibitor against Mpro is an ideal strategy to combat COVID-19. In this work, twenty-three hydroxamates 1a - i and thiosemicarbazones 2a - n were identified by FRET screening to be the potent inhibitors of Mpro, which exhibited more than 94% (except 1c) and more than 69% inhibition, and an IC 50 value in the range of 0.12–31.51 and 2.43–34.22 μM, respectively. 1a and 2b were found to be the most effective inhibitors in the hydroxamates and thiosemicarbazones, with an IC 50 of 0.12 and 2.43 μM, respectively. Enzyme kinetics, jump dilution and thermal shift assays revealed that 2b is a competitive inhibitor of Mpro, while 1a is a time-dependently inhibitor; 2b reversibly but 1a irreversibly bound to the target; the binding of 2b increased but 1a decreased stability of the target, and DTT assays indicate that 1a is the promiscuous cysteine protease inhibitor. Cytotoxicity assays showed that 1a has low, but 2b has certain cytotoxicity on the mouse fibroblast cells (L929). Docking studies revealed that the benzyloxycarbonyl carbon of 1a formed thioester with Cys145, while the phenolic hydroxyl oxygen of 2b formed H-bonds with Cys145 and Asn142. This work provided two promising scaffolds for the development of Mpro inhibitors to combat COVID-19. [ABSTRACT FROM AUTHOR]

A series of hydroxamates ( 4a–4l ) were prepared from p -aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds ( 4f & 4l ) were found to inhibit HDAC8 at concentrations (IC 50 ) less than 20 μM. [ABSTRACT FROM AUTHOR]

Despite the fact that heterotrophic nitrification was identified more than 100 years ago, the biochemistry of heterotrophic nitrifiers is poorly known and their contribution to nitrification in soil is still speculative. Heterotrophic nitrifiers need organic compounds as their energy source in contrast to the chemolithotrophic nitrifiers. Most of the potential pathways for nitrite/nitrate production by heterotrophs can be considered as secondary metabolism. Only nitrification and simultaneous denitrification by some heterotrophic bacteria is known to have connection to the energy metabolism. Evidently, the nitrification pathways of bacteria and fungi differ. Some heterotrophic bacteria oxidizing ammonia have ammonia monooxygenase (AMO), but there are also heterotrophic bacteria oxidizing ammonia without AMO. The structure of AMO of chemolithotrophic ammonia oxidizers and heterotrophs differs. AMO has not been found in nitrifying fungi. The conditions for heterotrophic nitrification in soil highly differ from those in waste waters where heterotrophic nitrification activity can be high. Heterotrophic nitrification in soil is limited by the low availability of easily decomposable organic substrates. Possible nitrification by heterotrophs in the rhizosphere and endophytic root microbes gaining a good supply of substrates from plants is not known. Fungi are of special interest in heterotrophic nitrification in soil because fungi can evidently nitrify not only easily decomposable substrates but also when decomposing recalcitrant organic compounds (like lignin) which are abundant in soil. Nitrite/nitrate production from easily decomposable nitrogenous organic compounds, such as amino acids, is common among heterotrophic bacteria and fungi. The general conclusion that heterotrophs use solely an "organic pathway" in their nitrification is, however, not valid because also ammonia can be oxidized. Owing to the diverse, poorly known biochemistry of heterotrophic nitrification and methodological difficulties to differentiate heterotrophic and chemolithotrophic nitrification in soil, the role of heterotrophic nitrification in soil nitrogen cycle remains uncertain. • Heterotrophic nitrification involves several poorly known mechanisms. • Heterotrophic bacteria, unlike fungi can possess ammonia monooxygenase. • Fungi are able to nitrify easily decomposable and recalcitrant organic compounds. • The methods available do not allow accurate determination of nitrification in soil. [ABSTRACT FROM AUTHOR]

Abstract: Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. [Copyright &y& Elsevier]

Abstract: Central heteroaryl ring analogues belonging to a series of potent hydroxamate TACE inhibitors were synthesized. The TACE inhibitory activities of these compounds were evaluated by in vitro WBA and in silico molecular modeling studies using crystal structure of human TACE. Compound 14 showed very good in vitro inhibition, supported by the in silico docking studies. [Copyright &y& Elsevier]

Abstract: An asymmetric method to synthesize cis-configured β-lactams using photochemistry has been developed. Aerobic photo-oxidation of l-cysteine-derived thiazolidine hydroxamate esters afforded C-3 hydroxylated products which when cyclized and deprotected gave the corresponding N-protio monocyclic β-lactams. [Copyright &y& Elsevier]