Hydroxamic Acid Groups Research Articles

Snapshots of Dynamic Adaptation: Two‐Dimensional Molecular Architectonics with Linear Bis‐Hydroxamic Acid Modules

AbstractLinear modules equipped with two terminal hydroxamic acid groups act as the building block of diverse two‐dimensional supramolecular motifs and patterns with room‐temperature stability on the close‐packed single‐crystal surfaces of silver and gold, revealing a complex self‐assembly scenario. By combining multiple investigation techniques (scanning tunneling microscopy, atomic force microscopy, X‐ray photoelectron spectroscopy, and density functional theory calculations), we analyze the characteristics of the ordered assemblies which range from close‐packed structures to polyporous networks featuring an exceptionally extended primitive unit cell with a side length exceeding 7 nm. The polyporous network shows potential for hosting and promoting the formation of chiral supramolecules, whereas a transition from 1D chiral randomness to an ordered racemate is discovered in a different porous phase. We correlate the observed structural changes to the adaptivity of the building block and surface‐induced changes in the chemical state of the hydroxamic acid functional group.

Snapshots of Dynamic Adaptation: Two-Dimensional Molecular Architectonics with Linear Bis-Hydroxamic Acid Modules.

Linear modules equipped with two terminal hydroxamic acid groups act as the building block of diverse two‐dimensional supramolecular motifs and patterns with room‐temperature stability on the close‐packed single‐crystal surfaces of silver and gold, revealing a complex self‐assembly scenario. By combining multiple investigation techniques (scanning tunneling microscopy, atomic force microscopy, X‐ray photoelectron spectroscopy, and density functional theory calculations), we analyze the characteristics of the ordered assemblies which range from close‐packed structures to polyporous networks featuring an exceptionally extended primitive unit cell with a side length exceeding 7 nm. The polyporous network shows potential for hosting and promoting the formation of chiral supramolecules, whereas a transition from 1D chiral randomness to an ordered racemate is discovered in a different porous phase. We correlate the observed structural changes to the adaptivity of the building block and surface‐induced changes in the chemical state of the hydroxamic acid functional group.

Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation

Neuroblastoma is the most common extracranial solid tumor found in children and survival rate is extremely meager. HDAC8, a class I zinc-dependent enzyme, is a potential drug target for treatment of neuroblastoma and T cell lymphoma. Most of the HDAC8 inhibitors discovered till date contains a hydroxamic acid group which acts as a zinc binding group. The high binding affinity to the zinc and other ions results in adverse effects. Also, the non-selective inhibition of HDACs cause a variety of side effects. The objective of this is to identify structurally diverse, non-hydroxamate, novel, potential and selective HDAC8 inhibitors. A number of five featured pharmacophore hypotheses were generated using 32 known selective HDAC8 inhibitors. The hypotheses ADDRR.4 were selected for building 3D QSAR model. This model has an excellent correlation coefficient and good predictive ability, which was employed for virtual screening of Phase database containing 4.3 × 106 molecules. The resultant hits with fitness score >1.0 were optimized using in-silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and XP glide docking studies. On the basis of pharmacophore matching, interacting amino acid residues, XP glide score, more affinity towards HDAC8 and less affinity towards other HDACs, and ADME results five hits- SD-01, SD-02, SD-03, SD-04 and SD-05 with new structural scaffolds, non-hydroxamate were selected for in vitro activity study. SD-01 and SD-02 were found to be active in the nanomolar (nM) range. SD-01 had considerably good selectivity for HDAC8 over HDAC6 and SD-02 had marginal selectivity for HDAC6 over HDAC8. The compounds SD-01 and SD-02 were found to inhibit HDAC8 at concentrations (IC50) 9.0 nM and 2.7 nM, respectively.

Virtual Screening Approach for the Identification of Hydroxamic Acids as Novel Human Ecto-5'-Nucleotidase Inhibitors.

Ecto-5'-nucleotidase (ecto-5'-NT, CD73) is a zinc-binding metallophosphatase that plays a key role in extracellular purinergic pathways, being implicated in several physiological and pathophysiological processes, such as immune homeostasis, inflammation, and tumor progression. As such, it has been recognized as a promising biological target for many diseases, including cancer, infections, and autoimmune diseases. Despite its importance, so far only a few inhibitors of this target enzyme are known, most of which are not suitable as drug candidates. Here, we aimed to search for hydroxamic acid-containing compounds as potential human ecto-5'-NT inhibitors, since this group is known to be a strong zinc chelator. To this end, we performed a hierarchical virtual screening (VS) search consisting of three consecutive steps (filtering for compounds bearing a hydroxamic acid group, shape-based matching, and docking followed by visual inspection), which were applied to screen the ZINC-14 database ("all purchasable subset"). Out of 25 compounds selected by this VS protocol, 12 were acquired and further submitted to enzymatic assays for VS experimental validation. Four of them (i.e., 33.3%) were found to inhibit human ecto-5'-NT in the low micromolar range. The most potent one showed an IC50 value of 6.2 ± 1.0 μM. All identified inhibitors satisfy drug-like criteria and provide novel scaffolds to be explored in further hit-to-lead optimization steps. Furthermore, to the best of our knowledge, they are the first hydroxamic acid-containing inhibitors of human ecto-5'-NT described so far.

Drawing with Iron on a Gel Containing a Supramolecular Siderophore.

Guanosine-5'-hydroxamic acid (3) forms hydrogels when mixed with guanosine (1) and KCl. The 5'-hydroxamic acid (HA) unit is pH-responsive and also chelates Fe3+ . When gels are prepared under basic conditions, the 5'-HA groups are deprotonated and the anionic hydrogel binds cationic thiazole orange (TO), signaled by enhanced fluorescence. The HA nucleoside 3, when immobilized in the G-quartet gel, acts as a supramolecular siderophore to form red complexes with Fe3+ . We patterned the hydrogel's surface with FeCl3 , by hand and by using a 3D printer. Patterns form instantly, are visible by eye, and can be erased using vitamin C. This hydrogel, combining self-assembled G-quartet and siderophore-Fe3+ motifs, is strong, can be molded into different shapes, and is stable on the bench or under salt water.

Drawing with Iron on a Gel Containing a Supramolecular Siderophore

AbstractGuanosine‐5′‐hydroxamic acid (3) forms hydrogels when mixed with guanosine (1) and KCl. The 5′‐hydroxamic acid (HA) unit is pH‐responsive and also chelates Fe3+. When gels are prepared under basic conditions, the 5′‐HA groups are deprotonated and the anionic hydrogel binds cationic thiazole orange (TO), signaled by enhanced fluorescence. The HA nucleoside 3, when immobilized in the G‐quartet gel, acts as a supramolecular siderophore to form red complexes with Fe3+. We patterned the hydrogel's surface with FeCl3, by hand and by using a 3D printer. Patterns form instantly, are visible by eye, and can be erased using vitamin C. This hydrogel, combining self‐assembled G‐quartet and siderophore–Fe3+ motifs, is strong, can be molded into different shapes, and is stable on the bench or under salt water.

Peculiarities of Sorption of Copper(II) Ions by Modified Wool Keratin

The results of studying the equilibrium and kinetics of Cu2+ ions’ sorption from aqueous solutions by the initial and modified wool keratin are presented. The modified sorbent’s strong sorption properties are the result of the formation of hydroxamic acid groups on its surface on retention of the initial keratin’s excess carboxyl groups. The sharp change of sorption by wool keratin in the range of an isoelectric point is related to the change in the degree of the dissociation of the excess carboxyl groups. The IR-spectra and SEM-images of the initial and modified sorbent samples that indicate the structural changes caused by the immobilization of new functional groups on the wool keratin surface are presented.

Glycocluster Tetrahydroxamic Acids Exhibiting Unprecedented Inhibition of Pseudomonas aeruginosa Biofilms.

Opportunistic Gram-negative Pseudomonas aeruginosa uses adhesins (e.g., LecA and LecB lectins, type VI pili and flagella) and iron to invade host cells with the formation of a biofilm, a thick barrier that protects bacteria from drugs and host immune system. Hindering iron uptake and disrupting adhesins' function could be a relevant antipseudomonal strategy. To test this hypothesis, we designed an iron-chelating glycocluster incorporating a tetrahydroxamic acid and α-l-fucose bearing linker to interfere with both iron uptake and the glycan recognition process involving the LecB lectin. Iron depletion led to increased production of the siderophore pyoverdine by P. aeruginosa to counteract the loss of iron uptake, and strong biofilm inhibition was observed not only with the α-l-fucocluster (72%), but also with its α-d-manno (84%), and α-d-gluco (92%) counterparts used as negative controls. This unprecedented finding suggests that both LecB and biofilm inhibition are closely related to the presence of hydroxamic acid groups.

"Covalent-Assembly"-Based Fluorescent Probe for Detection of a Nerve-Agent Mimic (DCP) via Lossen Rearrangement.

The highly selective and sensitive fluorescence "light-up" probe, 5'-(dimethylamino)-2'-formyl-N-hydroxy-[1,1'-biphenyl]-2-carboxamide(PTS), has been fabricated for the nerve-agent mimic diethyl chlorophosphate (DCP). The probe is designed by combining two novel strategies of "covalent assembly" and Lossen rearrangement. Formation of a phosphoryl intermediate from DCP and a hydroxamic acid group in PTS yields an isocyanate that quickly undergoes Lossen rearrangement to produce an aniline that condenses intramolecularly to a fluorescent phenanthridine system. PTS shows superior properties to probe DCP, such as rapid response (within 100 s), low detection limit (10.4 nM), specificity, and excellent linearity (R2 = 0.9993) in the range from 2 to 16 μM. More importantly, its application of detecting DCP vapor has also been achieved with satisfying results.

Utilization of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinone as a cap moiety in design of novel histone deacetylase inhibitors

A series of novel 5,6,7,8-Tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one derivatives bearing a hydroxamic acid, 2-aminoanilide and hydrazide moieties as zinc-binding group (ZBG) were designed, synthesized and evaluated for the HDAC inhibition activity and antiproliferative activity. Most of the tested compounds displayed strong to moderate HDAC inhibitory activity. Some of these compounds showed potent anti-proliferative activity against human HepG2, MCF-7 and HCT-116 cell lines. In particular, compounds IVa, IVb, IXa and IXb exhibited significant anti-proliferative activity against the three cell lines tested compared to SAHA as a reference. Compound IVb is equipotent inhibitor for HDAC1 and HDAC2 as SAHA. It is evident that the presence of free hydroxamic acid group is essential for Zn binding affinity with maximal activity with a linker of aliphatic 6 carbons. Docking study results revealed that compound IVb could occupy the HDAC2 binding site and had the potential to exhibit antitumor activity through HDAC inhibition, which merits further investigation.

Analisis Pembuatan Asam Lemak Hidroksamat Dari Minyak Kelapa Melalui Metode Enzimatis

Generally, fatty hydroxamic acids (FHA) are synthesized from basic ingredients containing fatty acids.Fatty acids can be obtained from coconut oil among several other sources. Coconut oil contains fatty acids with medium and long chains so it has enormous potential as a raw material for the synthesis of hydroxamic fatty acids. The purpose of this research is to synthesize FHA from coconut oil enzymatically and determine the amount of FHA products produced. The method used is the enzymatic method which includes several stages of work, namely the synthesis stage, the multiplication stage, and the purification stage. From the research results, the percentage obtained from the synthesis was around 48.58% of hydroxamic fatty acids from coconut oil after propagation using the synthesis conditions.The number of hydroxamic acid groups in 1 gram of dry hydroxamic fatty acid sample was 2.97 mmol. Thus, from the two results mentioned above, it was concluded that hydroxamic fatty acids can be synthesized from coconut oil

Analisis Pembuatan Asam Lemak Hidroksamat Dari Minyak Kelapa Melalui Metode Enzimatis

Generally, fatty hydroxamic acids (FHA) are synthesized from basic ingredients containing fatty acids.Fatty acids can be obtained from coconut oil among several other sources. Coconut oil contains fatty acids with medium and long chains so it has enormous potential as a raw material for the synthesis of hydroxamic fatty acids. The purpose of this research is to synthesize FHA from coconut oil enzymatically and determine the amount of FHA products produced. The method used is the enzymatic method which includes several stages of work, namely the synthesis stage, the multiplication stage, and the purification stage. From the research results, the percentage obtained from the synthesis was around 48.58% of hydroxamic fatty acids from coconut oil after propagation using the synthesis conditions.The number of hydroxamic acid groups in 1 gram of dry hydroxamic fatty acid sample was 2.97 mmol. Thus, from the two results mentioned above, it was concluded that hydroxamic fatty acids can be synthesized from coconut oil

A general concept for the introduction of hydroxamic acids into polymers.

Hydroxamic acids (HA) form stable complexes with a large variety of metal-ions, affording hydroxamates with high complexation constants. Hydroxamic acid moieties play a crucial role in the natural iron metabolism. In this work, 1,4,2-dioxazoles linked to a hydroxyl group are introduced as key compounds for the installation of hydroxamic acids at synthetic polymers in well-defined positions. A general synthetic scheme is developed that gives access to a series of novel functional key building blocks that can be universally used to obtain hydroxamic acid-based monomers and polymers, for instance as protected HA-functional initiators or for the synthesis of a variety of novel HA-based monomers, such as epoxides or methacrylates. To demonstrate the excellent stability of the dioxazole-protected hydroxamic acids, direct incorporation of the dioxazole-protected hydroxamic acids into polyethers is demonstrated via oxyanionic polymerization. Convenient subsequent deprotection is feasible under mild acidic conditions. α-Functional HA-polyethers, i.e. poly ethylene glycol, polypropylene glycol and polyglycerol based on ethylene oxide, propylene oxide and ethoxy ethyl glycidyl ether, respectively are prepared with low dispersities (<1.2) in the molecular weight range of 1000 to 8500 g mol-1. Water-soluble hydroxamic acid functional poly(ethylene glycol) (HA-PEG) is explored for a variety of biomedical applications and surface coating. Complexation of Fe(iii) ions, coating of various metal surfaces, enabling e.g., solubilization of FeO x nanoparticles by HA-PEGs, are presented. No impact of the polyether chain on the chelation properties was observed, while significantly lower anti-proliferative effects were observed than for deferoxamine. HA-PEGs show the same complexation behavior as their low molecular weight counterparts. Hydroxamic acid functional polymers are proposed as an oxidatively stable alternative to the highly established catechol-based systems.

Fluorinated Analogues of Desferrioxamine B from Precursor-Directed Biosynthesis Provide New Insight into the Capacity of DesBCD

The siderophore desferrioxamine B (DFOB, 1) native to Streptomyces pilosus is biosynthesized by the DesABCD enzyme cluster. DesA-mediated decarboxylation of l-lysine gives 1,5-diaminopentane (DP) for processing by DesBCD. S. pilosus culture medium was supplemented with rac-1,4-diamino-2-fluorobutane ( rac-FDB) to compete against DP to generate fluorinated analogues of DFOB, as agents of potential clinical interest. LC-MS/MS analysis identified fluorinated analogues of DFOB with one, two, or three DP units (binary notation: 0) exchanged for one (DFOA-F1[001] (2), DFOA-F1[010] (3), DFOA-F1[100] (4)), two (DFOA-F2[011] (5), DFOA-F2[110] (6), DFOA-F2[101] (7)), or three (DFOA-F3[111] (8)) rac-FDB units (binary notation: 1). The two sets of constitutional isomers 2-4 and 5-7 arose from the position of the substrates in the N-acetyl, internal, or amine-containing regions of the DFOB trimer. N-Acetylated fluorinated DFOB analogues were formed where the rac-FDB substrate was positioned in the amine region ( e.g., N-Ac-DFOA-F1[001] (2a)). Other analogues contained two hydroxamic acid groups and three amide bonds. Experiments using rac-FDB, R-FDB, or S-FDB showed a similar species profile between rac-FDB and R-FDB. These data are consistent with the following. (i) DesB can act on rac-FDB. (ii) DesC can act directly on rac-FDB. (iii) The products of DesBC or DesC catalysis of rac-FDB can undergo a second round of DesC catalysis at the free amine. (iv) DesD catalysis of these products gives N, N'-diacetylated compounds. (v) A minimum of two hydroxamic acid groups is required to form a viable DesD-substrate(s) precomplex. (vi) One or more DesBCD-catalyzed steps in DFOB biosynthesis is enantioselective. This work has provided a potential path to access fluorinated analogues of DFOB and new insight into its biosynthesis.

β-Hydroxyaspartic acid in siderophores: biosynthesis and reactivity.

A growing number of siderophores are found to contain β-hydroxyaspartic acid (β-OH-Asp) as a functional group for Fe(III) coordination, along with the more common catechol and hydroxamic acid groups. This review covers the structures, biosynthesis, and reactions of peptidic β-OH-Asp siderophores. Hydroxylation of Asp in siderophore biosynthesis is predicted to be carried out either through discrete aspartyl β-hydroxylating enzymes or through hydroxylating domains within non-ribosomal peptide synthetases, both of which display sequence homology to known non-heme iron(II), α-ketoglutarate-dependent dioxygenases. Ferric complexes of β-OH-Asp siderophores are photoreactive, resulting in reduction of Fe(III) and oxidative cleavage of the siderophore to yield distinct types of photoproducts. Probing the photoreactivity of synthetic Fe(III)-α-hydroxycarboxylate clusters yields mechanistic insights into the different photoproducts observed for β-OH-Asp and other α-hydroxycarboxylate siderophore Fe(III) complexes.

ANTIHYPERGLYCEMIC ACTIVITY OF PHENYL AND ORTHO-HYDROXY PHENYL LINKED IMIDAZOLYL TRIAZOLO HYDROXAMIC ACID DERIVATIVES

Objective: The paradigm was to establish phenyl and ortho-hydroxy phenyl linked imidazolyl triazolo hydroxamic acid derivatives as an antihyperglycemic agent.Methods: 100 mg/Kg body weight dose of phenyl and ortho-hydroxy Phenyl linked Imidazolyl triazolo Hydroxamic Acid derivatives (FP1-FP12) and standard glibenclamide were administered per os (p.o.) in the streptozotocin-induced hyperglycemic rats by glucose oxidase-peroxidase method and statistically evaluated by one way analysis of variance.Results: FP3 was potent as compare to standard glibenclamide (P &lt; 0.05-0.001) and FP6, FP9, and FP4 were also effective as an antihyperglycemic agent. The activity profile of the molecule was as follows FP9&lt; FP10&lt; FP4&lt; FP6&lt;FP12&lt; FP3. This study reflects that presence of para methoxy phenyl group linked with phenyl group in surface recognition portion and imidazolyl triazole group in linker portion associated with a sulfamethyl hydroxamic acid group in metal identifying the part in case of FP3 was resemble for antihyperglycemic activity.Conclusion: It was concluded that compounds possessing electron releasing groups on the aromatic rings in the surface recognition part considerably enhanced the antihyperglycemic activity.

Research into complexing properties of polyacrylonitrile complexite in the mixtures of water-dioxane

We studied complexing properties of a fibrous complexite based on polyacrylonitrile relative to copper(II) ions taking into consideration solvation parameters of polymer ligands in the mixed solvent of water-1.4-dioxane. The object was obtained through chemical modification of the industrial fiber nitron; it has in the grafted chains the complexing groups of amidoxime, hydroxamic acid and carboxylic groups. Complexation equilibria and stability of the complexes of copper(II) with the complexite were studied using the potentiometric titration methods, infrared spectroscopy, spectroscopy of diffuse reflection, swelling. Complexing properties of the polyacrylonitrile complexite have been identified relative to copper(II) ions in the mixtures of water-1.4-dioxane. Complexation takes place with the participation of hydroxamic groups of the polymer. In the range of pH 3.8 ‒ 6.2, along with hydroxamic groups, in the mixtures with a molar share of dioxane at 0.17 and 0.32, the formation of HMCC- С u 2+ involves amidoxime groups. The character of change in the stability constants of HMCC- С u 2+ with an increase in the content of dioxane is due to the structural characteristics of mixtures, particle over-solvation, restructuring of the coordination centers of HMCC by introducing to their coordination sphere the DO molecules, and reveals the essential role of specific solvation. It was found that solvation effects in the mixture of water-1.4-dioxane with a molar share of dioxane at 0.00 ‒ 0.17 reduce stability of the resulting complexes of HMCC- С u 2+ . The biggest impact of solvation parameters of the complexite is achieved in the composition of mixture at 0.32.

Ferrichrome Has Found Its Match: Biomimetic Analogues with Diversified Activity Map Discrete Microbial Targets.

Siderophores provide an established platform for studying molecular recognition principles in biological systems. Herein, the preparation of ferrichrome (FC) biomimetic analogues varying in length and polarity of the amino acid chain separating between the tripodal scaffold and the pendent FeIII chelating hydroxamic acid groups was reported. Spectroscopic and potentiometric titrations determined their iron affinity to be within the range of efficient chelators. Microbial growth promotion and iron uptake studies were conducted on E. coli, P. putida and U. maydis. A wide range of siderophore activity was observed in the current series: from a rare case of a species-specific growth promotor in P. putida to an analogue matching FC in cross-phylum activity and uptake pathway. A fluorescent conjugate of the broad-range analogue visualized siderophore destination in bacteria (periplasmic space) vs. fungi (cytosol) mapping new therapeutic targets. Quantum dots (QDs) decorated with the most potent FC analogue provided a tool for immobilization of FC-recognizing bacteria. Bacterial clusters formed around QDs may provide a platform for their selection and concentration.

Difluoromethylation Reactions of Organic Compounds.

The relevance of the -CF2 H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid, or amide groups. Being weakly acidic, the CF2 H moiety can establish hydrogen-bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF2 H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals. Consequently, the late-stage introduction of CF2 H is a sought-after strategy in designing bioactive compounds. Secondly, but nonetheless relevant and meaningful, is the study of synthetic pathways to introduce a CF2 -Y moiety (Y≠H, F) into organic substrates because compounds that contain a CF2 -Y functionality have also found vast applications in medicinal chemistry and in other areas, such as that of fungicides, insecticides, etc., and thus, this functionality deserves special attention. Although emphasis is made on difluoromethylation strategies to functionalize different families of organic compounds, three main methodological protocols will be presented in this review article for the late-stage introduction of a CF2 H or CF2 Y moieties into organic substrates: i) a metal-photoredox catalysis; ii) through transition metal-catalyzed thermal protocols; and iii) from transition-metal-free strategies.

A Hydroxamic Acid Anchoring Group for Durable Dye‐Sensitized Solar Cells Incorporating a Cobalt Redox Shuttle

A hydroxamic acid group has been employed for the first time as an anchoring group for cobalt-based dye-sensitized solar cells (DSSCs). The porphyrin dye YD2-o-C8HA including a hydroxamic acid anchoring group exhibited a power conversion efficiency (η) of 6.4 %, which is close to that of YD2-o-C8, a representative porphyrin dye incorporating a conventional carboxylic acid. More importantly, YD2-o-C8HA was found to be superior to YD2-o-C8 in terms of both binding ability to TiO2 and durability of cobalt-based DSSCs. Notably, YD2-o-C8HA photocells revealed a higher η-value (4.1 %) than YD2-o-C8 (2.8 %) after 500 h illumination. These results suggest that the hydroxamic acid can be used for DSSCs with other transition-metal-based redox shuttle to ensure high cell durability as well as excellent photovoltaic performance.