Search Results (58)

Theaflavin-3,3′-digallate (TF3), a flavan-3-ol derivative found in black tea, exhibits anti-tumor activity, but its mechanism of action in hepatocellular carcinoma (HCC) remains to be elucidated. Here we systematically delineate how TF3 targets Pin1 to suppress HCC through an integrated approach combining computational simulations, enzyme assay and cell-based assays. TF3 spontaneously occupies the active site of Pin1 with a docking score of −8.9 kcal/mol, inhibiting its PPIase activity (IC₅₀ = 60.33 μmol/L) and yielding a binding constant (K_a) of 3.1 × 10⁵ mol/L. Drug affinity responsive target stability (DARTS) assays further corroborated that TF3 directly engages Pin1 within HCC cells. Functionally, TF3 potently suppressed the viability of HepG2, SK-Hep-1 and Huh-7 cells in both dose- and time-dependent manners (IC₅₀ = 61.22, 14.09 and 69.85 μmol/L at 24 h, respectively), and exhibited a modest selectivity window against the viability of L02 and THLE-2 cells (IC₅₀ = 133.43 and 90.29 μmol/L at 24 h, respectively). In addition, TF3 triggers mitochondrial-mediated apoptosis, evidenced by ROS accumulation, loss of mitochondrial membrane potential, an elevated Bax/Bcl-2 ratio, cytochrome c release and enhanced PARP cleavage, and induces G₂/M phase arrest. It also robustly inhibits HCC cell proliferation, invasion and migration, coinciding with downregulation of proteins governing cell cycle progression and invasive behavior. Transcriptome profiling coupled with enrichment analysis discovered that TF3 treatment differentially regulated 5009 genes, which were prominently enriched in pathways linked to apoptosis, cell cycle control, MAPK and PI3K/AKT signaling pathways. Western blotting analysis revealed that TF3 selectively suppresses phosphorylation of p38 and the PI3K/AKT cascade, activating JNK phosphorylation. In summary, our findings indicate that TF3 suppresses HCC proliferation by targeting Pin1, with attendant modulation of the MAPK and PI3K/AKT pathways, thereby presenting a potential candidate for targeted HCC therapy. Full article

Amphiphilic cationic lipids based on the 1,4-dihydropyridine (1,4-DHP) scaffold represent a versatile platform for the development of self-assembling delivery systems. In this work, a series of ten new amphiphilic 1,4-DHP derivatives bearing branched ester substituents at the 3,5-positions and quaternized cationic groups at the 2,6-positions were designed and synthesized. The effect of branched ester chain length and branching on nanoparticle formation was investigated. The self-assembling properties of the synthesized amphiphiles were evaluated by dynamic light scattering using an ethanol injection method. All compounds formed positively charged nanoparticles with hydrodynamic diameters ranging from 52 to 439 nm and polydispersity index from 0.194 to 0.452. Amphiphiles 14b–17b with 2-hexyldecyl substituents formed smaller particles, with an average diameter below 100 nm. Several derivatives exhibited good stability over a 14-day storage period at room temperature. To clarify structure–property relationships, lipophilicity (AlogP), polar surface area (PSA), and pK_a values were calculated using Schrödinger computational tools. The compounds displayed high lipophilicity AlogP 8.98–19.32, while PSA values remained within a narrow range. The calculated pK_a values ranged from 7.20 to 10.99. The results demonstrate that both the length and architecture of branched ester chains significantly influence nanoparticle size, homogeneity, and stability, highlighting branched-chain 1,4-DHP amphiphiles as promising synthetic lipid candidates for further development of delivery systems after evaluation of biological properties. Full article

Acidic chitinase (Chia) degrades chitin, a structural polysaccharide in insect exoskeletons, and plays important roles in omnivorous and insectivorous mammals and birds. In birds, gene duplications have generated multiple Chia paralogs with functional divergence, but the molecular basis for this diversification remains unclear. Here, we characterized three chicken Chia paralogs (Chia1–3) and identified distinct pH-dependent enzymatic profiles. Chia1 is enzymatically inactive but was captured by chitin-affinity resin despite lacking a canonical chitin-binding domain, suggesting residual substrate interaction through the catalytic domain or a non-catalytic role. Chia2 exhibits maximal activity at pH 2.0, whereas Chia3 peaks at pH 5.0 and displays broader activity. Exon swapping and site-directed mutagenesis identified residues 104 (Ala in Chia2, Asp in Chia3) and 269 (His vs. Asn) as key contributors to pH-dependent activity differences. Reciprocal substitutions shifted pH profiles accordingly. Structural modeling and computational pKa predictions suggested that D213 and residue 269 may function as a pKa-regulating module influencing catalytic ionization. Comparative sequence analysis revealed lineage-specific conservation of these residues, consistent with adaptive divergence. Our findings show that limited amino acid substitutions can markedly modify pH-dependent enzymatic activity, providing mechanistic insight into how local residue variation contributes to the functional diversification of duplicated genes. Full article

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory respiratory disorder with a globally increasing prevalence. Current therapeutic strategies are limited by drug resistance and safety concerns. Studies suggest that inhibiting the secretion of inflammatory cytokines represents a promising approach for COPD treatment. Phosphodiesterase-4 (PDE4) inhibitors have emerged as potent anti-inflammatory agents for respiratory diseases. In this study, we integrated a marine-derived natural product with computer-aided drug design to develop 32 novel PDE4 inhibitors. Compound B7 exhibited potent PDE4 inhibitory activity and a favorable safety profile. In rat model of COPD, B7 significantly reduced inflammatory cell infiltration and cytokine levels, ameliorated pathological changes in the lung, decreased the percentage of goblet cell positivity, and reduced expiratory resistance. Furthermore, in vitro mechanistic studies revealed that B7 exerts its anti-inflammatory effects by activating the cAMP-PKA-CREB signaling pathway and suppressing the NF-κB pathway in RAW264.7 cells. In conclusion, B7 demonstrates potential as a safe and effective PDE4-targeted candidate for the treatment of COPD. Full article

Background/Objectives: Cells derived from direct chemical reprogramming into osteoblasts represent a promising source for bone regeneration, but the efficiency needs improvement. Here, we systematically evaluated whether the natural compound psoralen (Psr) could enhance this process and explored its therapeutic potential and mechanism of action. Methods: Mouse embryonic fibroblasts (MEFs) were treated with a cocktail of forskolin and phenamil (FP), supplemented with Psr. In vitro differentiation was assessed by alkaline phosphatase and Alizarin Red S staining, reverse transcription quantitative PCR, immunofluorescence and Western blot. The bone-regenerative potential of the derived chemically induced osteoblast-like cells (ciOBs) was evaluated in critical-sized calvarial defects, femoral cortical defects and a subcutaneous ectopic implantation model, using micro-computed tomography and histology. Mechanistic insights of Psr were gained by analyzing the adenylyl cyclase 9 (ADCY9)/cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) axis using inhibitor SQ22536. Results: Psr acted synergistically with the FP cocktail to drive efficient osteogenic reprogramming of MEFs. At an optimal concentration of 25 μM, Psr enabled the most robust induction of early osteogenic markers and generation of mature, mineralizing ciOBs in vitro. In vivo, FP + Psr-induced ciOBs repaired critical-sized calvarial and femoral cortical defects and generated substantial, vascularized bone tissue in ectopic sites. Mechanistically, Psr co-treatment potently activated the ADCY9/cAMP/PKA/CREB pathway, and pharmacological inhibition of this pathway completely abolished the pro-osteogenic effects of Psr. Conclusions: Psr acts as a potent synergistic enhancer of direct chemical reprogramming, generating functional osteoblast-like cells with robust bone-regenerative capacity via activation of the ADCY9/cAMP/PKA/CREB pathway. Full article

The relative position of the oxime group within pharmaceutically relevant pyridinium oximes is a pivotal factor that governs their intrinsic physicochemical properties and their biological reactivity. However, studies providing in-depth, molecular-level insight into these structure–reactivity relationships are still limited. In this work, we present an integrated experimental and computational study of N-methylpyridinium-2-aldoxime chloride (PAM2-Cl), N-methylpyridinium-3-aldoxime iodide (PAM3-I), and N-methylpyridinium-4-aldoxime iodide (PAM4-I), aimed at elucidating discrete differences in their ionization behavior, electronic structure, σ-donor properties, and nucleophilicity. The crystal structure of PAM3-I was determined by X-ray diffraction. Comparative structural and spectroscopic (UV–Vis, NMR, IR) analyses elucidated the structural and electronic effects arising from the position of the oxime group. Kinetic studies of substitution reactions with aquapentacyanoferrate(II) in aqueous solution enabled the determination of pentacyano(PAM)ferrate(II) formation and dissociation rate constants, coordination modes, pK_a values of the coordinated ligands, complex stability constants, and σ-donating capabilities. The DFT-based analysis of atomic charge distribution transcended experimental limitations, offering a new perspective on electronic structure-related properties. This study presents the first side-by-side, internally consistent structure–reactivity map across PAM2, PAM3, and PAM4 isomers that triangulates crystallography, UV–Vis-derived pK_a values, substitution kinetics, and DFT descriptors in a single framework. Full article

A novel series of benzoxazole-derived iminocoumarins was synthesized via a Knoevenagel condensation and fully characterized using NMR, UV–Vis spectroscopy, and computational methods. Their photophysical properties were systematically examined in solvents of varying polarity, revealing pronounced effects of both substituents and solvent environment on absorption maxima and intensity. Derivatives bearing electron-donating substituents on the coumarin core exhibited distinct and reversible pH-responsive spectral shifts, confirming their potential as optical pH probes. Experimental pK_a values derived from absorption titrations showed excellent agreement with DFT-calculated data, validating the proposed protonation-deprotonation equilibria and associated electronic structure changes. Structure–property relationships revealed that electron-donating groups enhance intramolecular charge transfer, while electron-withdrawing substituents modulate spectral response and stability. In parallel, the compounds were evaluated for antiproliferative, antiviral, and antifungal activities in vitro. Strong electron-donating substituents were associated with potent but non-selective cytotoxicity, whereas derivatives bearing electron-withdrawing groups displayed moderate and more selective antiproliferative effects against leukemia cell lines. Antifungal screening revealed moderate inhibition of phytopathogenic fungi, particularly for compounds with electron-withdrawing or methoxy substituents. Overall, these findings demonstrate that benzoxazole iminocoumarins represent a promising class of multifunctional heterocycles with potential applications as optical pH sensors and scaffolds for bioactive compound development. Full article

In this work, we report the one-pot synthesis and characterization of four water-soluble 2-hydroxybenzo[e][1,2]oxaphosphinine 2-oxides. The compounds were obtained by cascade reactions of (2-ethoxyvinyl)phosphonic dichloride with phenol or naphthol derivatives, and their acid–base, structural, and photophysical properties were investigated using a combination of experimental and computational methods. These compounds exhibit UV–vis absorption maxima at 209–341 nm and fluorescence maxima at 300–394 nm. Notably, these cyclic phosphonic acids exhibit unusually strong acidity with pK_a values from −1.3 to 0, comparable to mineral acids; complete protonation is not achieved even in concentrated HCl. The acidity trends and spectra were further analyzed by DFT using both explicit and implicit solvation models. Full article

A comprehensive analysis of key findings derived from density functional theory (DFT) studies reveals that current theoretical data on curcumin remain incomplete, underscoring the need for further computational investigation to achieve a more thorough understanding of its chemical and biological reactivity. This study addresses these gaps through four primary objectives: (i) determination of a complete set of thermodynamic descriptors and elucidation of the multi-step anti-radical mechanisms of the neutral, radical, anionic, and radical–anionic forms of curcumin; (ii) calculation of global chemical reactivity descriptors of curcumin in various solvent environments; (iii) theoretical reproduction of experimentally determined pK_a values for all active sites within the molecule; and (iv) examination of the effects of dispersion interactions and solvent polarity on the reactivity descriptors of keto–enol forms of curcumin. The results obtained provide enhanced insight into the molecular behavior of curcumin, facilitating improved predictions of its reactivity under diverse conditions. Moreover, the findings indicate a potential structural modification of the keto form of curcumin, involving the attachment of two 4-hydroxy-3-methoxyphenyl-prop-1-en-2-one moieties to the methylene group. The resulting modeled compound, referred to as di-curcumin, exhibits enhanced chemical reactivity and increased anti-radical potential. Full article

Nucleobases play diverse structural and functional roles in biological systems. Understanding the fundamental properties of nucleobases is important for their applications as chemical probes of nucleic acid function. As the nucleobases are modified to tune their fluorescence or binding properties, their physical properties such as pK_a may also change. Unlike the canonical nucleobases, modified nucleobases are less well understood in terms of their acid-base properties. Previously, theoretical pK_a values of canonical, naturally modified, and aza-/deaza-modified nucleobases were determined. In this study, the theoretical pK_a values for 25 different fluorescent modified nucleobases (55 total pK_a values) were calculated by using an ab initio quantum mechanical method employing the B3LYP density functional with 6-31+G(d,p) basis set along with an implicit–explicit solvation model. The results of these computations are compared to known experimental pK_a values. The ability to estimate theoretical pK_a values will be beneficial for further development and applications of fluorescent nucleobases. Full article

An important property of arylboronic acids, particularly when considering their use in medicinal chemistry, is their pK_a in aqueous solution. The results of computational determination of absolute pK_as of arylboronic acids can be very disappointing in comparison to available experimental results, particularly in the case of large substituents. In this paper, the main origin of this problem is identified. It is shown that in order to obtain accurate pK_a values for arylboronic acids from computational quantum chemistry, it is necessary to consider the effect of different possible conformations of the hydroxyl groups in the acid and its conjugate base together with the low-energy conformations of their substituents. An improved practical procedure for the computational determination of the pK_as of arylboronic acids is proposed and applied to a set of recently synthesized arylboronic acids, yielding consistent results. Full article

Background/Objectives: Prolonged sitting is linked to musculoskeletal discomfort, yet optimal sitting posture remains poorly defined, and the consistency with which individuals reproduce specific sitting strategies is unclear. This study examined postural variability across three sitting strategies—comfortable, habitual, and correct—using three common chair types: a stool, computer chair, and ergonomic chair. Methods: Thirty healthy young adults (fifteen men, fifteen women) participated. Global sagittal joint angles—head inclination (HI), trunk angle (TA), and knee angle (KA)—were measured using a motion analysis system across five repetitions per condition. Results: The chair type significantly influenced HI and TA (p < 0.001), with ergonomic chairs encouraging more upright trunk postures. The sitting strategy significantly affected TA and KA (p < 0.01), with comfortable sitting associated with more extended angles. Women exhibited greater TA (114.8° vs. 109.0°, p < 0.001) and lower within-subject variability. Substantial postural variability was observed across all conditions, with mean ranges exceeding minimum detectable change thresholds for HI (10.3°), TA (6.9°), and KA (11.3°). Notably, correct sitting reduced KA variability compared to other strategies (p < 0.01). Conclusions: These findings highlight the individualized and variable nature of sitting posture, even under controlled instructions. The results question the reliability of memory-based seat adjustments and emphasize the need for dynamic, user-centered ergonomic design and personalized clinical guidance to support musculoskeletal health. Full article

The increasing demand for sustainable and environmentally friendly materials has prompted intensive research into developing bioplastics as viable alternatives to conventional petroleum-derived plastics. Here, we report a novel approach to bioplastic production by employing plant extract-based solvents to partially dissolve cellulose, a fundamental biopolymer precursor. Using plant-derived solvents addresses concerns surrounding the environmental impact of traditional solvent-based processes, as per the principles of green chemistry. Using computational screening, some natural products were identified from the integrated database resource MEGx. Six natural sources were selected based on their molecular weight, high pKa, and chemical classification. Thin-layer chromatography (TLC) and column chromatography confirmed the presence of molecules in the extracts. Bioplastics were prepared with 1, 3, 6, 10, and 15 wt.% plant extract concentrations. Control samples without conventional dissolved and positive controls were also studied to compare their properties with novel bioplastics. Chemical characterization and biodegradability tests were performed. Degradation in water and soil tests for 35 days showed that the biodegradability of the bioplastics with natural extracts at higher concentrations was faster than that of the control samples. By day 35, bioplastics containing 15 wt.% of the D1 W extract showed rapid degradation, with higher weight loss compared with the conventional controls. The positive control (C4), containing NaOH and glycerol, degraded more slowly than the plant extract-based formulations. Also, the test indicated that the natural dissolvent’s influence on the water uptake of the material produced a better performance than the control samples. The surfaces of the bioplastic formulations were analyzed using a scanning electron microscope (SEM) at different magnifications. The findings presented here hold promise for advancing the field of bioplastics and contributing to the sustainable utilization of plant resources for eco-friendly material production. Full article

This study employed computational methods to investigate the basicity of a series of polyfluorinated phosphanes. Results revealed an exceptionally low basicity, with the computed pK_aH values in acetonitrile approaching −30, a value significantly lower than anticipated. The good agreement between the SMD and COSMO-RS methods provided confidence in the reliability of these values. This unexpected behavior challenges conventional perceptions of phosphane basicity and deepens our understanding of the electronic effects of fluorination. The findings hold important implications for catalysis, ligand design, and main-group chemistry, where a precise comprehension of phosphane electronic properties is crucial. pK_aH(MeCN) values, gas-phase basicities, and steric parameters are reported for 14 phosphanes. Full article

The kynurenine pathway is a significant metabolic route involved in the catabolism of tryptophan, producing various bioactive metabolites with crucial roles as antioxidants in immune regulation and neurobiology. This study investigates the acid-base properties of picolinic acid, kynurenic acid, kynurenine, and 3-hydroxykynurenine, utilizing computational simulations and experimental techniques, including potentiometric and nuclear magnetic resonance titrations. The results reveal distinct pK_a values, with kynurenic acid exhibiting a single dissociation step around 2.4, while kynurenine displays three dissociation steps governed by interactions between its functional groups. Additionally, 3-hydroxykynurenine shows overlapping dissociations in two separate pH regions, suggesting nuanced behavior influenced by its molecular structure. The analysis of intramolecular hydrogen bonding in protonation microspecies across varying pH highlights the relevance of the charge state and hydrogen transfer potential of these metabolites in the context of their radical scavenging ability. At physiological pH, most kynurenine and 3-hydroxykynurenine entities exist in zwitterionic form, with hydrogen bonding stabilizing the aromatic amino group, which may significantly influence their interactions with proteins and reactive oxygen species. This study provides critical insights into the acid-base equilibria of kynurenine pathway metabolites. Full article