Nickel-Catalyzed Electrophilic Amination of the Biphenylene C-C σ-Bond.

A nickel-catalyzed three-component carboamination of the biphenylene C-C σ-bond has been developed. Arylboronates and hydroxylamine derivatives work as carbon nucleophiles and nitrogen electrophiles, respectively, and the corresponding difunctionalized ring-opening products are obtained in good yields. The arylboronate nucleophile can be replaced with B2pin2 (boron nucleophile) and H-Si(OMe)3 (hydride nucleophile), thus allowing for the aminoboration and hydroamination of the biphenylene C-C σ-bond under similar nickel catalysis.

N-2,6-Di(isopropyl)phenyl-2-azaphenalenyl radical cations.

N-2,6-Di(isopropyl)phenyl-2-azaphenalenyl radical cations were obtained as a dark brown air-sensitive crystalline compound. The high HOMA values and the ACID calculation indicate relatively high aromatic character of a 5,8-di-tert-butyl derivative, and clean generation of a derivative without tert-butyl groups indicates that the di(isopropyl)phenyl group is sufficient for hampering the formation of the σ-dimer.

Water Fraction Dependence of the Aggregation Behavior of Hydrophobic Fluorescent Solutes in Water-Tetrahydrofuran.

This work investigates the water fraction dependence of the aggregation behavior of hydrophobic solutes in water-tetrahydrofuran (THF) and the elucidation of the role of THF using fluorescence microscopy, dynamic light scattering, neutron and X-ray scattering, and photoluminescence measurements. On the basis of the obtained results, the following model is proposed: hydrophobic molecules are molecularly dispersed in the low-water-content region (10-20 vol %), while they form mesoscopic particles upon increasing the water fraction to ∼30 vol %. This abrupt change is due to the composition fluctuation of the water-THF binary system to form hydrophobic areas in THF, followed by THF-rich droplets where hydrophobic solutes are incorporated and form loose aggregates. Further increasing the water content prompts the desolvation of THF, which decreases the particle size and generates tight aggregates of solute molecules. This model is consistent with the luminescence behavior of the solutes and will be helpful to control the aggregation state of hydrophobic solutes in various applications.

Differentiation-inducing factor-1 reduces lipopolysaccharide-induced vascular cell adhesion molecule-1 by suppressing mTORC1-S6K signaling in vascular endothelial cells.

AIMS: Differentiation-inducing factor-1 (DIF-1), a compound in Dictyostelium discoideum, exhibits anti-cancer effects by inhibiting cell proliferation and motility of various mammalian cancer cells in vitro and in vivo. In addition, DIF-1 suppresses lung colony formation in a mouse model, thus impeding cancer metastasis. However, the precise mechanism underlying its anti-metastatic effect remains unclear. In the present study, we aim to elucidate this mechanism by investigating the adhesion of circulating tumor cells to blood vessels using in vitro and in vivo systems. MAIN METHODS: Melanoma cells (1.0 × 105 cells) were injected into the tail vein of 8-week-old male C57BL/6 mice after administration of DIF-1 (300 mg/kg per day) and/or lipopolysaccharide (LPS: 2.5 mg/kg per day). To investigate cell adhesion and molecular mechanisms, cell adhesion assay, western blotting, immunofluorescence staining, and flow cytometry were performed. KEY FINDINGS: Intragastric administration of DIF-1 suppressed lung colony formation. DIF-1 also substantially inhibited the adhesion of cancer cells to human umbilical vein endothelial cells. Notably, DIF-1 did not affect the expression level of adhesion-related proteins in cancer cells, but it did decrease the expression of vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells by suppressing its mRNA-to-protein translation through inhibition of mTORC1-p70 S6 kinase signaling. SIGNIFICANCE: DIF-1 reduced tumor cell adhesion to blood vessels by inhibiting mTORC1-S6K signaling and decreasing the expression of adhesion molecule VCAM-1 on vascular endothelial cells. These findings highlight the potential of DIF-1 as a promising compound for the development of anti-cancer drugs with anti-metastatic properties.

Differentiation-inducing factor 1 activates cofilin through pyridoxal phosphatase and AMP-activated protein kinase, resulting in mitochondrial fission.

Differentiation-inducing factor 1 (DIF-1) is a morphogen produced by Dictyostelium discoideum that inhibits the proliferation and migration of both D. discoideum and most mammalian cells. Herein, we assessed the effect of DIF-1 on mitochondria, because DIF-3, which is similar to DIF-1, reportedly localizes in the mitochondria when added exogenously, however the significance of this localization remains unclear. Cofilin is an actin depolymerization factor that is activated by dephosphorylation at Ser-3. By regulating the actin cytoskeleton, cofilin induces mitochondrial fission, the first step in mitophagy. Here, we report that DIF-1 activates cofilin and induces mitochondrial fission and mitophagy mainly using human umbilical vein endothelial cells (HUVECs). AMP-activated kinase (AMPK), a downstream molecule of DIF-1 signaling, is required for cofilin activation. Pyridoxal phosphatase (PDXP)-known to directly dephosphorylate cofilin-is also required for the effect of DIF-1 on cofilin, indicating that DIF-1 activates cofilin through AMPK and PDXP. Cofilin knockdown inhibits mitochondrial fission and decreases mitofusin 2 (Mfn2) protein levels, a hallmark of mitophagy. Taken together, these results indicate that cofilin is required for DIF-1- induced mitochondrial fission and mitophagy.

DIF-1 exhibits anticancer activity in breast cancer via inhibition of CXCLs/CXCR2 axis-mediated communication between cancer-associated fibroblasts and cancer cells.

The tumor microenvironment (TME), largely composed of tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), plays a key role in cancer progression. A small molecule, differentiation-inducing factor-1 (DIF-1) secreted by Dictyostelium discoideum, is known to exhibit anticancer activity; however, its effect on the TME remains unknown. In this study, we investigated the effect of DIF-1 on the TME using mouse triple-negative breast cancer 4T1-GFP cells, mouse macrophage RAW 264.7 cells, and mouse primary dermal fibroblasts (DFBs). Polarization of 4T1 cell-conditioned medium-induced macrophage into TAMs was not affected by DIF-1. In contrast, DIF-1 decreased 4T1 cell co-culturing-induced C-X-C motif chemokine ligand 1 (CXCL1), CXCL5, and CXCL7 expression in DFBs and suppressed DFB differentiation into CAF-like cells. Additionally, DIF-1 inhibited C-X-C motif chemokine receptor 2 (CXCR2) expression in 4T1 cells. Immunohistochemical analyses of tumor tissue samples excised from breast cancer-bearing mice showed that DIF-1 did not affect the number of CD206-positive TAMs; however, it decreased the number of α-smooth muscle actin-positive CAFs and CXCR2 expression. These results indicated that the anticancer effect of DIF-1 was partially attributed to the inhibition of CXCLs/CXCR2 axis-mediated communication between breast cancer cells and CAFs.

Correlation of Postvaccination Fever With Specific Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 BNT162b2 Booster and No Significant Influence of Antipyretic Medication.

Background: A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine booster elicits sufficient antibody responses that protect against coronavirus disease 2019, whereas adverse reactions such as fever have been commonly reported. Associations between adverse reactions and antibody responses have not been fully characterized, nor has the influence of antipyretic use. Methods: This is a prospective observational cohort study in Japan, following our prior investigation of BNT162b2 2-dose primary series. Spike-specific immunoglobulin G (IgG) titers were measured for SARS-CoV-2-naive hospital healthcare workers who received a BNT162b2 booster. The severity of solicited adverse reactions, including the highest body temperature, and self-medicated antipyretics were reported daily for 7 days following vaccination through a web-based self-reporting diary. Results: The data of 281 healthcare workers were available. Multivariate analysis extracted fever after the booster dose (ß = .305, P < .001) as being significantly correlated with the specific IgG titers. The analysis of 164 participants with data from the primary series showed that fever after the second dose was associated with the emergence of fever after the booster dose (relative risk, 3.97 [95% confidence interval, 2.48-6.35]); however, the IgG titers after the booster dose were not associated with the presence or degree of fever after the second dose. There were no significant differences in the IgG titers by the use, type, or dosage of antipyretic medication. Conclusions: These results suggest an independent correlation between mRNA vaccine-induced specific IgG levels and post-booster vaccination fever, without any significant influence of fever after the primary series. Antipyretic medications for adverse reactions should not interfere with the elevation of specific IgG titers.

DIF-1 inhibits growth and metastasis of triple-negative breast cancer through AMPK-mediated inhibition of the mTORC1-S6K signaling pathway.

We have previously reported that the differentiation-inducing factor-1 (DIF-1), a compound identified in Dictyostelium discoideum, suppresses the growth of MCF-7 breast cancer cells by inactivating p70 ribosomal protein S6 kinase (p70S6K). Therefore, we first examined whether the same mechanism operates in other breast cancer cells, especially triple-negative breast cancer (TNBC), the most aggressive and refractory phenotype of breast cancer. We also investigated the mechanism by which DIF-1 suppresses p70S6K by focusing on the AMPK-mTORC1 system. We found that DIF-1 induces phosphorylation of AMPK and Raptor and dephosphorylation of p70S6K in multiple TNBC cell lines. Next, we examined whether AMPK-mediated inhibition of p70S6K leads to the suppression of proliferation and migration/infiltration of TNBC cells. DIF-1 significantly reduced the expression levels of cyclin D1 by suppressing the translation of STAT3 and strongly suppressed the expression levels of Snail, which led to the suppression of growth and motility, respectively. Finally, we investigated whether DIF-1 exerts anticancer effects on TNBC in vivo. Intragastric administration of DIF-1 suppressed tumor growth and spontaneous lung metastasis of 4T1-Luc cells injected into the mammary fat pad of BALB/c mice. DIF-1 is expected to lead to the development of anticancer drugs, including anti-TNBC, by a novel mechanism.

Long-wavelength visible to near infrared photoluminescence from carbon-bridged styrylstilbene and thiadiazole conjugates in organic and aqueous media.

Donor-acceptor-donor conjugates composed of electron-donating carbon-bridged styrylstilbene (COPV2) and electron-accepting thiadiazole derivatives equipped with carbazolyl (Cz) terminators, Cz-COPV2-A-COPV2-Cz (A = benzothiadiazole (BTz), naphthobis(thiadiazole) (NTz), or benzobis(thiadiazole) (BBTz)), were newly synthesized and found to serve as efficient and stable long-wavelength photoluminescent dyes in organic and aqueous media. In particular, Cz-COPV2-BBTz-COPV2-Cz showed photoluminescence in the near infrared region (895-927 nm) with a photoluminescence quantum yield (PLQY) of up to 0.19 in cyclohexane and of 0.02-0.03 in THF/water mixtures. Its analogues with weaker acceptors, Cz-COPV2-BTz-COPV2-Cz and Cz-COPV2-NTz-COPV2-Cz, showed yellow to deep-red emission in organic solvents, with PLQYs of up to 0.71 in organic solvents and 0.45 in THF/water mixtures.

Dimethylformamide-stabilised palladium nanoclusters catalysed coupling reactions of aryl halides with hydrosilanes/disilanes.

N,N-Dimethylformamide-stabilised Pd nanocluster (NC) catalysed cross-coupling reactions of hydrosilane/disilane have been investigated. In this reaction, the coupling reaction proceeds without ligands with low catalyst loading. N,N-Dimethylacetamide is a crucial solvent in these reactions. The solvent effect was considered by various techniques, such as transmission electron microscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis. The Pd NCs can be recycled five times under both hydrosilane and disilane reaction conditions.