Targeting the behavior of myeloid-derived suppressor cells (MDSCs), either by decreasing their population or inhibiting their immunosuppressive activity, has become a promising approach in breast cancer therapy. As pivotal mediators within the tumor microenvironment (TME), MDSCs facilitate tumor progression via diverse mechanisms, including T-cell suppression, epithelial-mesenchymal transition (EMT), and the preservation of cancer cell stemness. EK-16005, a novel 2-anilinopyrimidine derivative, has shown robust inhibitory activity against breast cancer cells. In this investigation, we examined the impact of EK-16005 on the reciprocal interactions between MDSCs and cancer cells that modulate cytokine production and signaling pathway activation. EK-16005 downregulated the secretion of critical cytokines such as G-CSF, VEGF, and CXCL1/2, leading to blockade of STAT3 and Notch signaling cascades in vitro and in vivo. As a result, EK-16005 decreased MDSC expansion, tumor growth, and cancer stemness properties. Collectively, these results establish EK-16005 as a potential therapeutic candidate for interrupting MDSC-mediated tumor progression and improving outcomes in breast cancer treatment.

The Roseobacter clade, a versatile Rhodobacteraceae lineage, comprises up to 20% of marine bacteria and drives key biogeochemical cycles. Phaeobacter inhibens, a representative model species, is associated with the alga Emiliania huxleyi, exhibiting a dual lifestyle that alternates between promoting symbiotic growth and displaying pathogenicity during algal senescence. In this study, we investigated the metabolic responses of P. inhibens cultured with sinapic acid, an algal-derived lignin catabolite known to modulate algal-bacterial interactions. Detailed LC-MS/UV-guided analysis of the sinapic acid-treated culture identified 10 metabolites, including two new compounds, roseochelins C (1) and D (2). All isolated compounds were tested for anti-allergic effects in Th2 cell-mediated immune responses, and sinatryptin A (4) showed the strongest activity by reducing Th2 cytokine production and blocking Th2 differentiation through inhibition of the IL-4/STAT6-GATA3/IRF4 pathway. These findings expand the chemical diversity of algal-bacterial interactions, and anti-allergic assays of the isolated metabolites highlight the potential of Roseobacter-derived compounds as novel bioactive resources.

Production of recombinant HRI and anti-HRI antiserum

Expression analysis of eIF2α kinases in 173 leukemic cell lines

We investigated the therapeutic potential and mechanisms of HR-19011, a novel eukaryotic translation initiation factor 2 subunit α (eIF2α) phosphorylation inducer, with a focus on its effects on the integrated stress response (ISR) pathway and cell-cycle regulation in K562 cells. Our findings revealed that HR-19011 exerts its anticancer effects primarily through the activation of heme-regulated inhibitor (HRI), leading to the phosphorylation of eIF2α, the induction of ISR signaling, and subsequent G1/S cell-cycle arrest. RNA sequencing analysis further highlighted significant changes in gene expression associated with the ISR pathway, particularly those involving the key components, activating transcription factor 4 and CHOP, underscoring the specific targeting of HRI by HR-19011. Additionally, HR-19011 suppressed the mTORC1 pathway, a critical regulator of cell growth and metabolism, through the downregulation of components such as phosphorylated S6K and phosphorylated 4EBP1, mediated by activating transcription factor 4 and CHOP. In vivo studies demonstrated that HR-19011 effectively inhibited tumor growth in a K562 xenograft model, without significant toxicity, and its broad efficacy across various hematologic malignancies further suggests its potential as a versatile anticancer agent. Our findings position HR-19011 as a promising candidate for targeting the HRI-eIF2α axis in cancer treatment, warranting further investigation and optimization for clinical application.

In vitro kinase assay demonstrating that HR-19011 does not directly activate HRI

List of antibodies used in western blotting

HR-19011-induced eIF2α phosphorylation is independent of PERK pathways

IC50 values of squaramide-based compounds in K562 cells with normal and reduced HRI expression levels

Schematic representation of the proposed mechanism of action of HR-19011 in K562 cells

Protein expression analysis of ISR inducers and eIF2α in selected hematologic cancer cell lines

Western blotting analysis of eIF2α phosphorylation induced by 37 compounds in K562 cells

Synthesis of benzo[a]fluorene, benzo[c]fluorene, and benzo[j]fluoranthene have been accomplished from readily accessible enol ether precursors via a Lewis acid-catalyzed Prins-type cycloaromatization. Mechanistically, it was proposed that Lewis acids catalyze the generation of oxonium species, which accelerate subsequent annulation and aromatization. This protocol offers the benefit of an operationally simple, transition-metal-free, and air-tolerant reaction condition, enabling gram-scale syntheses of the desired products. The total synthesis of viridistratin A further supported this synthetic strategy for establishing polycyclic aromatic hydrocarbon architectures.

Natural anmindenol A isolated from the marine-derived bacteria Streptomyces sp. caused potent inhibition of inducible nitric oxide synthase without any significant cytotoxicity. This compound consists of a structurally unique 3,10-dialkylbenzofulvene skeleton. We previously synthesized and screened the novel derivatives of anmindenol A and identified AM-18002, an anmindenol A derivative, as a promising anticancer agent. The combination of AM-18002 and ionizing radiation (IR) improved anticancer effects, which were exerted by promoting apoptosis and inhibiting the proliferation of FM3A mouse breast cancer cells. AM-18002 increased the production of reactive oxygen species (ROS) and was more effective in inducing DNA damage. AM-18002 treatment was found to inhibit the expansion of myeloid-derived suppressor cells (MDSC), cancer cell migration and invasion, and STAT3 phosphorylation. The AM-18002 and IR combination synergistically induced cancer cell death, and AM-18002 acted as a potent anticancer agent by increasing ROS generation and blocking MDSC-mediated STAT3 activation in breast cancer cells.

Oxidative stress plays a crucial role in the development and progression of various kidney diseases. Nuclear factor erythroid 2-related factor 2 (NRF2) is the primary transcription factor that protects cells from oxidative stress by regulating cytoprotective genes including those involved in the antioxidant glutathione (GSH) pathway. GSH maintains cellular redox status and affects redox signaling, cell proliferation, and cell death. Antimycin A, an inhibitor of complex III of the electron transport chain, causes oxidative stress and reduces GSH levels. In this study, we induced mitochondrial damage in rat renal proximal tubular cells using antimycin A and investigated cellular viability and levels of NRF2 and GSH. Treatment with antimycin A altered the expression of antioxidant genes, including reduction in the transcription of glutathionecysteine ligase subunits ( Gclc and Gclm) and glutathione reductase (Gsr1), followed by a reduction in total GSH content with a concomitant decrease in NRF2 protein expression. AR-20007, previously described as an NRF2 activator, stabilizes and increases NRF2 protein expression in cells. By stimulating NRF2, AR-20007 increased the expression of antioxidant and detoxifying enzymes, thereby enhancing protection against oxidative stress induced by antimycin A. These data suggest that NRF2 activation effectively inhibits antimycin A-induced oxidative stress and that NRF2 may be a promising therapeutic target for preventing cell death during acute kidney injury.

Concise and strategically unique asymmetric formal syntheses of epi-mutisianthol and epi-jungianol are presented. A novel disconnection approach is introduced to complement previous intramolecular cyclopentannulation strategies. Noteworthy features include: (a) control of the stereogenic benzylic carbon center through 1,3-chirality transfer from chiral indenols via the Johnson-Claisen rearrangement, which yields advanced indene-containing gamma,delta-unsaturated esters, and (b) the diastereoselective construction of the cis-1,3-dialkylindane backbone via catalytic hydrogenation of the resulting indene. This approach presents a remarkable method for synthesizing structurally intriguing indane motifs.

The development of ligands and the elucidation of their roles in the catalytic cycle are key to achieving high efficiency and selectivity in nondirected transition-metal-catalyzed C-H functional-ization. In particular, careful ligand design can enable the functionaliza-tion of previously inaccessible substrate positions, which can lead to regiodivergent transformations of common reactants. In this study, a series of pyrazolopyridone (PzPyOH) ligands that can be easily prepared in a single step was developed for the Pd-catalyzed perdeuteration and meta-selective alkenylation of arenes. In this system, the 2-pyridone moiety was incorporated to function as an internal base, facilitating C-H cleavage and rendering C-H activation reversible, even at challenging sp2 C-H bonds, thus enabling perdeuteration. In addition, the reversible activation of the C-H bonds implies that site selectivity is determined during the migratory insertion step in the alkenylation reaction, thereby preferentially functionalizing the meta-positions rather than the typically more reactive ortho- and para-positions of anisole derivatives. Further, the electronic and structural properties of the pyrazole moiety provide flexibility in the ligand binding to Pd, enabling the facile coordination of an alkene coupling partner during alkenylation. In this process, the hydrogen bonding between pyridone and acetate ligands was crucial to stabilize intermediates, allowing for different types of binding modes, including L,L-and L,X-type bidentate and monodentate binding. Kinetic and computational studies support the proposed mechanisms for perdeuteration and alkenylation, and the findings reveal crucial factors in the design of ligands for Pd-catalyzed C-H functionalization, which will be useful for further development of pyrazole-and pyridone-containing ligands in transition metal catalysis.

Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17, a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17, 18, and 22 will likely be of pharmacological utility.

Herein, Pd-catalyzed C-H acetoxylation reactions of arenes are developed using a pyrazolonaphthyridine ligand. In the presence of iodomesitylene diacetate as the oxidant, the electron-deficient ligand facilitates the C-H activation of the electron-rich positions while preventing the formation of Pd black via bidentate binding. Although both acetic acid and hexafluoroisopropanol are employed for directing group-assisted acetoxylation reactions, the latter proved to be more efficient for the nondirected reaction of arenes with the nitrogen ligand.