Cyclic Hydroxamic Acids Research Articles

Simple electrochemical synthesis of cyclic hydroxamic acids by reduction of nitroarenes.

The electrochemical reduction of nitroarenes allows direct access to manifold nitrogen containing heterocycles. This work reports the simple and direct electro-organic synthesis of 18 different examples of 2H,4H-4-hydroxy-1,4-benzoxazin-3-ones in up to 81% yield. The scalability of the method was demonstrated on a gram-scale.

Complexes of Fe(III) and Ga(III) Derived from the Cyclic 6‐ and 7‐Membered Hydroxamic Acids Found in Mixed Siderophores

AbstractSix‐ and seven‐membered cyclic hydroxamic acids are found as terminal binding units in different families of siderophores, including exochelins and mycobactins. The simplest models of these preorganized chelating ligands were known, but their coordination chemistry with Fe3+, the target metal ion of siderophores, had never been reported. Four complexes were synthesized and studied: two Fe3+ complexes, one with the six‐membered ring hydroxamate PIPO− and one with the seven‐membered ring hydroxamate AZEPO−, and the two corresponding Ga3+ complexes. X‐ray diffraction studies showed that the interligand repulsion energies were better minimized in the case of the AZEPO− complexes whatever the metal cation considered, and that the Fe−O bond distances were shorter in [Fe(AZEPO)3] by comparison with [Fe(PIPO)3].

Acylative Kinetic Resolution of Cyclic Hydroxamic Acids.

Racemic cyclic hydroxamic acids bearing an aryl substituent adjacent to the hydroxyl group undergo effective acylative kinetic resolution promoted by benzotetramisole (BTM).

New reagent space and new scope for the Castagnoli-Cushman reaction of oximes and 3-arylglutaconic anhydrides.

The Castagnoli-Cushman reaction of oximes, discovered originally for homophthalic anhydride, stimulated the search for other cyclic anhydrides that would be workable in that reaction. Finally, 3-arylglutaconic acid anhydrides were identified as displaying the right reactivity towards a wide range of oximes (including those which did not react with homophthalic anhydride, such as derivatives of aliphatic aldehydes or ketones and substrates with nucleophilic side groups) and delivering, after 18 h at 110 °C in DMSO, β,γ-unsaturated N-hydroxylactam products lacking the carboxylic acid functionality as the result of decarboxylation accompanying the cyclocondensation process. The reaction was found to be scalable to gram quantities of the starting anhydrides. The products were shown to be easily amenable to post-condensational double-bond transposition or reduction. As expected from cyclic hydroxamic acids, the reaction products were shown to bind Fe(III) and Cu(II) ions (selectively out of a panel of 16 metal cations) and potentially serve as fluorescent metal sensors.

Mechanisms of the Cytotoxic Action of Novel Cyclic Hydroxamic Acids

Cyclic hydroxamic acids (CHAs) based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. Among the synthesized CHAs two compounds-hits exhibiting the multipharmacological type of the antineoplastic activity have been identified. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species (ROS) and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases (HDACs), involved in the epigenetic regulation of tumor genesis. Thus, the synthesized CHAs may be considered as a promising basis for creating potential oncolytics.

Powdery mildew (Blumeria graminis f. sp. tritici) infection and amount of key defence chemicals - cyclic hydroxamic acids - of field cultivated wheat (Triticum aestivum L.)

Cultivated wheat varieties have different degrees of resistance against powdery mildew. Cyclic hydroxamic acids are key defence chemicals of wheat. Examinations comprised the measurement of cyclic hydroxamic acid content and powdery mildew infection of three varieties (Lukullus, Lennox, Ispan) and a hybrid (Hystar) of field cultivated wheat, and the effectivity of two biological (Polyversum and Trifender) and one conventional fungicide (Solyom) on powdery mildew. Sample collection and measurement of fungus infection were carried out on three occasions: at BBCH 23-24, BBCH 32-33 and BBCH 77-83 phenological phases. Variety/hybrid and sampling time has significant effect on cyclic hydroxamic acid content, but there was no direct correlation between hydroxamic acid content and powdery mildew infection. Differences were found amongst varieties/hybrid in powdery mildew infection too. Only the hybrid, Hystar, showed considerable infection at every sampling time. The conventional chemical out of fungicides alone proved to be effective, and its effectivity lasted for five weeks.

Mechanisms of cytotoxic action of a series of directionally synthesized heterocyclic hydroxamic acids

Cyclic hydroxamic acids based on quinazoline-4(3H)-one and dihydroquinazoline-4(1H)-one have been synthesized. The antioxidant and iron-chelating properties of these compounds, their effect on the activity of the histone deacetylase enzyme, and their cytotoxic effect on cells of various tumor lines have been investigated. We have identified two compounds-hits, which exhibit the multipharmacological type of the antineoplastic activity. Their cytotoxic effect on cells of human lung carcinoma A549 and breast adenocarcinoma MCF-7 is obviously associated with their ability to modulate the level of reactive oxygen species and to chelate Fe(II) ions, as well as to inhibit the metalloenzymes, histone deacetylases, involved in the epigenetic regulation of tumor genesis. Thus, the synthesized hydroxamic acids may be considered as a promising basis for creating potential oncolytics.

Design and Synthesis of Optically Pure Dibenzo-difuso-azacentrotriquinacene-based Pseudo-C2-Symmetric Cyclic Hydroxamic Acid

Cyclic hydroxamic acids are found in various natural products and bioactive compounds, which exhibit various bioactivities, such as HDAC inhibition and MMP inhibition. Furthermore, they have relati...

Facile Access to Fe(III)-Complexing Cyclic Hydroxamic Acids in a Three-Component Format.

Cyclic hydroxamic acids can be viewed as effective binders of soluble iron and can therefore be useful moieties for employing in compounds to treat iron overload disease. Alternatively, they are analogs of bacterial siderophores (iron-scavenging metabolites) and can find utility in designing antibiotic constructs for targeted delivery. An earlier described three-component variant of the Castagnoli—Cushman reaction of homophthalic acid (via in situ cyclodehydration to the respective anhydride) was extended to involve hydroxylamine in lieu of the amine component of the reaction. Using hydroxylamine acetate and O-benzylhydroxylamine was key to the success of this transformation due to greater solubility of the reagents in refluxing toluene (compared to hydrochloride salt). The developed protocol was found suitable for multigram-scale syntheses of N-hydroxy- and N-(benzyloxy)tetrahydroisoquinolonic acids. The cyclic hydroxamic acids synthesized in the newly developed format have been tested and shown to be efficient ligands for Fe3+, which makes them suitable candidates for the above-mentioned applications.

Establishing biotic stress tolerance of maize (Zea mays L.) by measuring hydroxamic acid contents


 Cyclic hydroxamic acids are the most considerable secondary metabolites in grasses and their main task is to protect these species from pathogens and pests. The cyclic hydroxamic acid content and common smut susceptibility were examined in our experiments. 27 maize hybrids were used for experimental plants in a climate room, where the plants were grown on a nutrient solution. An infiltration method was used for the inoculation of the plants. The total quantity of cyclic hydroxamic acids was determined and the ratio of infected plants and the ratio of inhibition was determined, too. Based on our results, on the basis of all hybrids’ data, the total hydroxamic acid content of the infected plants was higher than in the control. On the level of individual hybrids, only 9 of them had higher cyclic hydroxamic acid content in the case of infection. Increase in cyclic hydroxamic content induced by the fungus in this case is a tool for the fungus to suppress other pathogens and pests. Amongst the hybrids’ cyclic hydroxamic acid contents, significant differences were detected in the control and in the infected treatment, too. The so-called “sweetcorn” hybrids showed high level of cyclic hydroxamic acid content. According to the differences amongst hybrids, homogenous groups were created which groups differed in the case of control and infected treatment, because of the difference in increase of cyclic hydroxamic acid content. The examined hybrids showed different levels of infection and different rate of growth inhibition for the effect of inoculation. According to the infection caused damage hybrids were ranked. Infection caused notable damage for hybrids Prelude, Desszert 73, DKC5276 and DK440.

Chemosensitizing Activity of Histone Deacetylases Inhibitory Cyclic Hydroxamic Acids for Combination Chemotherapy of Lymphatic Leukemia

Anti-tumor effect of hydroxamic acid derivatives is largely connected with its properties as efficient inhibitors of histone deacetylases, and other metalloenzymes involved in carcinogenesis. The work was aimed to (i) determine the anti-tumor and chemosensitizing activity of the novel racemic spirocyclic hydroxamic acids using experimental drug sensitive leukemia P388 of mice, and (ii) determine the structure-activity relationships as metal chelating and HDAC inhibitory agents. Outbreed male rat of 200-220 g weights were used in biochemical experiments. In vivo experiments were performed using the BDF1 hybrid male mice of 22-24 g weight. Lipid peroxidation, Fe (II) -chelating activity, HDAC fluorescent activity, anti-tumor and anti-metastatic activity, acute toxicity techniques were used in this study. Chemosensitizing properties of water soluble cyclic hydroxamic acids (CHA) are evaluated using in vitro activities and in vivo methods and found significant results. These compounds possess iron (II) chelating properties, and slightly inhibit lipid peroxidation. CHA prepared from triacetonamine (1a-e) are more effective Fe (II) ions cheaters, as compared to CHA prepared from 1- methylpiperidone (2a-e). The histone deacetylase (HDAC) inhibitory activity, lipophilicity and acute toxicity were influenced by the length amino acids (size) (Glycine < Alanine < Valine < Leucine < Phenylalanine). All compounds bearing spiro-N-methylpiperidine ring (2a-e) are non-toxic up to 1250 mg/kg dose, while compounds bearing spiro-tetramethylpiperidine ring (1a-e) exhibit moderate toxicity which increases with increasing lipophility, but not excite at 400 mg/kg. It was shown that the use of combination of non-toxic doses of cisplatin (cPt) or cyclophosphamide with CHA in most cases result in the appearance of a considerable anti-tumor effect of cytostatics. The highest chemosensitizing activity with respect to leukemia Р388 is demonstrated by the CHA derivatives of Valine 1c or 2c.

Acanthus mollis L. leaves as source of anti-inflammatory and antioxidant phytoconstituents

This work expands the phytochemical composition knowledge of Acanthus mollis and evaluates antioxidant and anti-inflammatory activities which could be related with its traditional uses. Extracts from leaves, obtained by sequential extraction, were screened using TLC and HPLC-PDA. The ethanol extract was the most active on DPPH assay (IC50 = 20.50 μg/mL) and inhibited nitric oxide (NO) production in RAW 264.7 macrophages (IC50 = 48.31 μg/mL). Significant amounts of cyclic hydroxamic and phenolic acids derivatives were detected. A lower antioxidant effect was verified for a fraction enriched with DIBOA derivatives (IC50 = 163.02 μg/mL), suggesting a higher contribution of phenolic compounds for this activity in ethanol extract. However, this fraction exhibited a higher inhibition of NO production (IC50 = 32.32 μg/mL), with absence of cytotoxicity. These results support the ethnomedical uses of this plant for diseases based on inflammatory processes. To our knowledge, it is the first report to the anti-inflammatory activity for DIBOA derivatives.

Cyclic Hydroxamic Acid Analogues of Bacterial Siderophores as Iron-Complexing Agents prepared through the Castagnoli-Cushman Reaction of Unprotected Oximes.

The first application of multicomponent chemistry (the Castagnoli-Cushman reaction) toward the convenient one-step preparation of cyclic hydroxamic acids is described. Cyclic hydroxamic acids are close analogues of bacterial siderophores (iron-binding compounds) and form stable complexes with Fe3+ ions as confirmed by spectrophotometric measurements. These compounds are potential components for the design of chelating agents for iron overload disease therapy, as well as siderophore-based carrier systems for antibiotic delivery across the bacterial cell wall.

A safe and selective method for reduction of 2-nitrophenylacetic acid systems to N-aryl hydroxamic acids using continuous flow hydrogenation

The cyclic hydroxamic acid functional group is critical to the biological activity of numerous natural products and drug candidates. Efficient, reliable, and green synthetic methods to produce cyclic hydroxamic acids are needed. Herein, flow hydrogenation has been explored as a novel approach toward achieving the selective partial reduction of 2-nitrophenylacetic acid to 1-hydroxyindolin-2-one. The bidentate ligand, 1,10-phenanthroline, has been identified as a unique inhibitor for modulating product selectivity in this Pt/C-catalyzed process. Under the newly optimized reaction conditions, the targeted hydroxamic acid is produced with high selectivity (49:1) over the lactam by-product. The scope of the reaction is demonstrated for a variety of 2-nitrophenylacetic acid derivatives.

Extract from Maize (Zea mays L.): Antibacterial Activity of DIMBOA and Its Derivatives against Ralstonia solanacearum.

Many cereals accumulate hydroxamic acids involved in defense of plant against various fungi, bacteria, and insects. 2,4-dihydroxy-7-methoxy-1,4-benzoxazine-3-one, commonly known as DIMBOA, is one of the principal cyclic hydroxamic acids in aqueous extracts of maize. The aim of this study was to evaluate the antibacterial activity of the isolated DIMBOA and its derivatives 2-benzoxazolinone (BOA), 6-chloro-2-benzoxazolinone (CDHB), and 2-mercaptobenzothiazole (MBT) against Ralstonia solanacearum. MBT showed the strongest antibacterial activity, followed by CDHB and DIMBOA, with minimum inhibitory concentrations (MICs) of 50, 100 and 200 mg/L, respectively, better than the BOA with 300 mg/L. These compounds also significantly affect bacterial growth, reduce biofilm formation, and inhibit swarming motility within 24 h. This paper is the first to report the anti-R. solanacearum activity of DIMBOA from Z. mays. The bioassay and pot experiment results suggested that DIMBOA and its derivatives exhibit potential as a new matrix structure of designing target bactericide or elicitor for controlling tobacco bacterial wilt. Further studies must evaluate the efficacy of DIMBOA and its derivatives in controlling bacterial wilt under natural field conditions where low inoculum concentrations exist.

THE EFFECT OF CYCLIC HYDROXAMIC ACIDS ON ACTIVITY OF CА&lt;sup&gt;2&lt;/sup&gt;+-ATPASE OF SARCOPLASMIC RETICULUM AND CYCLIC GUANOSINE MONOPHOSPHODIESTERASE

Objective. The aim of the study was to research effect of new cyclic hydroxamic acids (CHA) I-VI on activity of Ca 2 +-ATPase of sarcoplasmic reticulum and cyclic guanosine monophosphodiesterase. Materials and methods. Activity of Ca 2 +-ATPase of sarcoplasmic reticulum and cyclic guanosine monophosphodiesterase has been evaluated. Results. It has been shown that at studied concentration (0.1 mM; 0.01 and 1 mM), CHA I-VI separate hydrolytic and transporting functions of Ca 2 +-ATPase of sarcoplasmic reticulum. Therefore, the antimetastatic effect of these compounds is assumed. Thus, at concentration of 0.1 mM, CHA inhibit active transport of calcium through the sarcoplasmic reticulum membrane by 40 ± 4 % (CHA-I), 50 ± 5% (CHA-II), 53 ± 5% (CHA-III), 70 ± 8% (CHA-V) and 75 ± 8% (CHA-VI) and inhibit hydrolysis of ATP by 20 ± 2%, 0 %, 0 %, 45 ± 5 % and 47 ± 3 % respectively. CHA-III, CHA-V and CHA-VI inhibit active transport of Са 2 + by 46 ± 5 %, 47 ± 5 % and 60 ± 6 %, and not inhibit or inhibit by 23 ± 2 % and 27 ± 3 % respectively, hydrolysis of ATP at concentration of 0.01 mM. CHA-V inhibits reversibly and non-competitively the hydrolytic function of Ca 2 +-ATPase of sarcoplasmic reticulum with K = 4 x 10 -5 M. All studied CHA inhibit activity of cyclic guanosine monophosphodiesterase at concentration of 0.1 mM, by less than 20 %. Conclusion. The data obtained predicts the antimetastatic activity of compounds CHA-II, CHA-III, CHA-V, CHA-VI. We recommend to study of CHA-II, CHA-III, CHA-V, CHA-VI on animal models as promising antimetastatic drugs.

Ring expansions of acyloxy nitroso compounds

Treatment of cyclopentanone and cyclobutanone-derived oximes with lead(IV) tetraacetate gives the bright blue acyloxy nitroso compounds, which upon basic hydrolysis yields the ring expansion product cyclic hydroxamic acids in 12–81% yield. Reactions of substituted cyclopentanones provide ring expanded products where the –NOH group regioselectively inserts to the more substituted position and gives a better yield compared to the treatment of the same ketone with a basic solution of Piloty’s acid. Reaction of phosphines with acyloxy nitroso compounds generally generates a ring-expanded Beckmann rearrangement product that can be hydrolyzed to the corresponding lactam. Acyloxy nitroso compounds that undergo rapid hydrolysis to HNO do not show this ring expansion reactivity. These results further demonstrate the versatility of acyloxy nitroso compound to yield structurally complex materials.

Synthesis and Structural Study of Tetravalent (Zr4+, Hf4+, Ce4+, Th4+, U4+) Metal Complexes with Cyclic Hydroxamic Acids

AbstractSix‐ and seven‐membered cyclic hydroxamic acids, such as 1‐hydroxypiperidine‐2‐one (1H, 1,2‐PIPOH) and 1‐hydroxyazepan‐2‐one (2H), have recently been identified in some mixed siderophores as one of their three chelating subunits. Compared to their ubiquitous noncyclic counterparts, cyclic hydroxamates are preorganized for metal binding. Surprisingly, the coordination chemistry of these bidentate, monoanionic ligands remains virtually unknown, even in the case of iron(III). We report herein the first structural study of the complexes of 1– and of 6–, an unsaturated seven‐membered ring analog of 2–, with tetravalent cations of transition metals (zirconium and hafnium), lanthanide (cerium), and actinides (thorium and uranium). Structural characterization by means of X‐ray crystallography of the corresponding ML4 complexes evidenced distorted square antiprismatic coordination geometries with the exception of U4+, which favors a dodecahedral arrangement.

5-Membered cyclic hydroxamic acids as HDAC inhibitors

The new histone deacylases inhibitors (HDACi) were synthesized in the class of 5-membered cyclic hydroxamic acids (5-CHA), showing medium size CHA as a new Zn-binding group. New reaction sequence was proposed for the synthesis of 5-membered alkylidene-cyclic-hydroxamic acids starting from butyrolactone. Compound 10c showed low µM activity on HeLa cell extracts. From these results, cyclic hydroxamic acids will be further investigated to find more potent compounds.

Effect of Cyclic Hydroxamic Acids Derived from Glycine and D,L-Alanine on Activity of Ca2+, Mg2+-ATPase Hydrolases of Sarcoplasmic Reticulum and Cyclic Guanosine Monophosphate Phosphodiesterase

The effects of cyclic hydroxamic acids (CHAs) derived from glycine and D,L-alanine on the enzymatic activity of Ca2+,Mg2+-ATPase from sarcoplasmic reticulum (Ca2+,Mg2+-ATPase SR) and cyclic guanosine monophosphate phosphodiesterase (PDEcGMP) were investigated. CHAs I (C5H10N2O2), II (C6H12N2O2), III (C8H15N3O2), IV (C9H17N3O2), V (C11H21N3O2), and VI (C12H23N3O2) were modulators of Ca2+,Mg2+-ATPase SR enzyme activity. Compounds I-VI decoupled to various extents the hydrolytic and transport functions of Ca2+,Mg2+-ATPase SR, disrupting the ratio of intra- and extracellular Ca2+ ions. This affected the adhesion of metastatic cells to capillary endothelium. Compounds IV and VI had the highest metastasis inhibition indices (MII%) for B-16 melanoma of 33 and 81%, respectively. This correlated with a decreased Ca2+ transmembrane transfer coefficient into SR vesicles of 0.75 for IV and 0.5 for VI compared with a [Ca2+]/[ATP] ratio in the control of 1.4. CHAs I-VI did not affect the functioning of PDEcGMP. The results enabled potential antimetastatic drugs in the CHA series to be predicted.