Search Results (260)

Background: Inhibition of histone deacetylase is a highly sought-after objective in the fight against cancer. Thus, the development of innovative HDAC inhibitors with significantly higher potency than SAHA against specific cancer cell types represents complex and demanding work. Method: The utilization of the underexplored and privileged scaffold 4-chlorothieno[2,3-b]pyridine as a cap tethering diverse aliphatic and aromatic linkers, followed by the screening of both cellular and enzymatic activities, is undertaken in this study. Results: Compounds 7a and 9a demonstrated impressive mean GI₅₀ values of 2.15 µM and 1.89 µM, respectively. Both compounds reduced caspase-3 levels in RPMI-8226 cells, suggesting induction of apoptosis. Compound 7a showed remarkable IC₅₀ values of 0.37 µM, 0.58 µM, and 0.70 µM against HDACs 1, 4, and 6, respectively, consistent with the cellular assay. Additionally, compound 7a exhibited a selectivity index of 11 for RPMI-8226 cells over PBMCs, reflecting its high selectivity and potential safety. Moreover, ADMET prediction tools indicated that compounds 7a and 9b may have more favorable pharmacokinetic properties than the gold-standard HDAC inhibitor, SAHA. Conclusions: Further study and exploration of the derivatives of compounds 7a and 9a can lead to further advancement in the development of potent HDAC inhibitor anticancer drugs. 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

2-Aryl-2-(3-indolyl)acetohydroxamic acids have emerged as promising antitumor agents; however, their poor pharmacokinetic profile remains a significant drawback. To address this limitation, we have synthesized a homolog of such acids—specifically 2-aryl-2-(3-indolyl)propionic acid (IC₅₀ > 100 mM (U87)), along with several other derivatives: ethyl ester (IC₅₀ > 100 mM (U87)), hydroxamate (IC₅₀ 21.2 ± 1.0 mM (U87)) and hydrazide (IC₅₀ > 100 mM (U87)). The cytotoxicity of these compounds against glioblastoma cell lines was evaluated and compared to that of the parent acetohydroxamic acid derivatives. Full article

A mechanistically unusual CuCN-catalyzed electrophilic amidation of Grignard reagents with N-H containing O-allyl- and O-benzyl-hydroxamic acid derivatives as leaving groups to give secondary amides is reported. Computational DFT examination of the reaction points to the intermediate formation of electrophilic acyl nitrenoid species triggered by the presence of CuCN and magnesium salts. The work also provides some experimental evidence about the molecular composition and reactivity of organomagnesium cuprates, the structural nature of which remains a subject of ongoing debate. Full article

Background and Clinical Significance: Phosphoglyceride crystal deposition disease (PCDD) is an extremely rare condition characterized by the deposition of phosphoglyceride crystals, occasionally forming tumor like lesions that present significant diagnostic challenges. Here, we report, to our knowledge, the first documented recurrent case of PCDD confined to the mandible, which clinically and radiologically mimicked a malignant bone tumor. Case Presentation: An 80-year-old female patient presented with a progressively enlarging mandibular mass, and imaging studies demonstrated an osteolytic lesion with cortical bone destruction and marked fluorodeoxyglucose uptake on positron emission tomography-computed tomography, raising a strong suspicion of malignancy. Histopathological examination revealed foreign-body granulomatous inflammation with characteristic crystal deposition, and the diagnosis of PCDD was definitively established through the combined use of gold hydroxamic acid staining, Raman spectroscopy, and ultrastructural analysis. Although surgical excision with curettage was initially achieved, local recurrence was observed 6 years later, indicating the potential for long-term disease persistence. In addition, a comprehensive literature review conducted in accordance with the PRISMA guidelines was performed to summarize previously reported cases of PCDD, with particular attention to anatomical distribution, radiological characteristics, recurrence patterns, and proposed pathogenic mechanisms. The review confirmed the extreme rarity of mandibular involvement and demonstrated that recurrence can occur apparently even after surgical treatment. Conclusions: This case underscores the importance of a multimodal diagnostic strategy integrating imaging, histopathology, and spectroscopic analyses for the accurate identification of PCDD and highlights the necessity of histopathological confirmation to prevent unnecessary aggressive treatment. Full article

Soil salinization represents a significant abiotic constraint to global agricultural sustainability. The potential of extremophile plant growth-promoting bacteria (PGPB) to alleviate such stress in maize was investigated in this study. Siderophore-producing PGPB enhance plant growth and improve the rhizosphere microenvironment by increasing nutrient availability and inducing systemic resistance. Two salt-tolerant, high-siderophore-producing PGPB strains, Bacillus toyonensis TRM58010 and Peribacillus frigoritolerans TRM58009, were isolated and identified from soil samples collected on the Pamir Plateau. In this study, we found that B. toyonensis TRM58010 synthesized catechol-type siderophores, which enhanced iron availability for maize in saline–alkaline conditions, thereby improving iron nutrition and directly promoting root and stem growth under salt stress. P. frigoritolerans TRM58009 produced hydroxamate-type siderophores, which increased maize iron uptake and stimulated antioxidant enzyme activity, mitigating oxidative stress caused by salinity and alkalinity and supporting overall plant health. Both strains demonstrated robust tolerance to extreme alkaline and saline conditions. Hydroponic and pot experiments showed that these strains significantly improved maize germination rate, root and stem development, plant height, leaf growth, antioxidant enzyme activities, and chlorophyll content under saline–alkaline stress. Notably, the application of P. frigoritolerans TRM58009 bacterial suspension increased maize leaf catalase, peroxidase, and superoxide dismutase activities by 15.712%, 11.584%, and 2.820%, respectively (all p < 0.05), while decreasing malondialdehyde (MDA) content by 15.685% (p < 0.05). P. frigoritolerans TRM58009 elevated chlorophyll a content by 23.4% (p < 0.05). These findings demonstrate the potential of extremophile PGPB strains to mitigate the impact of saline–alkaline stress on maize growth. The distinct growth-promoting effects of these strains, isolated from Pamir Plateau meadow soils, present a promising strategy for bioremediation of saline–alkaline lands and the development of efficient microbial fertilizers. By advancing the use of salt-tolerant siderophore-producing bacteria, this study lays the foundation for innovative approaches to enhance crop resilience and productivity in challenging environments. Full article

Background: Oxazolidinone derivatives are a novel class of synthetic antibacterial agents, characterized by a five-membered heterocyclic ring containing oxygen and nitrogen and a carbonyl functionality at position 2. This pharmacophore is responsible not only for antibacterial activity but also for a variety of other biological activities, including anticancer activity, anticoagulant activity, and several others. A series of novel oxazolidinone derivatives containing a hydroxamic acid moiety were synthesized in our laboratories and identified as potent inhibitors of the enzyme 5-lipoxygenase (5-LO), a key enzyme involved in the biosynthesis of leukotrienes (LTs). LTs are proinflammatory mediators implicated in allergic and inflammatory diseases. Currently, zileuton is the only FDA-approved 5-LO inhibitor, emphasizing the need to develop new agents for the treatment of such diseases. This project aims to develop validated stability-indicating analytical methods for the four most potent novel 5-(hydroxamic acid)methyl oxazolidinone derivatives (PH-211, PH-247, PH-249, and PH-251). Methods: The compounds were analyzed using Waters Acquity Ultra-High-Performance Liquid Chromatography (UHPLC-UV) with an ultraviolet detector to determine their stability in human plasma and under various forced degradation conditions, including acidic, basic, oxidative, and thermal conditions. Liquid chromatography–quadrupole time-of-flight mass spectrometry (LC-QToF-MS) was used to identify possible degradation products. Results: The compounds were found to be stable in human plasma and under thermal degradation conditions with high extraction recoveries (82–90%) but unstable in acidic, basic, and oxidative conditions. Conclusions: The findings show that the compounds are stable in biological conditions; they hold promise for the treatment of inflammatory and allergic diseases. Full article

Garlic’s vegetative reproduction limits genetic improvement, necessitating advanced biotechnological tools like protoplast culture. However, efficient protoplast regeneration in monocots such as garlic remains a significant challenge. This study establishes an optimized protocol for embryogenic callus induction and subsequent protoplast-to-plant regeneration in garlic (Allium sativum L.), aiming to overcome current limitations using suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, and phytosulfokine-alpha (PSK). We successfully induced embryogenic callus from four garlic accessions and refined protoplast isolation and culture conditions. Key optimizations included using a specific enzyme mixture (2% cellulase R-10 and 0.2% pectolyase Y23) for high yields (from 0.8 to 2.1 × 10⁶ protoplasts per g FM) of viable (approx. 90%) protoplasts and employing the enriched K8M culture medium. Short exposure of protoplasts to SAHA (0.05 or 0.1 µM) significantly improved microcallus formation and plant regeneration. Notably, only callus derived from SAHA-treated cultures displayed regeneration potential, highlighting its pivotal role in embryo differentiation and development. This optimized protocol achieved a 70% success rate for plant acclimatization to ex vitro conditions, with 97% of regenerated plants retaining the ploidy of the donor accession. We demonstrate that SAHA and PSK application enhances garlic protoplast regeneration efficiency. This reliable system provides the groundwork for advanced biotechnological applications, including gene editing technologies in garlic. Full article

Histone deacetylases (HDACs) are pivotal epigenetic regulators that control gene expression, cell proliferation, and differentiation, and their dysregulation is closely associated with the onset and progression of multiple cancers. The therapeutic importance of these enzymes is reflected by FDA approval of HDAC inhibitors for oncology indications. Despite this clinical success, most FDA-approved agents employ conventional zinc-binding groups (ZBGs) such as hydroxamic acid and 2-aminoanilide, which are frequently linked to metabolic instability, genotoxicity, and poor pharmacokinetic behavior. These limitations have spurred the development of structurally diverse and safer HDAC inhibitors incorporating alternative ZBGs. This review provides a comprehensive analysis of recently developed HDAC inhibitors reported in the last few years, emphasizing their structure–activity relationships (SARs), chemical scaffolds, and binding features—including cap, linker, and ZBG motifs. Both hydroxamate-based and non-hydroxamate inhibitors, such as benzamides, hydrazides, and thiol-containing analogs, are critically evaluated. Moreover, the potency and selectivity profiles of these inhibitors are summarized across different cancer and normal cell lines, as well as specific HDAC isoforms, providing a clearer understanding of their therapeutic potential. Emerging dual-target HDAC inhibitors, such as HDAC–tubulin, HDAC–PI3K and HDAC–CDK hybrids, are also discussed for their synergistic anticancer effects. Full article

The extraction of rare earth elements is becoming increasingly essential due to their many applications in current and emerging advanced material technologies. However, in many rare earth deposits, rare earth minerals are associated with radionuclides; specifically, thorium and uranium. The radioactive nature of these elements is a major concern during processing. Techniques such as solvent extraction and precipitation have been employed in this regard to minimize the radioactivity levels and address any related processing or environmental concerns. However, they face various challenges such as high chemical reagent consumption, secondary waste generation, and limited selectivity, which hinder either their scalability or sustainability. The current study provides a literature review about these technologies to provide critical insights on their applications and discuss the challenges hampering their extensive use in the mining industry. Biotechnology is also evaluated and highlighted as a promising, cost-effective, and low-environmental-impact option for the selective recovery of radionuclides from rare earth elements. Specifically, pyoverdine siderophores were discussed due to their catecholates and hydroxamate moieties which have high affinity for radionuclides to enhance selective recovery during rare earth processing. Conversely, integration of this approach into existing mineral processing flowsheets is a constraint. Hence, future studies should focus on optimizing the kinetics of siderophore synthesis and explore a hybrid approach to combine the biotechnological and conventional techniques. Full article

Helicobacter pylori urease (HpU) plays a central role in bacterial survival and virulence by hydrolyzing urea into ammonia and carbon dioxide, neutralizing gastric acidity, and facilitating host colonization. The increasing prevalence of antibiotic resistance underscores the need for alternative strategies targeting essential bacterial enzymes such as urease. In this study, a multistage computational pipeline integrating pharmacophore modeling, machine learning (ML), ensemble docking, and enhanced molecular dynamics simulations were applied to identify novel triazole-based HpU inhibitors. Starting from over seven million compounds in the ZINC15 database, pharmacophore- and ML-based filters progressively reduced the chemical space to 7062 candidates. Ensemble docking across 25 conformational frames of HpU, followed by quantum-polarized ligand docking (QPLD), identified seven promising ligands exhibiting strong binding energies and stable metal coordination. Molecular dynamics (MD) simulations under progressively relaxed restraints revealed three highly stable complexes (CA1, CA3, and CA6). Subsequent well-tempered metadynamics (WT-MetaD) simulations reconstructed free-energy landscapes showing deep, localized basins for CA3 and CA6, comparable to the potent reference inhibitor DJM, supporting their potential as strong urease binders. Finally, unsupervised chemical space mapping using the UMAP algorithm positioned these candidates within molecular regions associated with potent urease inhibitors, further validating their structural coherence and pharmacophoric relevance. An ADMET assessment confirmed that the selected candidates exhibit physicochemical and early safety properties compatible with subsequent in vitro evaluation. This multilevel screening strategy demonstrates the power of combining ML-driven classification, ensemble docking, and enhanced sampling simulations to discover non-hydroxamic urease inhibitors. Although the current findings are computational, they provide a rational foundation for future in vitro validation and for expanding the discovery of triazole-based scaffolds targeting ureolytic enzymes. Full article

Corneal problems, such as delayed and incomplete wound repair, are frequent in diabetes, affecting up to 70% of diabetic patients. In skin, histone deacetylases (HDACs) have been previously found to repress expression of the glycerol channel aquaporin-3 (AQP3), the deficiency of which delays corneal wound healing. We hypothesized that the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would improve corneal healing in diabetic mice. Diabetic and normoglycemic C57BL/6J male and female mice were subjected to corneal debridement. Wounds were treated topically with vehicle or SAHA every four hours until they healed. Treatment with SAHA improved wound healing in both normoglycemic and hyperglycemic male mice but, unexpectedly, no changes were detected in female mice. In male mice interleukin-1beta (IL-1β) and tumor necrosis factor (TNF) were significantly increased in diabetic corneas, and SAHA reduced their expression, returning IL-1β and TNF to levels comparable to those in normoglycemic mice regardless of treatment. In normoglycemic male mice, AQP3 levels were not changed in the cornea with SAHA treatment but the expression of AQP3 was increased in the wound’s edge relative to the rest of the cornea. In vitro SAHA treatment of human corneal epithelial cells (HCECs) significantly increased protein expression of AQP3, important for corneal wound healing, but had no effect on ROS production. In conclusion, treatment with SAHA improved corneal wound healing, not only in male mice with diabetes and delayed wound healing but also in normoglycemic male mice; therefore, SAHA could potentially be repurposed as a topical treatment clinically to improve corneal wound healing. Full article

Hydroxamic acid extractants, such as LIX984, demonstrate high efficiency in extracting nickel from electron-free nickel waste solutions; however, they suffer from a slow extraction rate. This study investigated the effect of adding 2–5 vol.% of three organophosphate extractants (P507, P204, and Cyanex272) to LIX984. The results show that incorporating 2–5 vol.% of P507 or Cyanex272 significantly improves both extraction efficiency and kinetics. The addition of organophosphate extractants increased the extraction rate by 1.5–10 times, indicating a direct correlation between the extractant content and the acceleration of the extraction process, with higher concentrations yielding faster extraction. Compared to the use of LIX984 alone, where nickel extraction efficiency was only 46%, the addition of 5 vol.% P507 increased efficiency to over 99%, with a substantial improvement in extraction rate. Similarly, 2 vol.% P204 achieved a nickel removal efficiency of 99.8%. In non-electroplating waste solutions (pH 4–6), selective removal of iron and zinc impurities was achieved by first adding 2–5 vol.% P204 or P507, followed by adjusting the pH to 6–7 and using a mixture of organophosphate extractants. The spent electroless nickel plating baths were then treated with LIX984 combined with organophosphoric acid extractants, yielding nickel salt solutions of higher purity. Thus, P507, P204, and Cyanex272 serve as effective promoters for the hydroxamic acid extractant LIX984, resulting in both enhanced nickel extraction efficiency and faster extraction kinetics. 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

Epigenetics garnered significant scientific interest in recent decades, with histone acetylation emerging as the most prevalent epigenetic deregulation process observed in malignancies. The clinical application of histone deacetylase (HDAC) inhibitors faced challenges, including complex therapeutic mechanisms and inconsistent treatment outcomes. In Acute Lymphoblastic Leukemia (ALL), the dysregulation of HDAC activity presents a promising therapeutic target. To investigate cellular-level tumor suppression by HDAC inhibitors possessing potent target engagement, we developed two novel azetidine-hydroxamic acid conjugates. Compared to N-hydroxy-4-((quinolin-4-ylamino)methyl)benzamide (NBU-1), N-hydroxy-6-((5-methyl-4-nitro-9-oxo-9,10-dihydroacridin-1-yl)amino)hexanamide (NBU-2) demonstrated enhanced inhibitory activity against HDAC1 (class I) and HDAC6 (class II) with IC₅₀ values of 7.75 nM and 7.34 nM, respectively, consistent with binding mode analysis and docking energy calculations. In vitro evaluation across 12 tumor cell lines revealed NBU-2’s potent antiproliferative effects, particularly against the ALL-derived Jurkat cells (IC₅₀ = 0.86 μM). Subsequent mechanistic studies were therefore conducted in this ALL model. Proteomic profiling indicated its potential involvement in modulating AKT signaling and histone modification pathways in Jurkat cells. Mechanistic investigations demonstrated that NBU-2 elevated histone acetylation while suppressing AKT phosphorylation. This compound altered apoptotic regulators by downregulating Bcl-2 and Bcl-XL expression while upregulating BAX, ultimately activating Caspase-9 and Caspase-3 to induce apoptosis. Cell cycle analysis revealed NBU-2-mediated G0/G1 arrest through reduced expression of Cyclin D1 and CDK4, diminished Rb protein phosphorylation, and increased p21 expression. These findings propose a strategic framework for developing next-generation HDAC inhibitors for ALL treatment and elucidating their mechanism-specific anti-cancer actions. Full article