Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Synthesis of α-Aminophosphonates via Phosphonylation of an Aryne-Imine Adduct.

Multicomponent phosphonylation is accomplished upon the reaction of an imine with an aryne generated in situ in the presence of a dialkyl phosphite. This transition-metal-free protocol shows a broad substrate scope, providing a variety of α-aminophosphonates in moderate to good yields. A plausible mechanism for the reaction is proposed based on a deuterium exchange experiment.

Sulfur fluoride exchange.

Sulfur Fluoride Exchange (SuFEx) is a click reaction par excellence that has revolutionized multiple research fields. In this Primer, we delve into the essential elements of SuFEx operation, catalysis, and SuFExable connective hubs. We also explore the cutting-edge applications of SuFEx in drug development, polymer science, and biochemistry. Additionally, we examine the potential limitations and promising prospects for this versatile click reaction.

Reduction of imines with a reusable bimetallic PdCo-Fe3O4 catalyst at room temperature under atmospheric pressure of H2.

Bimetallic nanocatalysts have been used for the development of organic reactions, owing to the synergistic effect between the transition metals. A new procedure for synthesizing amines by the reduction of imines with H2 at atmospheric pressure and room temperature in the presence of PdCo-Fe3O4 nanoparticles is reported. The straightforward procedure, mild reaction conditions, high turnover number, and recyclability extend the scope of this reaction to practical applications.

Oxidative N-Formylation of Secondary Amines Catalyzed by Reusable Bimetallic AuPd-Fe3O4 Nanoparticles.

Bimetallic catalysts are gaining attention due to their characteristics of promoting reactivity and selectivity in catalyzed reactions. Herein, a new catalytic N-formylation of secondary amines using AuPd-Fe3O4 at room temperature is reported. Methanol was utilized as the formyl source and 1.0 atm of O2 gas served as an external oxidant. The bimetallic catalyst, consisting of Au and Pd, makes the reaction more efficient than that using each metal separately. In addition, the catalyst can be effectively recycled owing to the Fe3O4 support.

Toxin-Activating Stapled Peptides Discovered by Structural Analysis Were Identified as New Therapeutic Candidates That Trigger Antibacterial Activity against Mycobacterium tuberculosis in the Mycobacterium smegmatis Model.

The structure-function relationships of toxin-antitoxin (TA) systems from Mycobacterium tuberculosis have prompted the development of novel and effective antimicrobial agents that selectively target this organism. The artificial activation of toxins by peptide inhibitors can lead to the growth arrest and eventual death of bacterial cells. Optimizing candidate peptides by hydrocarbon α-helix stapling based on structural information from the VapBC TA system and in vitro systematic validation led to V26-SP-8, a VapC26 activator of M. tuberculosis. This compound exhibited highly enhanced activity and cell permeability owing to the stabilizing helical propensity of the peptide. These characteristics will increase its efficacy against multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Similar approaches utilizing structural and biochemical information for new antibiotic targets opens a new era for developing TB therapies.

Structure-Based De Novo Design of Mycobacterium Tuberculosis VapC-Activating Stapled Peptides.

Toxin-antitoxin (TA) systems have been considered essential factors for bacterial survival. During our drug development program aimed against tuberculosis (TB), we discovered certain peptides that mimic the binding of the VapBC30 complex, leading to the arrest of bacterial cell growth and eventually cell death. Herein, we optimized these candidate peptides based on a hydrocarbon stapling strategy and performed biological in vitro evaluations. The V30-SP-8 peptide successfully penetrated Mycobacterium smegmatis cell membranes and exerted bactericidal activity at a minimum inhibitory concentration that inhibited 50% of the isolates (MIC50) < 6.25 µM. With the aid of structural and biochemical information for the VapBC30 TA system from M. tuberculosis, we suggest potential antimicrobial agents that could provide a platform to establish a novel antibacterial strategy. Reflecting the limited number of therapeutic agents targeting TA systems, we believe that this study not only provides chemical tools for exploring the biological events relevant to TA systems but also opens a new gateway toward TB drug discovery.

Structure-activity relationships of fluorene compounds inhibiting HCV variants.

Approximately 71 million people suffer from hepatitis C virus (HCV) infection worldwide. Persistent HCV infection causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, resulting in approximately 400,000 deaths annually. Effective direct-acting antiviral agents (DAAs) have been developed and are currently used for HCV treatment targeting the following three proteins: NS3/4A proteinase that cleaves the HCV polyprotein into various functional proteins, RNA-dependent RNA polymerase (designated as NS5B), and NS5A, which is required for the formation of double membrane vesicles serving as RNA replication organelles. At least one compound inhibiting NS5A is included in current HCV treatment regimens due to the high efficacy and low toxicity of drugs targeting NS5A. Here we report fluorene compounds showing strong inhibitory effects on GT 1b and 3a of HCV. Moreover, some compounds were effective against resistance-associated variants to DAAs. The structure-activity relationships of the compounds were analyzed. Furthermore, we investigated the molecular bases of the inhibitory activities of some compounds by the molecular docking method.

AuPd-Fe3 O4 Nanoparticle-Catalyzed Synthesis of Furan-2,5-dimethylcarboxylate from 5-Hydroxymethylfurfural under Mild Conditions.

Efficient one-pot oxidative esterification of 5-hydroxymethylfurfural (HMF) to furan-2,5-dimethylcarboxylate (FDMC) was achieved under extremely mild reaction conditions by using AuPd alloy nanoparticles (NPs) supported on Fe3 O4 . A high yield of FDMC (92 %) was obtained at room temperature under atmospheric O2 . The reaction proceeded through the synergistic effects of the AuPd heterobimetallic catalyst system. The most effective molar ratio of noble metal contents for HMF oxidation was 1.00:1.18. If Au-Fe3 O4 NPs were used as the catalyst, selective synthesis of 5-hydroxymethylfuroic acid methyl ester (HMFE) was achieved. Additionally, the AuPd-Fe3 O4 catalyst could be successfully reused.

A Novel Design Strategy for Suppressing Efficiency Roll-Off of Blue Thermally Activated Delayed Fluorescence Molecules through Donor-Acceptor Interlocking by C-C Bonds.

The short material lifetime of thermally activated delayed fluorescence (TADF) technology is a major obstacle to the development of economically feasible, highly efficient, and durable devices for commercial applications. TADF devices are also hampered by insufficient operational stability. In this paper, we report the design, synthesis, and evaluation of new TADF molecules possessing a sterically twisted skeleton by interlocking donor and acceptor moieties through a C-C bond. Compared to C-N-bond TADF molecules, such as CPT2, the C-C-bond TADF molecules showed a large dihedral angle increase by more than 30 times and a singlet-triplet energy-gap decrease to less than 0.22 eV because of the steric hindrance caused by the direct C-C bond connection. With the introduction of a dibenzofuran core structure, devices comprising BMK-T317 and BMK-T318 exhibited a magnificent display performance, especially their external quantum efficiencies, which were as high as 19.9% and 18.8%, respectively. Moreover, the efficiency roll-off of BMK-T318 improved significantly (26.7%). These results indicate that stability of the material can be expected through the reduction of their singlet-triplet splitting and the precise adjustment of dihedral angles between the donor-acceptor skeletons.

Efficient synthesis of enantiomerically pure beta2-amino acids via chiral isoxazolidinones.

We report a practical and scalable synthetic route for the preparation of alpha-substituted beta-amino acids (beta(2)-amino acids). Michael addition of a chiral hydroxylamine, derived from alpha-methylbenzylamine, to an alpha-alkylacrylate followed by cyclization gives a diastereomeric mixture of alpha-substituted isoxazolidinones. These diastereomers are separable by column chromatography. Subsequent hydrogenation of the purified isoxazolidinones followed by Fmoc protection affords enantiomerically pure Fmoc-beta(2)-amino acids, which are useful for beta-peptide synthesis. This route provides access to both enantiomers of a protected beta(2)-amino acid.

Accommodation of alpha-substituted residues in the beta-peptide 12-helix: expanding the range of substitution patterns available to a foldamer scaffold.

Beta-amino acid oligomers composed exclusively of homochiral trans-2-aminocyclopentanecarboxylic acid (ACPC) residues and/or related pyrrolidine-based residues are known to favor a specific helical secondary structure that is defined by 12-membered ring C=O(i)- -H-N(i+3) hydrogen bonds ("12-helix"). The 12-helix is structurally similar to the familiar alpha-helix and therefore represents a source of potential alpha-helix-mimics. The 12-helix will be most useful in this regard if this conformational scaffold can be employed to arrange specific sets of protein-like side chains in space. Here we examine whether the 12-helix tolerates insertion of acyclic beta-amino acid residues bearing a substituent in the alpha-position ("beta(2)-residues"). Seventeen homologous beta-peptide heptamers have been prepared in which one to four beta(2)-residues reside among ACPC and/or pyrrolidine residues. Circular dichroism comparisons suggest that beta(2)-residues have a lower 12-helical propensity than do residues preorganized by a five-membered ring, as expected, but that beta-peptides containing beta(2)-residues at one or two of the seven positions retain a significant preference for 12-helix formation. These results indicate that a limited number of beta(2)-residues can be used to introduce side chains at specific positions along the surface of a 12-helix.