Search Results (765)

Our previous study demonstrated that thiophene-substituted synthetic curcumin analogs possessed better antibacterial activity and stability than natural curcumin, demethoxycurcumin, or bisdemethoxycurcumin in antibacterial photodynamic therapy (aPDT). In addition, the activity of the furan-substituted analogs was weaker than that of the thiophene-substituted compounds. As oxygen, sulfur, and selenium belong to the same group in the periodic table, the antibacterial and anticancer activities of these three different elemental analogs were compared and investigated. The thiophene-substituted analog (compound 3) exhibited the most potent antibacterial activity in aPDT experiments. However, the furan-substituted analog (compound 1) exhibited the most potent anticancer activity. These results indicate that the differences in atomic radii or energy levels in these compounds produce different cell-attack results on generated free radicals. Ruthenium(II) complexes have a good reputation for use in PDT for cancer treatment. Our results show that complexation of ruthenium(II) with thiophene-substituted curcumin analogs does not enhance their antibacterial or anticancer activity. Full article

The number of structurally investigated cyclopentadienyl (Cp⁻) complexes of technetium is limited in contrast to the situation with its heavier homolog, rhenium. Although this could be attributed to the radioactivity of all isotopes of the radioelement, there are also clear chemical differences to analogous compounds of the other group seven elements, manganese and rhenium. Technetium Cp⁻ compounds are known with the metal in the oxidation states “+1” to “+7”, with a clear dominance of Tc(I) carbonyls and nitrosyls. Corresponding carbonyl complexes also play a significant role in the development of ^99mTc-based radiopharmaceuticals with the aromatic ring as an ideal position for the attachment of biomarkers. In this paper, the present status of the synthetic and structural chemistry of technetium with Cp⁻ ligands is discussed, together with recent developments in the corresponding ^99mTc labeling chemistry. Full article

In this essay I argue that there are necessarily true synthetic a priori moral propositions whose truth does not depend on the existence of God. To make my case, I appeal to an analogy with arithmetic truths such as 2 + 2 = 4 whose truth does not depend on the existence of God. I criticize views like Peter Railton’s that hold that moral truths are like truths about natural kinds such as water and heat, and non-cognitivists who hold that there are no robust moral truths. The point of my criticisms is to answer challenges to my view that there are necessarily true synthetic a priori moral propositions and, in the case of Railton, to block an argument by Robert Adams for a Divine Command Theory of ethics. Second, I argue by example that there can be conflicts between what is best for me and those for whom I care and what is morally required that cannot be reconciled by a theistic ethics. It can be rational to violate moral requirements that have the same contents as the commands of a loving God even if there would be most reason to adhere to those requirements IF God exists, just as it can be rational to leave your umbrella at home even if there would be most reason to take it IF it rained. This will be true regardless of whether the reason to adhere to God’s commands, IF God exists, is because our greatest good is the love of God (and that requires adhering to his commands) or because God will punish you if you do not and reward you if you do. The problem of evil is the primary reason to believe that God does not exist, and so to believe that there are no divine commands that there would be most reason to follow if God did exist. Full article

Ultra-soft injectable hydrogels are paramount in biomedical applications such as tissue fillers, drug depots, and tissue regeneration scaffolds. Synthetic approaches relying on linear polymers are confronted by the necessity for significant dilution of polymer solutions to reduce chain entanglements. Bottlebrush polymers offer an alternative approach due to suppressed chain overlap and entanglements, which facilitates lower solution viscosities and increased gel softness. Leveraging the bottlebrush architecture in linear-bottlebrush-linear (LBL) block copolymer systems, where L is a thermosensitive linear poly(N-isopropylacrylamide) block, and B is a hydrophilic polyethylene glycol brush block, injectable hydrogels were designed to mimic tissues as soft as the extracellular matrix at high polymer concentrations. Compared to an analogous system with shorter brush side chains, increasing the side chain length enables a decrease in modulus by up to two orders of magnitude within 1–100 Pa at 20 wt% polymer concentrations, near to the physiological water content of ~70%. This system further exhibits thermal hysteresis, enabling stability with inherent body temperature fluctuations. The observed features are ascribed to kinetically hindered network formation by bulky macromolecules. Full article

Kynurenic acid (KYNA) has recognized anti-inflammatory and immunosuppressive properties. Previous studies demonstrated that KYNA reduces TNF-α, S100A12, S100A8/9, and α-defensin production while increasing tumor necrosis factor-stimulated gene-6 protein (TSG-6) levels in rheumatoid arthritis. This study evaluated a synthetic KYNA analog’s effects on TNF-α, S100A8/9, S100A12, α-defensin, and interleukin-17 (IL-17) production and TSG-6 expression in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Peripheral blood mononuclear cells from 54 AS and 38 PsA patients and 11 healthy controls were stimulated with heat-inactivated Staphylococcus aureus (SA1). Parallel cultures were pretreated with the KYNA analog. Cytokine and alarmin concentrations were measured by ELISA. SA1 stimulation increased TNF-α, TSG-6, calprotectin, and α-defensin production, with minimal effects on S100A12 and none on IL-17. The KYNA analog significantly reduced SA1-induced TNF-α, calprotectin, and α-defensin levels and enhanced TSG-6 production, without affecting S100A12 or IL-17. Notably, the TNF-α inhibitory and TSG-6 stimulatory effects were inversely correlated. Conclusion: KYNA analogs may exert anti-inflammatory effects via TSG-6 upregulation, contributing to the suppression of key cytokines. These findings support further exploration of KYNA derivatives as therapeutic options in immune-mediated diseases including AS and PsA. Full article

Hypergraphs, a generalisation of traditional graphs in which hyperedges may connect more than two vertices, provide a natural framework for modeling higher-order interactions in complex biological systems. In the context of protein complexes, hypergraphs capture relationships in which a single protein may participate in multiple complexes simultaneously. A fundamental question is how such protein complex hypergraphs evolve over time. Motivated by duplication–divergence–deletion models often used for protein–protein interaction networks, we propose a novel Duplication–Divergence Hypergraph (DDH) model for the evolutionary dynamics of protein complex hypergraphs. To evaluate network resilience, we simulate targeted attack strategies analogous to drug treatments or genetic knockouts that remove selected proteins and their associated hyperedges. We measure the resulting structural changes using hypergraph-based efficiency metrics, comparing synthetic networks generated by the DDH model with empirical E. coli protein complex data. This framework demonstrates closer alignment with empirical observations than standard pairwise duplication–divergence models, suggesting that hypergraphs provide a more realistic representation of protein interactions. Full article

Cancer is one of the most feared diseases in the world. Its incidence has increased steadily in recent years; it represents a significant burden of disease and is among the leading causes of death globally. Consequently, the search for novel compounds that serve as potential candidates for pharmacotherapeutic options and that can be used as treatments or adjuvants to control this disease is urgent. In this context, plant-derived phenolic diterpenes have shown antitumor activity against several types of cancer, inhibiting DNA synthesis, lipid metabolism, and bioenergetics of these cells, among other mechanisms, making these compounds an excellent alternative to continue investigating. The objective of this research was to evaluate the action of the previously undescribed natural diterpene 3,3′-diisopropyl-2,2′,5,5′-tetramethoxy-6,6′-dimethylbiphenyl-4,4′-diol (biisoespintanolcompound 2), against several human tumor cell lines (A549, MDA-MB-231, DU145, A2780, A2780-cis) and the non-tumor cell line MRC-5. Experiments with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and fluorescence with propidium iodide (PI), 4′,6-diamidino-2-phenylindole dilactate (DAPI), and green plasma revealed the cytotoxicity of 2 against these cells. Furthermore, morphological and chromogenic studies demonstrated the action of 2 on cell morphology and its inhibitory capacity of reproductive viability for colony formation in A549 cells. Furthermore, 3D experiments validated the damage caused by this diterpene in these cells. These results contribute to the search for novel compounds with antitumor potential and serve as a basis for advancing studies into the mechanisms of action of these compounds and the development of synthetic derivatives or analogs with a better antitumor profile. Full article

The paper focuses on a transition from studying synthetic analogs of rare titanosilicate minerals (lintisite, ivanyukite, and zorite) in the powdery state to investigating their new granulated forms. Five different methods for granulating titanosilicate samples are tested: fluidized bed and spray dry granulation, spray bed granulation, screw rotor granulation, and manual pressing of paste through a stainless-steel sieve with a 1 mm mesh size. The results of studying sorption of trace amounts of ¹³⁷Cs and ⁹⁰Sr radionuclides from model solutions of various compositions onto inorganic sorbents in powdered and granulated forms are presented. Full article

Background/Objectives: Vincamine is an indole alkaloid initially isolated from plants of the Vinca genus and has previously been demonstrated to have antioxidant, hypoglycemic, and hypolipidemic activities. Vinpocetine, a synthetic derivative of vincamine with an enhanced pharmacological profile, has demonstrated promising antiproliferative properties. While previously reported vinpocetine derivatives have undergone extensive investigation for their pharmacological properties, the role of the E-ring ethyl ester in the antiproliferative properties of compounds with this scaffold has not yet been fully described. Methods: Here, the antiproliferative activity of two vinpocetine analogs with modifications at the E-ring was evaluated through cell viability and LDH assays, and their mechanism of action was investigated through cell cycle analysis, apoptosis detection, and reporter assays for Wnt-1, NF-κB, and STAT3 signaling. Results: Cell viability assays revealed that reduction of the ethyl ester to an alcohol exhibited strong dose-dependent antiproliferative activity across five mammalian cell lines, but did not induce significant markers of apoptosis or necrotic death as determined by FITC/Annexin V and cell cycle flow cytometry, respectively. Through label-free cell imaging, we found the antiproliferative activity of vinpocetine alcohol to be correlated with a decrease in membrane integrity in treated cells. We further observe that both analogs exhibit dose-dependent modulation of TCF/LEF, NF-kB, and STAT3 reporter cells, which appears to be coupled with trends in antiproliferative activity. Conclusions: Altogether, this work demonstrates the potential for E-ring modifications of vinpocetine as antiproliferative agents. Full article

Pyridinium ylides, along with related azaheterocyclic ylides, are widely used in synthetic organic chemistry. However, reactions that yield stable zwitterionic adducts from these ylides remain underexplored. In this work, we demonstrate that the reaction of pyrrole-2,3-diones with in situ-generated pyridine-based azomethine ylides affords stable zwitterionic adducts, which are typically transient species in analogous processes. These betaines are used as key intermediates for the synthesis of cyclopropane-fused pyrroles or pyridine-2,3-diones via thermolysis in chlorobenzene. Full article

Phytohormones are key signaling molecules that regulate plant growth, stress adaptation, and fruit ripening. However, their low abundance and structural diversity complicate accurate quantification in food matrices. This study presents a validated LC–MS/MS method for the simultaneous detection of seven phytohormones in tomato fruit, including two synthetic analogs that mimic natural auxins and cytokinins. Method optimization focused on extraction efficiency, solid-phase cleanup, and mobile phase composition, achieving high recovery (85–95%) and reduced matrix effects. Chromatographic separation was performed on a C18 column, with detection by triple quadrupole mass spectrometry in MRM mode. The method demonstrated excellent linearity (R² > 0.98), precision, and robustness, with detection limits as low as 0.05 ng/mL for abscisic acid and 6-benzylaminopurine. Validation followed US-FDA and EC 2021/808 guidelines, ensuring regulatory compliance and analytical reliability. Analysis of tomato samples from five geographic origins revealed significant differences in phytohormone profiles, particularly in abscisic and salicylic acids, highlighting the method’s ability to capture biologically and agriculturally relevant variation. This workflow offers a sensitive, transferable platform for monitoring bioactive compounds in tomatoes and other food crops, supporting post-harvest quality assessment and food metabolomics research. Full article

Tyrosine kinases (TKs) and cyclin-dependent kinases (CDKs) contain reactive cysteines that can be exploited by targeted covalent inhibitors. In this exploratory computational study, we asked whether selected natural-product-like (NP-like) electrophiles bearing Michael-acceptor (MA) motifs could adopt geometries consistent with covalent approaches to these cysteines, in a manner analogous to approved covalent TKIs. Using AutoDockFR with cysteine-centered grids and explicit side-chain flexibility, we performed pocket-focused, within-receptor covalent docking for EGFR, VEGFR2/KDR, PDGFRβ (via PDGFRα surrogate), BTK, CDK7, and CDK12. Reference inhibitors (osimertinib–EGFR, ibrutinib–BTK, THZ1–CDK7, and THZ531–CDK12) reproduced the expected geometries and served as internal controls. NP-like electrophiles (parthenolide, withaferin A, celastrol, and curcumin as a low-reactivity geometry probe) displayed pocket-compatible orientations in several targets, particularly EGFR and BTK, suggesting feasible pre-reaction alignment toward the reactive cysteine. Although no quantitative affinity was inferred, the consistent geometric feasibility supports their potential as structural templates for covalent-binding natural scaffolds. These results provide a qualitative, structure-based rationale for further chemoproteomic and enzymatic validation of NP-derived or hybrid compounds as potential leads in cancer therapy, expanding covalent chemical space beyond existing synthetic scaffolds. Full article

Increasing evidence suggests that, under physiological conditions, the carbonate anion radical CO₃^•− could be the major source of oxidative stress, instead of the commonly accepted hydroxyl radical HO^•. In aqueous solutions, CO₃^•− exists as a hydrated species, which may influence its properties and activities. CO₃^•− acts as a one-electron oxidant via a single electron transfer (SET) mechanism. Impact of the number of explicit water molecules (0, 4, 6, and 9) on inactivation of CO₃^•− by Trolox, a water-soluble analog of α-tocopherol, was theoretically investigated using the DFT approach. Also, the role of Trolox solvation by H-bonded water molecules was examined. The obtained results indicate that an increased number of explicit water molecules in CO₃^•− hydration shell increases exergonicity and decreases the reaction barrier of the SET pathway, causing minor alterations of intrinsic reactivity, i.e., apparent rate constant. Amongst Trolox species, explicit hydration of the dianion has a notable impact on the reaction rate. Trolox belongs to phenolic antioxidants, but electron transfer to CO₃^•− proceeds from the aromatic part of the chroman moiety rather than from the phenoxide or carboxylate group of ionic species. The presented microhydration approach may serve as a way for estimating the potency of natural and synthetic compounds to suppress oxidative damage caused by CO₃^•−, a topic scarcely computationally considered so far. Full article

The transition to organic farming is one of the most desirable achievements of our time. Rational use of organic farming approaches not only enables a reduction in costs and increased yields but also limits the risks associated with the use of pesticides and chemicals. Despite the widest practical application of numerous biocontrol agents based on Bacillus strains, their metabolome, including the main active substances, often remains unknown. In order to understand the basic principles of the functioning of the Bacillus velezensis K-3618 strain, widely used in organic farming, we studied its spectrum of antimicrobial metabolites in detail. It was shown that the main antimicrobial agents of B. velezensis K-3618 are representatives of the macrolactin family. The identified macrolactin A (MLN A) and its acylated analogs 7-O-malonyl macrolactin A (mal-MLN A) and 7-O-succinyl macrolactin A (suc-MLN A) are active against Gram-positive bacterial pathogens, including multidrug-resistant strains. Among them, suc-MLN A is the most potent antimicrobial, highly active (MIC = 0.1 μg/mL) against the common human pathogen methicillin-resistant Staphylococcus aureus (MRSA). It was revealed that the primary mechanism of action of MLN A-based macrolactins is protein translation inhibition. Acylated macrolactins outperform MLN A in the prokaryotic cell-free system, displaying high efficiency in low micromolar concentrations. We observed that acylated MLN A analogs undergo pathogen-mediated biotransformation into MLN F analogs, having their antimicrobial activity reduced by two orders of magnitude. Hence, both acylation of MLNs and stabilization of the MLN A core are essential for the creation of new synthetic MLNs with improved antimicrobial activity and stability. However, we speculate that these degradability modes are of prime importance for bacterial ecology, and they are highly conserved in Bacillus species from various ecological niches. Full article

Bromoepiandrosterone (BEA), a synthetic analog of the adrenal steroid DHEA, holds promise as a host-directed therapy for both active and latent tuberculosis (TB). Unlike DHEA, BEA lacks hormonal side effects yet retains potent immunomodulatory activity. It promotes a Th1-skewed immune response by enhancing interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), critical cytokines for macrophage activation and intracellular control of Mycobacterium tuberculosis (Mtb), while suppressing Th2 cytokines such as IL-4. BEA also inhibits 11β-hydroxysteroid dehydrogenase-1, lowering intracellular cortisol levels and reversing the local immunosuppression commonly seen in TB. These features enable BEA to restore immune competency in TB-infected tissues. In murine TB models, BEA halted bacterial growth, reduced pulmonary inflammation, and synergized with standard anti-TB drugs to enhance bacterial clearance. Additionally, DHEA and its analogues have demonstrated direct antimycobacterial activity, likely by interfering with Mtb mycolic acid synthesis, a property BEA is believed to share. For latent TB, BEA’s ability to sustain Th1-mediated immunity and counteract immune suppression could help maintain latency and prevent reactivation, especially in immunocompromised individuals. By boosting immune surveillance and potentially contributing to bacillary clearance, BEA offers a unique adjunctive approach that complements existing TB treatments without contributing to drug resistance. Its dual function, an immune modulator and antimicrobial agent, supports its use across the TB disease spectrum. These properties position BEA as a novel candidate for host-directed therapy aimed at improving outcomes in both drug-sensitive and drug-resistant TB, as well as therapies aimed at enhancing long-term containment of latent infection. Full article