BACKGROUND/AIM:We previously demonstrated that a novel coumarin-based compound, 7,8-dihydroxy-3-(4'-hydroxyphenyl)coumarin (DHC), suppresses metastasis of LM8 osteosarcoma cells both in vitro and in vivo. However, the molecular target of DHC remains unclear. The aim of this study was to develop novel DHC-derived compounds and to identify their target molecule. MATERIALS AND METHODS:Novel coumarin-based compounds were designed and evaluated for their effects on LM8 osteosarcoma cell invasion and migration. To identify a candidate target molecule of the newly synthesized compound SSKP-0076, liquid chromatography-mass spectrometry analysis was performed. The identified candidate molecule was further validated using RNA interference. RESULTS:Three novel coumarin-based compounds, SSKP-0076, SSKP-0081, and SSKP-0082, were synthesized. All compounds significantly inhibited invasion and migration of LM8 cells. Liquid chromatography-mass spectrometry combined with Mascot database searching identified Y-box binding protein 1 (Ybx1) as a candidate target molecule of SSKP-0076. Knockdown of Ybx1 by specific siRNAs significantly suppressed invasion and migration of LM8 cells and reduced the protein expression of the small GTP-binding proteins RhoA and Rac1, without affecting their mRNA expression levels. These effects were consistent with those observed following DHC treatment. CONCLUSION:Ybx1 is a potential target molecule of the novel anti-metastatic coumarin-based compound SSKP-0076.

The Ordered Set Theory is a branch of Mathematics that studies partially ordered sets (usually posets) and lattices. The meaning of dimension is one of the main parts of this field. In particular, the covering dimension, the Krull dimension and the small inductive dimension have been studied extensively for the class of finite lattices. In this paper, we insert a new meaning of dimension for finite lattices called large inductive dimension. We study various of its properties based on minimal covers. Also, given two finite lattices, we study the dimension Ind of their linear sum, Cartesian, lexicographic and rectangular product, investigating the "behavior" of this dimension. In addition, we study relations of this new dimension with the small inductive dimension, covering dimension and Krull dimension, presenting various facts and examples that strengthen the corresponding results.

Undoubtedly, Topological Dimension Theory contains many important chapters, including the studies of different notions of dimensions such as the small inductive dimension and the covering dimension. In this paper, we extend such studies. Given a topological space (X, tau), we introduce the notions of zero-dimensional extensions of tau with respect to the small inductive dimension ind and the covering dimension dim. Based on these meanings, new cardinal invariants are inserted, the so-called zero-dimensional structural numbers with respect to ind and dim, succeeding to present the topology tau as an intersection of zero-dimensional extensions of it. We study properties of these invariants and their "behavior" in different classes of topological spaces. (c) 2025 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

The total synthesis and structure determination of enantiomerically pure (+)- and (-)-ephedroidin from the leguminous plant is described. (+)- and (-)-Ephedroidin were a flavonoid with a chiral secondary alcohol on a side chain derived from a prenyl group. These compounds were obtained by optical resolution of (±)-ephedroidin through α-methoxyphenylacetic acid (MPA) esterification. The racemic secondary hydroxy group of (±)-ephedroidin was generated by photooxidation of prenylated flavonoid. Based on the total synthesis and Trost's method using α-MPA ester derivatives, the absolute configurations of (+)- and (-)-ephedroidin were revealed.

A streamlined radiosynthetic methodology enables the precise sequential assembly of boronic ester precursors on diol resin, seamlessly integrating copper-mediated radioiododeboronation and azide-alkyne cycloaddition. This approach yields radioiodinated compounds with high radiochemical conversion (>90%) without requiring column purification until the final stage, thereby accelerating the efficient development of advanced radioiodinated molecular probes.

Verubecestat, atabecestat, and elenbecestat are small-molecule BACE1 inhibitors. Based on their structures, we designed and synthesized a novel BACE1 inhibitor with a hydroxyproline-derived N-amidinopyrrolidine scaffold. The initially synthesized derivative 7a showed a weak but detectable inhibitory activity against recombinant BACE1, which suggested that this novel scaffold was a viable BACE1 inhibitor. To enhance its activity, 22 derivatives with various substituents on the terminal benzene rings of the two biphenyl groups were synthesized and evaluated. Structure-activity relationship studies showed that introducing a substituent at the meta position of the biphenyl group on the hydroxy terminal improved the activity, and we identified the highly active derivative 12f. In contrast, substituents at the para position of the biphenyl group on the carboxy terminal increased activity. Additionally, we investigated the absolute configuration of the substituted pyrrolidine ring, which showed that the (2S,4R)-derivative exhibited the highest activity. Docking simulations suggested that a bulkier substituent tended to be located in the S1 and S3 pockets and that the binding mode significantly changed depending on which biphenyl group the substituent was attached to. These results show that the new scaffold would be useful for further development of small-molecule BACE1 inhibitors.

Synthesis of (−)‐mucocin isolated from Rollinia mucosa (Annonaceae) was achieved. Stereoselective construction of the tetrahydropyran (THP) ring moiety was performed using diastereoselective oxypalladation. The tetrahydrofuran (THF) ring moiety was prepared from (S)‐(−)‐malic acid. The cross‐metathesis reaction between the THP and THF moieties afforded the nonadjacent THP–THF core part. Sonogashira cross‐coupling of the γ‐lactone portion with the THP–THF core part followed by reduction of the enyne and removal of the protecting groups afforded (−)‐mucocin.

Copper-mediated one-pot two-step radioiodination proceeds under mild conditions. Furthermore, this methodology operates with continuous incorporation of reagents into the reaction system and a single-step purification.

The copper-catalyzed Chan-Evans-Lam (CEL) coupling reaction advances carbon-heteroatom cross-coupling and has facilitated the development of radiohalogenation methodologies in radiochemistry. This study investigated the mechanisms and side reactions of CEL iodination under conditions relevant to radiosynthesis and typical organic synthesis, focusing on the effects of sodium iodide. The concentrations of copper and iodide, as well as the copper-to-iodide ratio, were identified as significant factors for successful copper-mediated CEL iodination, influencing the reaction mechanisms and side reactions. Excess iodide relative to the copper salt led to the formation of poorly soluble iodinated copper(I) complexes that competed with that of the desired aryl iodide. Additionally, the predominant copper complex involved in the catalytic cycle differed between the early and late stages of the reaction, depending on the copper-to-iodide ratio. The results of this study indicate that the specialized radiosynthesis conditions meet the requirements for efficient CEL iodination. In particular, an extremely low concentration of iodide is optimal for CEL iodination. These in-depth mechanistic insights not only provide a detailed comparison of CEL iodination across radiochemistry and synthetic organic chemistry but can also inspire the development of novel (radio)iodination methods.

BACKGROUND/AIM:Aberrant activation of the Wnt/β-catenin signaling pathway contributes to the pathogenesis of acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt/β-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells. MATERIALS AND METHODS:We evaluated the inhibitory effect of compound #41 on T cell factor (TCF)/β-catenin transcriptional activity using a luciferase (Luc) reporter assay. The anti-tumor effects were assessed on KG1a and MV4;11 human AML cells using RT-qPCR, western blotting, and WST-8, cell cycle, and apoptosis assays. Differentially expressed genes were analyzed by RNA-sequencing (RNA-seq). Additionally, we investigated the in vivo effects of compound #41 using KG1a-Luc/GFP cells in an orthotopic mouse model. RESULTS:The Luc reporter assay showed that compound #41 decreased the TCF/β-catenin transcriptional activity. Compound #41 blocked the cell cycle progression, inhibited cell proliferation, and induced apoptosis in AML cells. Treatment with compound #41 down-regulated the expression of β-catenin, Survivin, and β-catenin-specific target genes, as demonstrated by RNA-seq. In vivo analysis showed that compound #41 blocked the expansion of KG1a-Luc/GFP cells in the bone marrow and prolonged the overall survival of KG1a-Luc/GFP-transplanted mice. CONCLUSION:Compound #41 suppressed the Wnt/β-catenin signaling pathway by reducing CTNNB1 levels and induced apoptosis in AML cells. Furthermore, compound #41 inhibited the proliferation of KG1a-Luc/GFP cells in the bone marrow and extended the overall survival of mice. Thus, compound #41 is an attractive Wnt/β-catenin signaling pathway inhibitor of AML.

The inhibition mode of a retro-inverso (RI) inhibitor containing a hydroxyethylamine dipeptide isostere against the human T-cell leukemia virus type-1 (HTLV-1) protease was examined. Enzymatic evaluation of the RI-modified inhibitor containing a D-allo-Ile residue revealed that HTLV-1 was competitively inhibited. IC50 values of the RI-modified inhibitor and pepstatin A, a standard inhibitor of aspartic proteases, were nearly equivalent.

Direct radioiodination of peptides using copper-mediated iododeboronation is a promising radiosynthetic method for solving issues of classical direct radiolabeling, such as toxicity of the organotin precursor (iododestannylation) or formation of radio byproducts (by electrophilic iodination of a tyrosine residue). However, the parameters for optimizing the reaction conditions for various peptides are not completely understood. In particular, considering peptide solubility, the effects of water-containing solvents on labeling efficiency should be thoroughly investigated. Herein, we describe the effect of water on copper-mediated radioiododeboronation and the key factors for ensuring the successful radiolabeling of small molecules and peptides in water-organic solvents. 125I-labeled substrates containing peptides ([125I]m/p-IBTA) were obtained with high radiochemical conversions (RCCs: >95%) using an alcohol solvent, and a decrease in these RCCs was observed with increasing water content in the methanol solvent. Additionally, when using water-methanol solvents, a difference in RCC due to the substituent effect was also observed. However, the RCCs can be improved without the use of other additives by adjusting the copper catalyst and time of the labeling reaction or by utilizing substituent effects. This study contributes to the improvement of the design of boronic peptide precursors and radiolabeling protocols using copper-mediated iododeboronation.

While γ-glutamylcyclotransferase (GGCT) has been implicated in cancer-cell proliferation, the role of GGCT enzymatic activity in the regulation of cancer-cell growth remains unclear. Toward further understanding of GGCT in vivo, here we report a novel cell-permeable chemiluminogenic probe "MAM-LISA-103" that detects intracellular GGCT activity and apply it to in vivo imaging. We first developed a chemiluminogenic probe LISA-103, which simply and sensitively detects the enzymatic activity of recombinant GGCT through chemiluminescence. We then designed the cell-permeable GGCT probe MAM-LISA-103 and applied it to several biological experiments. MAM-LISA-103 successfully detected the intracellular GGCT activity in GGCT-overexpressing NIH-3T3 cells. Moreover, MAM-LISA-103 demonstrated tumor-imaging ability when administered to a xenograft model using immunocompromised mice inoculated with MCF7 cells.

We designed and synthesized a novel platinum complex conjugated with 2-fluorinated 2-deoxyglucoside, named FGC-Pt, to capitalize on the Warburg effect and metabolic trapping properties of [18F]2-deoxy-2-fluoro-d-glucose ([18F]FDG). Then, we conducted comprehensive in vitro and in vivo studies to evaluate the effects of FGC-Pt. In vitro cytotoxicity assays using HeLa cells revealed that FGC-Pt exhibited concentration-dependent cytotoxicity, even though its cytotoxic effect was less pronounced than that of cisplatin. In the evaluation of in vivo biodistribution in mice, platinum concentration in tumors and major organs (muscle, bone, blood, liver, and kidney) and the ratio of platinum concentration in tumors to major organs following the tail vein injection of FGC-Pt and cisplatin suggest that FGC-Pt is more retained in tumors than in other organs and tends to accumulate in tumors more than cisplatin. Furthermore, an in vivo assessment of the antitumor effect conducted in A549 cell-bearing mice demonstrated that FGC-Pt possesses substantial potential as an antitumor agent. It exhibited a tumor growth-inhibitory effect comparable to that of cisplatin while inducing lower toxicity, as evidenced by lower weight loss after administration. Herein, we successfully produced a novel compound with a tumor-growth-inhibitory effect comparable to that of cisplatin and low toxicity.

The universality problem focuses on finding universal elements in classes of topological spaces and frames. In [4], [5], [7], [8], [10], [11], [12], [13], [14], [15], [22] notions of dimensions and the so-called base dimensions for topological spaces and frames are studied under the view of the universality problem. Simultaneously, a new notion of dimension for frames, which is called quasi covering dimension and denoted by dimq, is introduced and studied in [9]. In this paper, we define the base dimension like-function of the type dimq for frames and based on the notion of the saturated class of bases of frames, which is introduced and studied in [8], we prove that in a class of bases of frames which is characterized by this dimension there exist universal elements. Also, we study the notion of saturated class of frames, which is introduced in [7], proving that in a class of frames which is determined by the quasi covering dimension dimq there exist universal elements.