AlCl3-catalyzed chemoselective cascade reactions of 4-anilinocoumarins with 2-furylcarbinols: access to densely functionalized chromeno[4,3-b]pyrrol-4(1H)-one derivatives.

An unprecedented protocol has been developed for the preparation of highly functionalized chromeno[4,3-b]pyrrol-4(1H)-ones, which are not only valuable architectures of many biologically active molecules but also key building blocks for rich photophysical properties. The transformation proceeded through chemoselective intermolecular α-carbon nucleophilic attacking/ring-opening/Michael addition/deprotonation aromatization processes from 4-aminocoumarins and 2-furylcarbinols.

TfOH-Catalyzed Cascade C-H/N-H Chemo-/Regioselective Annulation of Indole-2-carboxamides with Benzoquinones for the Construction of Anticancer Tetracyclic Indolo[2,3-c]quinolinones.

An efficient TfOH-catalyzed cascade C-H/N-H annulation of indole-2-carboxamides with benzoquinones has been developed for the synthesis of tetracyclic indolo[2,3-c]quinolinones. This reaction exhibits excellent chemo-/regioselectivity, achieving functionalization of the C-3 of indole and N-H of the amide moiety to form the new C-C and C-N bonds. Various expected products were synthesized from readily available starting materials in good to high yields with a wide substrate scope and good functional group tolerance. Among all synthetic products, 3d showed the most potent cytotoxicity toward the 4T1 cancer cell line with an IC50 value of 0.62 ± 0.05 µM. In vivo study demonstrated that 3d remarkably suppressed 4T1 xenograft tumor growth without body weight loss.

Atom-Economic Synthesis of Highly Functionalized Bridged Ring Systems Initiated by Ring Expansion of Indene-1,3-dione.

An atom economic procedure for the regioselective synthesis of bridged seven-membered-ring compounds from simple reactants such as ynones and indene-1,3-dione has been developed. This process was realized through the one-pot reactions of ring-expansion of indene-1,3-dione with alkynyl ketones and successive formal [4+2] cycloaddition. The Michael addition reaction is the key for the regioselectivity of the formal [4+2] cycloaddition.

Sirtuin1 activator SRT2183 suppresses glioma cell growth involving activation of endoplasmic reticulum stress pathway.

BACKGROUND: Glioblastoma (GBM) is an extremely deadly form of brain cancer with limited treatment options and thus novel therapeutic modalities are necessary. Histone deacetylase inhibitors (HDACi) have demonstrated clinical and preclinical activities against GBM. (Silent mating type information regulation 2 homolog, Sirt1) abbreviated as Sirtuin 1, has been implicated in GBM. We explored the activity of the Sirt1 activator SRT2183 in glioma cell lines in terms of biological response. METHODS: The effects of SRT2183 on glioma cell growth and neurosphere survival were evaluated in vitro using the CCK-8, clonogenic and neurosphere assays, respectively. Glioma cell cycle arrest and apoptosis were determined by flow cytometry. SRT2183-induced autophagy was investigated by detection of GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3) puncta, conversion of the nonlipidated form of LC3 (LC3-I) to the phosphatidylethanolamine-conjugated form (LC3-II). Acetylation of STAT3 and NF-κB in SRT2183-treated glioma cells was examined using immunoprecipitation. The expression levels of anti-apoptotic proteins were assayed by immunoblotting. RESULTS: SRT2183 suppressed glioma cell growth and destroyed neurospheres in vitro. Furthermore, SRT2183 induced glioma cell cycle arrest and apoptosis, accompanying by upregulation of the pro-apoptotic Bim and downregulation of Bcl-2 and Bcl-xL. Notably, ER stress was triggered in glioma cells upon exposure to SRT2183 while the pre-exposure to 4-PBA, an ER stress inhibitor, significantly antagonized SRT2183-mediated growth inhibition in glioma cells. In addition, SRT2183 induced autophagy in glioma cells and pharmacological modulation of autophagy appeared not to affect SRT2183-inhibited cell growth. Of interest, the acetylation and phosphorylation of p65 NF-κB and STAT3 in glioma cells were differentially affected by SRT2183. CONCLUSIONS: Our data suggest the ER stress pathway is involved in SRT2183-mediated growth inhibition in glioma. Further investigation in vivo is needed to consolidate the data.

Controllable synthesis of pyrido[2,3-b]indol-4-ones or indolo[3,2-b]quinolines via formal intramolecular C(sp2)-H functionalization.

A novel Fe-catalyzed protocol for the controllable synthesis of pyrido[2,3-b]indol-4-ones or indolo[3,2-b]quinolines has been developed by using indole-2-carboxylic derivatives as starting materials. Indole-2-carboxenamines were transformed into pyrido[2,3-b]indol-4-ones through intramolecular N-H/C-H coupling, in which a carbonyl 1,2-migration was involved. Whereas, when indole-2-carboxarylamines were employed, indolo[3,2-b]quinolones were produced through direct N-H/C-H coupling. The desired products were obtained under mild reaction conditions in moderate to good yields with wide substrate scope. The natural product quindolinone was conveniently prepared by this reaction.

Transition-metal-free C-C σ-bond activation of α-aryl ketones and subsequent Zn-catalyzed intramolecular cyclization: synthesis of tetrasubstituted furans.

A highly atom-economical protocol for the synthesis of tetrasubstituted furans has been developed. This process is realized through the tandem reactions of Cs2CO3 promoted C-C σ-bond activation of α-aryl ketones followed by Zn-catalyzed intramolecular cyclization. This represents the first example for the preparation of tetrasubstituted furans through rearrangement of molecular skeletons and subsequent transformations. Mild reaction conditions and readily accessible starting materials make the protocol attractive in organic synthesis.

Synthesis of cyano-substituted carbazoles via successive C-C/C-H cleavage.

A highly efficient protocol for the synthesis of polysubstituted cyano carbazoles has been developed. This process is realized through the tandem reactions of Cs2CO3 promoted C-C σ-bond activation of α-cyano ketones followed by Fe-catalyzed selective C-H and/or C-C bond activations. Two of the sp2 C-H bonds are functionalized, and two of the C-C σ-bonds are cleaved involving a 1,2-acyl migration during the reaction process.

Recombinant oncolytic Newcastle disease virus displays antitumor activities in anaplastic thyroid cancer cells.

BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the most aggressive of all solid tumors for which no effective therapies are currently available. Oncolytic Newcastle disease virus (NDV) has shown the potential to induce oncolytic cell death in a variety of cancer cells of diverse origins. However, whether oncolytic NDV displays antitumor effects in ATC remains to be investigated. We have previously shown that the oncolytic NDV strain FMW (NDV/FMW) induces oncolytic cell death in several cancer types. In the present study, we investigated the oncolytic effects of NDV/FMW in ATC. METHODS: In this study, a recombinant NDV expressing green fluorescent protein (GFP) was generated using an NDV reverse genetics system. The resulting virus was named after rFMW/GFP and the GFP expression in infected cells was demonstrated by direct fluorescence and immunoblotting. Viral replication was evaluated by end-point dilution assay in DF-1 cell lines. Oncolytic effects were examined by biochemical and morphological experiments in cultural ATC cells and in mouse models. RESULTS: rFMW/GFP replicated robustly in ATC cells as did its parent virus (NDV/FMW) while the expression of GFP protein was detected in lungs and spleen of mice intravenously injected with rFMW/GFP. We further showed that rFMW/GFP infection substantially increased early and late apoptosis in the ATC cell lines, THJ-16 T and THJ-29 T and increased caspase-3 processing and Poly (ADP-ribose) polymerase (PARP) cleavage in ATC cells as assessed by immunoblotting. In addition, rFMW/GFP induced lyses of spheroids derived from ATC cells in three-dimensional (3D) cultures. We further demonstrated that rFMW/GFP infection resulted in the activation of p38 MAPK signaling, but not Erk1/2 or JNK, in THJ-16 T and THJ-29 T cells. Notably, inhibition of p38 MAPK activity by SB203580 decreased rFMW/GFP-induced cleavage of caspase-3 and PARP in THJ-16 T and THJ-29 T cells. Finally, both rFMW/GFP and its parent virus inhibited tumor growth in mice bearing THJ-16 T derived tumors. CONCLUSION: Taken together, these data indicate that both the recombinant reporter virus rFMW/GFP and its parent virus NDV/FMW, display oncolytic activities in ATC cells in vitro and in vivo and suggest that oncolytic NDV may have potential as a novel therapeutic strategy for ATC.

Cobalt-catalyzed regioselective syntheses of indeno[2,1-c]pyridines from nitriles and diynes bearing propargyl fragments.

A highly efficient CoI2/o-phenanthroline catalyzed cycloaddition reaction of diynes bearing TBS protected propargylic alcohol fragments with nitriles has been developed. This methodology offers regioselective access, with good functional group tolerance, to various indeno[2,1-c]pyridine derivatives in moderate to excellent yields. It was found that o-phenanthroline as a bidentate nitrogen ligand showed high efficacy in this cycloaddition reaction.

Base-mediated insertion reaction of alkynes into carbon-carbon σ-bonds of ethanones: synthesis of hydroxydienone and chromone derivatives.

Transition-metal free insertions of alkynes into carbon-carbon σ-bonds of ethanones have been reported. These tandem reactions offer an efficient synthesis of hydroxydienones and multi-substituted chromones. This is the first example of base-promoted insertion reactions of isolated carbon-carbon triple bonds into carbon-carbon σ-bonds with active methylene compounds bearing only one electron-withdrawing group.

LDA-Promoted Synthesis of 3-Amino Furans by Selective Lithiation of Enaminones.

An efficient cascade ß-metalation/addition/cyclization reaction promoted by LDA is described in which 3-amino furans were constructed from enaminones and aldehydes. A broad range of substituents on the starting compounds was tolerated, and the polysubstituted furans were gained with moderate to excellent yields within 2 h.

Copper-catalyzed synthesis of substituted quinolines via C­N coupling/condensation from ortho-acylanilines and alkenyl iodides.

An efficient cascade copper-catalyzed intermolecular Ullmann-type C­N coupling/enamine condensation reaction is described, in which ortho-acylanilines and alkenyl iodides converted to multisubstituted quinolines in good to excellent yields.

Ezetimibe inhibits the migration and invasion of triple-negative breast cancer cells by targeting TGFß2 and EMT.

The important role of cholesterol in tumor metastasis has been widely studied in recent years. Ezetimibe is currently the only selective cholesterol uptake inhibitor on the market. Here, we explored the effect of ezetimibe on breast cancer metastasis by studying its impact on breast cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT). Differential gene expression analysis and validation were also carried out to compare ezetimibe-treated and untreated breast cancer cells. Finally, breast cancer cells overexpressing TGFß2 were constructed, and the effect of TGFß2 on the migration and invasion of ezetimibe-treated breast cancer cells was examined. Our results show that ezetimibe treatment of breast cancer cells inhibited cell migration, invasion, and EMT, and it significantly suppressed the expression of TGFß2. Overexpression of TGFß2 reversed the inhibitory effect of ezetimibe on the migration and invasion of breast cancer cells. Taken together, our results suggest that ezetimibe might be a potential candidate for the treatment of breast cancer metastasis.

MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells by binding ITGB4/LAMB3 to activate the AKT signaling pathway.

Colorectal cancer (CRC) is one of the most lethal cancers. Single-cell RNA sequencing (scRNA-seq) and protein-protein interactions (PPIs) have enabled the systematic study of CRC. In our research, the activation of the AKT pathway in CRC was analyzed by KEGG using single-cell sequencing data from the GSE144735 dataset. The correlation and PPIs of MDFI and ITGB4/LAMB3 were examined. The results were verified in the TCGA and CCLE and further tested by coimmunoprecipitation experiments. The effect of MDFI on the AKT pathway via ITGB4/LAMB3 was validated by knockdown and lentiviral overexpression experiments. The effect of MDFI on oxaliplatin/fluorouracil sensitivity was probed by colony formation assay and CCK8 assay. We discovered that MDFI was positively associated with ITGB4/LAMB3. In addition, MDFI was negatively associated with oxaliplatin/fluorouracil sensitivity. MDFI upregulated the AKT pathway by directly interacting with LAMB3 and ITGB4 in CRC cells, and enhanced the proliferation of CRC cells via the AKT pathway. Finally, MDFI reduced the sensitivity of CRC cells to oxaliplatin and fluorouracil. In conclusion, MDFI promotes the proliferation and tolerance to chemotherapy of colorectal cancer cells, partially through the activation of the AKT signaling pathway by the binding to ITGB4/LAMB3. Our findings provide a possible molecular target for CRC therapy.

Oncolytic adenovirus encoding apolipoprotein A1 suppresses metastasis of triple-negative breast cancer in mice.

BACKGROUND: Dysregulation of cholesterol metabolism is associated with the metastasis of triple-negative breast cancer (TNBC). Apolipoprotein A1 (ApoA1) is widely recognized for its pivotal role in regulating cholesterol efflux and maintaining cellular cholesterol homeostasis. However, further exploration is needed to determine whether it inhibits TNBC metastasis by affecting cholesterol metabolism. Additionally, it is necessary to investigate whether ApoA1-based oncolytic virus therapy can be used to treat TNBC. METHODS: In vitro experiments and mouse breast cancer models were utilized to evaluate the molecular mechanism of ApoA1 in regulating cholesterol efflux and inhibiting breast cancer progression and metastasis. The gene encoding ApoA1 was inserted into the adenovirus genome to construct a recombinant adenovirus (ADV-ApoA1). Subsequently, the efficacy of ADV-ApoA1 in inhibiting the growth and metastasis of TNBC was evaluated in several mouse models, including orthotopic breast cancer, spontaneous breast cancer, and human xenografts. In addition, a comprehensive safety assessment of Syrian hamsters and rhesus monkeys injected with oncolytic adenovirus was conducted. RESULTS: This study found that dysregulation of cholesterol homeostasis is critical for the progression and metastasis of TNBC. In a mouse orthotopic model of TNBC, a high-cholesterol diet promoted lung and liver metastasis, which was associated with keratin 14 (KRT14), a protein responsible for TNBC metastasis. Furthermore, studies have shown that ApoA1, a cholesterol reverse transporter, inhibits TNBC metastasis by regulating the cholesterol/IKBKB/FOXO3a/KRT14 axis. Moreover, ADV-ApoA1 was found to promote cholesterol efflux, inhibit tumor growth, reduce lung metastasis, and prolonged the survival of mice with TNBC. Importantly, high doses of ADV-ApoA1 administered intravenously and subcutaneously were well tolerated in rhesus monkeys and Syrian hamsters. CONCLUSIONS: This study provides a promising oncolytic virus treatment strategy for TNBC based on targeting dysregulated cholesterol metabolism. It also establishes a basis for subsequent clinical trials of ADV-ApoA1 in the treatment of TNBC.

Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma.

The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.

A novel approach for the analysis of single-cell RNA sequencing identifies TMEM14B as a novel poor prognostic marker in hepatocellular carcinoma.

A fundamental goal in cancer-associated genome sequencing is to identify the key genes. Protein-protein interactions (PPIs) play a crucially important role in this goal. Here, human reference interactome (HuRI) map was generated and 64,006 PPIs involving 9094 proteins were identified. Here, we developed a physical link and co-expression combinatory network construction (PLACE) method for genes of interest, which provides a rapid way to analyze genome sequencing datasets. Next, Kaplan‒Meier survival analysis, CCK8 assays, scratch wound assays and Transwell assays were applied to confirm the results. In this study, we selected single-cell sequencing data from patients with hepatocellular carcinoma (HCC) in GSE149614. The PLACE method constructs a protein connection network for genes of interest, and a large fraction (80%) of the genes (screened by the PLACE method) were associated with survival. Then, PLACE discovered that transmembrane protein 14B (TMEM14B) was the most significant prognostic key gene, and target genes of TMEM14B were predicted. The TMEM14B-target gene regulatory network was constructed by PLACE. We also detected that TMEM14B-knockdown inhibited proliferation and migration. The results demonstrate that we proposed a new effective method for identifying key genes. The PLACE method can be used widely and make outstanding contributions to the tumor research field.

Four-Component Ring-Opening Reaction of Pyrroles via C-N Bond Cleavage under Multiple Functions of Elemental Sulfur.

We report a four-component ring-opening reaction of pyrroles via C-N bond cleavage. In this process, elemental sulfur is used as the sulfur source of thiazole and thioamide and the reductant of olefin. A series of benzothiazoles functionalized with thiopropionamides at the C2 position were synthesized using this method. A plausible reaction mechanism is proposed based on the concise control experiments.

Ezetimibe inhibits triple-negative breast cancer proliferation and promotes cell cycle arrest by targeting the PDGFR/AKT pathway.

Cholesterol levels were strongly associated with tumor progression and metastasis. Targeted cholesterol metabolism has broad prospects in tumor treatment. Ezetimibe, the only FDA-approved inhibitor of cholesterol absorption, has been reported to be able to inhibit angiogenesis in liver cancer. However, the efficacy and specific mechanisms of Ezetimibe in the treatment of Triple-Negative Breast Cancer (TNBC)have not been reported. Our research shows Ezetimibe inhibits TNBC cell proliferation and blocks the cell cycle in the G1 phase. Mechanistically, Ezetimibe inhibits the activation of PDGFRß/AKT pathway, thereby promoting cell cycle arrest and inhibiting cell proliferation. By overexpressing PDGFRß in TNBC cells, we found that PDGFRß significantly reduced the inhibitory effect of Ezetimibe on TNBC cell proliferation and the cell cycle. Similarly, SC79, an AKT agonist, can reduce the proliferation inhibitory and cycle-blocking effects of Ezetimibe on TNBC cells. Furthermore, the AKT inhibitor MK2206 enhanced the inhibitory effect of Ezetimibe on the cell cycle and proliferation ability of TNBC cells overexpressing PDGFRß. In xenograft tumor models, we also found that Ezetimibe inhibited TNBC growth, an effect that can be blocked by overexpression of PDGFR or activation of AKT. In summary, we have demonstrated that EZ inhibits the PDGFR/AKT pathway, thereby halting TNBC cycle progression and tumor growth.

The impact of the gut microbiome on tumor immunotherapy: from mechanism to application strategies.

Immunotherapy is one of the fastest developing areas in the field of oncology. Many immunological treatment strategies for refractory tumors have been approved and marketed. Nevertheless, much clinical and preclinical experimental evidence has shown that the efficacy of immunotherapy in tumor treatment varies markedly among individuals. The commensal microbiome mainly colonizes the intestinal lumen in humans, is affected by a variety of factors and exhibits individual variation. Moreover, the gut is considered the largest immune organ of the body due to its influence on the immune system. In the last few decades, with the development of next-generation sequencing (NGS) techniques and in-depth research, the view that the gut microbiota intervenes in antitumor immunotherapy through the immune system has been gradually confirmed. Here, we review important studies published in recent years focusing on the influences of microbiota on immune system and the progression of malignancy. Furthermore, we discuss the mechanism by which microbiota affect tumor immunotherapy, including immune checkpoint blockade (ICB) and adoptive T-cell therapy (ACT), and strategies for modulating the microbial composition to facilitate the antitumor immune response. Finally, opportunity and some challenges are mentioned to enable a more systematic understanding of tumor treatment in the future and promote basic research and clinical application in related fields.