Efficient copper-catalyzed direct intramolecular aminotrifluoromethylation of unactivated alkenes with diverse nitrogen-based nucleophiles.

A mild, convenient, and step-economical intramolecular aminotrifluoromethylation of unactivated alkenes with a variety of electronically distinct, nitrogen-based nucleophiles in the presence of a simple copper salt catalyst, in the absence of extra ligands, is described. Many different nitrogen-based nucleophiles (e.g., basic primary aliphatic and aromatic amines, sulfonamides, carbamates, and ureas) can be employed in this new aminotrifluoromethylation reaction. The aminotrifluoromethylation process allows straightforward access to diversely substituted CF3-containing pyrrolidines or indolines, in good to excellent yields, through a direct difunctionalization strategy from the respective acyclic starting materials. Mechanistic studies were conducted and a plausible mechanism was proposed.

Enantioselective C-H bond functionalization triggered by radical trifluoromethylation of unactivated alkene.

An asymmetric unactivated alkene/C-H bond difunctionalization reaction for the concomitant construction of C-CF3 and C-O bonds was realized by using a Cu/Brønsted acid cooperative catalytic system, thus providing facile access to valuable chiral CF3-containing N,O-aminals with excellent regio-, chemo-, and enantioselectivity. Mechanistic studies revealed that this reaction may proceed by an unprecedented 1,5-hydride shift involving activation of unactivated alkenes and a radical trifluoromethylation to initiate subsequent enantioselective functionalization of C-H bonds. Control experiments also suggested that chiral Brønsted acid plays multiple roles and not only controls the stereoselectivity but also increases the reaction rate through activation of Togni's reagent.

Positive feedback loop of c-myc/XTP6/NDH2/NF-κB to promote malignant progression in glioblastoma.

BACKGROUND: Recent studies have highlighted the significant role of the NF-κB signaling pathway in the initiation and progression of cancer. Furthermore, long noncoding RNAs (lncRNAs) have been identified as pivotal regulators in sustaining the NF-κB signaling pathway's functionality. Despite these findings, the underlying molecular mechanisms through which lncRNAs influence the NF-κB pathway remain largely unexplored. METHODS: Bioinformatic analyses were utilized to investigate the differential expression and prognostic significance of XTP6. The functional roles of XTP6 were further elucidated through both in vitro and in vivo experimental approaches. To estimate the interaction between XTP6 and NDH2, RNA pulldown and RNA Immunoprecipitation (RIP) assays were conducted. The connection between XTP6 and the IκBα promoter was examined using Chromatin Isolation by RNA Purification (ChIRP) assays. Additionally, Chromatin Immunoprecipitation (ChIP) assays were implemented to analyze the binding affinity of c-myc to the XTP6 promoter, providing insights into the regulatory mechanisms at play. RESULTS: XTP6 was remarkedly upregulated in glioblastoma multiforme (GBM) tissues and was connected with adverse prognosis in GBM patients. Our investigations revealed that XTP6 can facilitate the malignant progression of GBM both in vitro and in vivo. Additionally, XTP6 downregulated IκBα expression by recruiting NDH2 to the IκBα promoter, which resulted in elevated levels of H3K27me3, thereby reducing the transcriptional activity of IκBα. Moreover, the progression of GBM was further driven by the c-myc-mediated upregulation of XTP6, establishing a positive feedback loop with IκBα that perpetuated the activation of the NF-κB signaling pathway. Notably, the application of an inhibitor targeting the NF-κB signaling pathway effectively inhibited the continuous activation induced by XTP6, leading to a significant reduction in tumor formation in vivo. CONCLUSION: The results reveal that XTP6 unveils an innovative epigenetic mechanism instrumental in the sustained activation of the NF-κB signaling pathway, suggesting a promising therapeutic target for the treatment of GBM.

N6-methyladenosine (m6A)-connected lncRNAs are linked to survival and immune infiltration in glioma patients.

BACKGROUND: The connection between m6A-assiociateed lncRNAs and prognosis has been demonstrated in multiple types of tumors. However, potential roles of m6A-assiociateed lncRNAs in glioma is still rare. METHODS: We implemented consensus cluster analysis to group the downloaded samples into two subtypes. The least absolute shrinkage and selection operator (LASSO) analysis was used to create a risk model. Additionally, the conjunction between m6A-related lncRNAs and immune cells infiltration was explored by conducting the R package. Ultimately, we inspected the underlying downstream pathways of the two subtypes by performing Gene Set Enrichment Analysis (GSEA). The expression level of m6A-connected lncRNAs in glioma were examined by conducting in vitro experiments. RESULTS: We ascertained two subtypes of glioma in line with the consensus clustering of m6A-associated lncRNAs. We confirmed that age, grade, and IDH are related to the two subtypes. Additionally, the immune cells infiltration and immune checkpoint molecules of the two clusters were discussed. A risk signature including AL359643.3, AL445524.1, AL162231.2, AL117332.1, AP001486.2, POLR2J4, AC120036.4, LINC00641, LINC00900, CRNDE, and AL158212.3, was identified using the Cox regression and LASSO analyses. We also verified the prognostic value and discussed the immune cells infiltration and immune checkpoint molecules of the risk signature. In vitro experiments verified that the m6A-associated lncRNAs was abnormally expressed in glioma. CONCLUSION: We elaborated the significant role of m6A-connected lncRNAs in glioma prognosis and immune infiltration and suggest that these key regulators may serve as underlying therapeutic targets to build up the efficacy of glioma immunotherapy.

Macropinocytosis: mechanism and targeted therapy in cancers.

Macropinocytosis is a form of endocytosis which provides an effective way for non-selective uptakes of extracellular proteins, liquids, and particles. The endocytic process is initiated by the activation of the growth factors signaling pathways. After activation of the biochemical signal, the cell starts internalizing extracellular solutes and nutrients into the irregular endocytic vesicles, known as macropinosomes that deliver them into the lysosomes for degradation. Macropinocytosis plays an important role in the nutritional supply of cancer cells. Due to the rapid expansion of cancer cells and the abnormal vascular microenvironment, cancer cells are usually deprived of oxygen and nutrients. Therefore, they must transform their metabolism to survive and grow in this harsh microenvironment. To satisfy their energy needs, cancer cells enhance the activity of macropinocytosis. Therefore, this metabolic adaptation that is used by cancer cells can be exploited to develop new targeted cancer therapies. In this review, we discuss the molecular mechanism that actuates the process of macropinocytosis in a variety of cancers, and the novel anti-cancer therapeutics in targeting macropinocytosis.

Metal-free direct intramolecular carbotrifluoromethylation of alkenes to functionalized trifluoromethyl azaheterocycles.

The first example of a metal-free direct carbotrifluoromethylation of alkenes using inexpensive TMSCF3 as the CF3 source is described. The methodology not only exhibits high chemoselectivity for this transformation but also expands the substrate scope that is difficult to access by known transition-metal-catalyzed methods.

Direct access to α-trifluoromethyl enones via efficient copper-catalyzed trifluoromethylation of Meyer-Schuster rearrangement.

A novel domino copper-catalyzed trifluoromethylated Meyer-Schuster rearrangement reaction with Togni's reagent was developed, leading to α-trifluormethyl (CF3) enone products with moderate to good yields. Furthermore, α-CF3 enones can be transformed toward important trifluoromethyl heterocyclic motifs in a one-pot version.