Search Results (43)

Background: Zirconium-89 (⁸⁹Zr) is a key PET radionuclide and the limited in vivo stability of its clinically used ⁸⁹Zr-DFO complexes has driven the pursuit of improved chelator architectures. Among these, DFO* has attracted particular attention due to its exceptional complex stability with ⁸⁹Zr⁴⁺ and favorable pharmacokinetics of the corresponding bioconjugates in vivo. Despite these advantages, DFO*’s broader application has been hampered by significant synthetic challenges, primarily arising from its pronounced acid sensitivity. Methods: Here, we present a systematic investigation of the acid lability of DFO and DFO*-derived systems, revealing substantial degradation under acidic conditions being commonly applied during preparation and purification. These findings highlight critical limitations of conventional synthetic and purification protocols. To address this, we developed two complementary synthetic routes that consistently avoid fragmentation-inducing conditions. Results: THP/Boc- and TBDPS/Fmoc-based routes provide robust five- and six-step syntheses of DFO*, affording overall yields of 11% and 13%/6.1% and high purity (≥98%) without detectable degradation. Conclusions: By systematically investigating the acid sensitivity of DFO/DFO*-based chelators and providing practical synthetic solutions, this work enables reliable access to DFO* and advances its application in ⁸⁹Zr radiopharmaceutical development. Full article

Siderophores are classically understood as microbial iron-acquisition metabolites: low-molecular-weight ligands secreted by bacteria to solubilize and transport Fe(III) under iron-limited conditions. In this review, we expand that paradigm by highlighting an emerging and underappreciated chemical axis—boron coordination by siderophores—that links terrestrial (soil/rhizosphere) and marine microbiomes. Across diverse bacterial taxa, siderophore production is widespread and central to competitive fitness because Fe(III) is poorly soluble and frequently sequestered in environmental or host matrices. Yet in boron-rich settings (seawater and borate-enriched soils), the same oxygen-donor architectures that support Fe(III) chelation can also engage boron chemistry. We synthesize evidence that carboxylate/α-hydroxyacid (dicitrate-type) and catecholate siderophores can form tetrahedral borate/boronate complexes, whereas hydroxamate siderophores generally lack the vicinal dianionic O,O motif required for stable boron binding. Structurally characterized examples—including vibrioferrin, rhizoferrin, and petrobactin—demonstrate that boron complexation is experimentally observable by ESI-MS and multinuclear NMR and can be modulated by pH and microenvironment. Integrating these findings with datasets on boron-tolerant bacteria, we propose that when iron is scarce and boron is available, boron–siderophore complexation becomes chemically feasible and may influence microbial physiology by altering ligand conformation, metal selectivity, and potentially extracellular signaling behavior—especially in marine systems where borate is abundant at oceanic pH. Overall, this review frames boron-binding siderophores as a cross-ecosystem phenomenon and a promising conceptual bridge between environmental boron geochemistry, microbial metal economy, and metalloid-mediated signaling. Full article

Iron (Fe) chelators are used to treat iron-overloaded disorders, metal detoxification, radionuclides, and molecular imaging; however, they can cause side effects. In this study, we identified and characterized Coprogen B (CPGB), a hexadentate trihydroxamate siderophore secreted by the opportunistic dimorphic fungus Talaromyces marneffei and compared its properties with deferoxamine (DFO). Siderophore production was enriched from a ΔsreA strain and purified via Amberlite XAD2 and Sephadex LH20 chromatography, followed by reverse-phase HPLC. Active fractions were confirmed by Ultraviolet–Visible (UV–Vis) spectral fingerprints (≈230 nm) for hydroxamate, with a band at 430–450 nm upon Fe(III) complexation, as well as by chrome azurol A assay, Nuclear Magnetic Resonane (NMR) spectroscopy, High-Performance Liquid Chromatography–Mass Spectrometry (HPLC-MS), and Matrix-Assisted Laser Desorption/Ionization–Time-of-Flight Mass Spectrometry (MALDI-TOF-MS). CPGB exhibited strong molar absorptivity and rapid, concentration-dependent chelation of Fe(III), yielding a sustained binding profile that matched or exceeded that of DFO over time. In determining n-octanol/water partitioning for CPGB and DFO (230 nm) and their Fe(III) complexes, the partitioning (P) assay revealed that CPGB was moderately hydrophilic (P = 0.505 ± 0.063; cLogP = −0.299 ± 0.053), while DFO was strongly hydrophilic (P = 0.098 ± 0.005; cLogP = −1.010 ± 0.022). Fe(III) complexation reduced lipophilicity: CPGB–Fe partitioned ~30–35% into octanol, while DFO–Fe complex partitioned ~7–8%, remaining largely aqueous. Overall, this outcome potentially suggested improved clearance in vivo. These data nominate CPGB as a promising alternative to existing iron chelators. The siderophore exhibited greater lipophilicity, emphasizing better passive membrane permeability than DFO, while siderophore–Fe(III) binding indicated increased biases toward the aqueous phase. Future in vivo studies are warranted to confirm its pharmacokinetics, safety, and therapeutic efficacy. Full article

The hydroxamic acid moiety is part of many bioactive molecules, including several clinical drugs, which can be constructed through, generally, the parent carboxylic acid and a source of hydroxylamine by a variety of methods. Hydroxamic acids compose a remarkable group of N-hydroxy amides with high capacity to chelate certain transition metal ions such as Fe(III), considered siderophores in Nature, and Ni(II), for instance. During a synthetic program towards the derivatization of natural resinic acids, it was decided to prepare some corresponding hydroxamic acid derivatives with potential biological activity for further studies. There are few reports on hydroxamate-derived terpenoids. It was predicted that adding a hydroxamic acid moiety to the carbon skeleton could enhance the antiproliferative activities or other pharmacological properties, as it occurs in other terpenoid compounds. In this communication, we describe the several issues that we faced in this generally straightforward conversion. Generally, the carboxylic group needs to be activated towards coupling with hydroxylamine. We screened several methods and realized that the desired conversion is difficult in this kind of substrate. After extensive testing, we propose a new protocol via a phosphate intermediate for better results than standard procedures. A basic computational study on the mechanism of this transformation was also carried out to support our experimental results. Full article

Histone deacetylase 11 (HDAC11), the sole member of class IV HDACs, has gained prominence due to its unique enzymatic profile and pathological relevance in cancer, neurodegenerative, inflammatory diseases, and metabolic disorders. However, only a limited number of selective HDAC11 inhibitors have been identified, and many of these contain a potentially mutagenic hydroxamic acid as a zinc-chelating motif. Consequently, there is an imperative to identify potent and selective non-hydroxamate HDAC11 inhibitors with improved physicochemical properties. In this study, we conducted an extensive experimental high-throughput screening of 10,281 structurally diverse compounds to identify novel HDAC11 inhibitors. Two promising candidates, caffeic acid phenethyl ester (CAPE) and compound 9SPC045H03, both lacking a hydroxamic acid warhead, were discovered, showing micromolar inhibitory potency (IC₅₀ = 1.5 and 2.3 µM, respectively), fast and reversible binding, and remarkable isozyme selectivity. Molecular docking revealed distinct zinc-chelating mechanisms involving either carbonyl oxygen (CAPE) or pyridine nitrogen (9SPC045H03), in contrast to canonical hydroxamates. Both compounds are drug-like and exhibit favorable physicochemical and pharmacokinetic profiles, particularly beneficial water solubility and good adsorption, making them valuable starting points for further optimization. These findings open new avenues for the development of selective, non-hydroxamate HDAC11 inhibitors with potential therapeutic applications. Full article

Recently, the emerging class of hydroxamate-based metal–organic frameworks (MOFs) has demonstrated significant structural diversity and chemical robustness, both essential for potential applications. Combining the favorable hard–hard Bi-O interactions and chelating chemistry of hydroxamate groups, a rigid and symmetrical three-dimensional bismuth-hydroxamate metal–organic framework was successfully prepared via solvothermal synthesis and structurally elucidated via X-ray crystallography. The MOF, namely SUM-91 (SUM = Sichuan University Materials), features one-dimensional Bi-oxo secondary building blocks (SBUs), which are bridged by chelating 1,4-benzenedihydroxamate linkers. With the demonstrated permanent porosity and molecular sieving effect (CO₂ vs. N₂), SUM-91 was also found to be stable under harsh chemical conditions (aqueous solutions with pH = 2–12 and various organic solvents). As the structural robustness of SUM-91 could be attributed to the finetuning of the coordinative sphere of Bi centers, this work shed light on the further development of (ultra-)microporous materials with high stability and selective adsorption properties. Full article

Background: Actinium-225 (²²⁵Ac) has gained interest in nuclear medicine for use in targeted alpha therapy (TAT) for the treatment of cancer. However, the number of suitable chelators for the stable complexation of ²²⁵Ac³⁺ is limited. The promising physical properties of ²²⁵Ac result in an increased demand for the radioisotope that is not matched by its current supply. To expand the possibilities for the development of ²²⁵Ac-based TAT therapeutics, a new hydroxamate-based chelator, DFO*¹², is described. We report the DFT-guided design of dodecadentate DFO*¹² and an efficient and convenient automated solid-phase synthesis for its preparation. To address the limited availability of ²²⁵Ac, a small-scale ²²⁹Th/²²⁵Ac generator was constructed in-house to provide [²²⁵Ac]AcCl₃ for research. Methods: DFT calculations were performed in ORCA 5.0.1 using the BP86 functional with empirical dispersion correction D3 and Becke–Johnson damping (D3BJ). The monomer synthesis over three steps enabled the solid-phase synthesis of DFO*¹². The small-scale ²²⁹Th/²²⁵Ac generator was realized by extracting ²²⁹Th from aged ²³³U material. Radiolabeling of DFO*¹² with ²²⁵Ac was performed in 1 M TRIS pH 8.5 or 1.5 M NaOAc pH 4.5 for 30 min at 37 °C. Results: DFT calculations directed the design of a dodecadentate chelator. The automated synthesis of the chelator DFO*¹² and the development of a small-scale ²²⁹Th/²²⁵Ac generator allowed for the radiolabeling of DFO*¹² with ²²⁵Ac quantitatively at 37 °C within 30 min. The complex [²²⁵Ac]Ac-DFO*¹² indicated good stability in different media for 20 h. Conclusions: The novel hydroxamate-based dodecadentate chelator DFO*¹², together with the developed ²²⁹Th/²²⁵Ac generator, provide new opportunities for ²²⁵Ac research for future radiopharmaceutical development and applications in TAT. Full article

The isolation and characterization of bioactive metabolites from Streptomyces species continue to represent a vital area of research, given their potential in natural product drug discovery. In this study, we characterize a new siderophore called legonoxamine I, together with a known compound, streptimidone, from the talented soil bacterium Streptomyces sp. MA37, using chromatographic techniques and spectroscopic analysis. Legonoxamine I is a new holo-siderophore, which is likely to be a derailed product from the biosynthetic pathway of legonoxamine A. We also demonstrate that legonoxamine A possesses potent anticancer activity (IC₅₀ = 2.2 µM), exhibiting a remarkable ~30-fold increase in potency against MCF-7 ATCC HTB-22 breast cancer cells compared to desferrioxamine B, a structural analogue of legonoxamine A (IC₅₀ = 61.1 µM). Comparing the structural difference between legonoxamine A and desferrioxamine B, it is deduced that the phenylacetyl moiety in legonoxamine A may have contributed significantly to its enhanced potency. Our findings contribute to the growing library of Streptomyces-derived metabolites and underscore the genus’ potential as a promising source of lead compounds. Full article

The DFO, a special hexadentate chelator with three hydroxamate moieties, is a bifunctional 1-(4-isothiocyanatophenyl)-3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-(N-acetylhydroxylamino)- 6,11,17, 22- tetraazaheptaeicosine] thiourea (p-SCN-Bn-Df), a significant next-generation ligand. The presence of the thiocyanate (-SCN) group makes it capable of hydrolysis and the protonation process. In this study aims to optimize the HPLC protocol for 1-(4-isothiocyanatophenyl)-3-[6,17-dihydroxy-7,10,18,21-tetraoxo-27-(n-acetylhydroxylamino)-6,11,17,22-tetraazaheptaeicosine] thiourea (p-SCN-Bn-Df) via the Reversed-Phase Chromatography (RP-HPLC) method. A variety of mobile phases were tested in various ratios of solvent constituents such as methanol/water, acetonitrile/water, and phosphate buffer along with at variable pH concentrations. However, when employing a mobile phase consisting of water to acetonitrile containing 0.1% TFA (05:95, v/v) in an isocratic manner, satisfactory separation and symmetric peaks were observed. This method utilized an Eclipsed C-18 column (5 μm, 4.6 × 250 mm) column with a flow rate of 0.5 mL/min. The maximum absorption of p-SCN-Bn-Dfat 254 nm wavelength was selected as the detection wavelength. The Retention time (t_R) of p-SCN-Bn-Df was found at 5.205 min. The ICH guideline was used to evaluate the linearity, accuracy, precision, limit of detection (LOD), limit of quantitation (LOQ), specificity, and system appropriateness criteria to validate the optimized chromatographic and spectrophotometric procedures. For accurate compound separation in pharmaceutical and environmental analyses, this phase is adaptable and often used. This study is useful for the evaluation of p-SCN-Bn-Df QC parameters and chelation rates with different radioisotopes e.g., Zirconuim-89 (Zr-89). Full article

To qualify as competent sorbents for airborne contaminants such as iodine vapor, permanent porosity and chemical stability are key criteria for the selection of candidate metal-organic frameworks (MOFs). To ensure these characteristics, in the present study, an unsymmetrical bifunctional ligand incorporating both carboxylic acid and hydroxamic acid groups was employed for MOF [Zn(CBHA)](DMF) [SUM-13; CPHA = 4-carboxyphenylhydroxamate, DMF = N,N-dimethylformamide] design and synthesis. Though coupled with Zn²⁺, which does not typically yield kinetically robust MOFs with hard acids, the SUM-13 featuring differentiated coordination modes of chelating, bridging and monodentate bonding exhibited exceptional chemical stability and permanent porosity, with a Brunauer–Emmett–Teller (BET) surface area of 296.9 m²/g and a total pore volume of 0.1196 cm³/g. Additionally, with porosity and open metal sites at the five-coordinate Zn²⁺ centers, SUM-13 was demonstrated to be an eligible iodine adsorbent, reaching a maximum uptake of 796 mg/g. These findings underscore the validity and potential of the design strategy in constructing stable metal–organic frameworks. Full article

The pollution of water bodies by heavy metal ions has recently become a global concern. In this experiment, a novel chelating resin, D851-6-AHHA, was synthesized by grafting 6-amino-N-hydroxyhexanamide (6-AHHA) onto the (-CH₂N-(CH₂COOH)₂) group of the D851 resin, which contained a hydroxamic acid group, amide group, and some carboxyl groups. This resin was developed for the purpose of removing heavy metal ions, such as Cr(III) and Pb(II), from water. The findings from static adsorption experiments demonstrated the remarkable adsorption effectiveness of D851-6-AHHA resin towards Cr(III) and Pb(II). Specifically, the maximum adsorption capacities for Cr(III) and Pb(II) were determined to be 91.50 mg/g and 611.92 mg/g, respectively. Furthermore, the adsorption kinetics of heavy metal ions by D851-6-AHHA resin followed the quasi-second-order kinetic model, while the adsorption isotherms followed the Langmuir model. These findings suggest that the adsorption process was characterized by monolayer chemisorption. The adsorption mechanism of D851-6-AHHA resin was comprehensively investigated through SEM, XRD, FT-IR, and XPS analyses, revealing a high efficiency of D851-6-AHHA resin in adsorbing Cr(III) and Pb(II). Specifically, the (-C(=O)NHOH) group exhibited a notable affinity for Cr(III) and Pb(II), forming stable multi-elemental ring structures with them. Additionally, dynamic adsorption experiments conducted using fixed-bed setups further validated the effectiveness of D851-6-AHHA resin in removing heavy metal ions from aqueous solutions. In conclusion, the experimental findings underscored the efficacy of D851-6-AHHA resin as a highly efficient adsorbent for remediating water bodies contaminated by heavy metal ions. Full article

Hydroxamic acid and fatty acid collectors are commonly used in cassiterite flotation but face issues like poor selectivity, high dosage, and strict requirements on ore composition and grinding fineness. This study investigates the collecting performance of a novel flotation reagent, 5-dodecylsalicylaldoxime (DSA), in cassiterite flotation. DSA exhibits remarkable selectivity, achieving an impressive 82.5% recovery of Sn at a concentration of only 9 × 10⁻⁵ mol/L in single mineral flotation tests. Moreover, DSA significantly outperforms benzohydroxamic acid (BHA), enhancing Sn recovery by 33.55% in artificially mixed ore flotation experiments. In the flotation test of a copper–tin polymetallic ore, compared with the BHA flotation effect, the recovery rate of DSA increased by 12.29% when the Sn grade remained basically unchanged. Analyses such as zeta potential, FT-IR, and XPS indicate that DSA’s superior collecting performance stems from its stable adsorption onto cassiterite surfaces through a chelating ring formation, resembling the adsorption mechanism of hydroxamic acid collectors. Furthermore, DSA’s larger cluster size in the solution compared to BHA contributes to its enhanced selectivity and collectability. Overall, DSA emerges as a promising alternative to traditional cassiterite flotation collectors, offering a combination of enhanced selectivity, lower dosage requirements, and robustness in complex ore systems. Full article

In this study, the performance of 2-hydroxy-3-naphthylmethyl hydroxamic acid (NHA) in cassiterite flotation was investigated. The aim was to understand the mechanism of action of NHA for the first time. The effect of NHA as a collector in the flotation separation of cassiterite, calcite, and quartz was investigated via microbubble flotation experiments. The experimental results showed that the maximum recovery of cassiterite in the presence of NHA was 91.76%. This was attributed to the selective adsorption of NHA on the cassiterite surface. NHA showed a stronger collection performance for cassiterite than calcite and quartz. Therefore, the mechanism of NHA-cassiterite interaction was investigated using zeta potential, the logarithmic solubility plot (LSD), Fourier Transform Infrared (FT-IR), X-ray Photoelectron Spectroscopy (XPS), and Scanning Electron Microscope (SEM) analyses. This study introduces a new adsorption process and mechanism for the NHA-based adsorption of cassiterite. The results show that, under neutral conditions, the solute components of cassiterite surface lattice ions mainly exist in the form of Sn–OH complexes. Chemisorption occurs between cassiterite and NHA which is adsorbed onto the cassiterite surfaces through interaction with O sites, rather than Sn sites as is traditionally expected. Further, the hydroxyl and hydroxyl groups of NHA are chemically coordinated with Sn–OH on the surface of cassiterite to form a six-membered chelate ring. This proposed mechanism can be extended to most systems in which metal ions interact with hydroxamic acids bearing hydroxyl groups. This contributes to a better understanding of the activation mechanism of hydroxamic acid collectors in cassiterite flotation. Full article

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a zinc amidase that catalyzes the second step of the biosynthesis of lipid A, which is an outer membrane essential structural component of Gram-negative bacteria. Inhibitors of this enzyme can be attributed to two main categories, non-hydroxamate and hydroxamate inhibitors, with the latter being the most effective given the chelation of Zn²⁺ in the active site. Compounds containing diacetylene or acetylene tails and the sulfonic head, as well as oxazoline derivatives of hydroxamic acids, are among the LpxC inhibitors with the most profound antibacterial activity. The present article describes the synthesis of novel functional derivatives of hydroxamic acids—bioisosteric to oxazoline inhibitors—containing 1,2,4- and 1,3,4-oxadiazole cores and studies of their cytotoxicity, antibacterial activity, and antibiotic potentiation. Some of the hydroxamic acids we obtained (9c, 9d, 23a, 23c, 30b, 36) showed significant potentiation in nalidixic acid, rifampicin, and kanamycin against the growth of laboratory-strain Escherichia coli MG1655. Two lead compounds (9c, 9d) significantly reduced Pseudomonas aeruginosa ATCC 27853 growth in the presence of nalidixic acid and rifampicin. Full article

Aminopeptidase N (APN) was closely associated with cancer invasion, metastasis, and angiogenesis. Therefore, APN inhibitors have attracted more and more attention of scientists as antitumor agents. In the current study, we designed, synthesized, and evaluated one new series of pyrazoline-based hydroxamate derivatives as APN inhibitors. Moreover, the structure–activity relationships of those were discussed in detail. 2,6-Dichloro substituted compound 14o with R₁ = CH₃, showed the best capacity for inhibiting APN with an IC₅₀ value of 0.0062 ± 0.0004 μM, which was three orders of magnitude better than that of the positive control bestatin. Compound 14o possessed both potent anti-proliferative activities against tumor cells and potent anti-angiogenic activity. At the same concentration of 50 μM, compound 14o exhibited much better capacity for inhibiting the micro-vessel growth relative to bestatin in the rat thoracic aorta ring model. Additionally, the putative interactions of 14o with the active site of APN are also discussed. The hydroxamate moiety chelated the zinc ion and formed four hydrogen bonds with His²⁹⁷, Glu²⁹⁸ and His³⁰¹. Meanwhile, the terminal phenyl group and another phenyl group of 14o interacted with S₂′ and S₁ pockets via hydrophobic effects, respectively. Full article