Programmable Deoxychlorination/Aromatization of 1-Tetralones to Access Multisubstituted 1-Chloronaphthalenes via an Interrupted Vilsmeier-Haack Reaction.

An unprecedented programmable sequential orthogonal deoxychlorination/aromatization of various tetralones was successfully developed for the straightforward construction of valuable multisubstituted 1-chloronaphthalenes via an interrupted Vilsmeier-Haack reaction. High efficiency, excellent site selectivity, as well as good functional group compatibility were achieved under noble-metal-free inexpensive conditions. Aiming to realize precision chemistry goal, several artificially controllable sequences were further rationally designed to access a series of highly functionalized useful 1-chloronaphthalene derivatives, which were prepared costly by previously reported methods.

Targeting PRDX1 impairs acute myeloid leukemic blasts and stem cells by disrupting redox homeostasis.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a poor prognosis and limited therapeutic options. Leukemic stem cells (LSCs), which drive disease progression and confer resistance to therapy, pose a significant challenge to conventional treatment strategies. In this study, we identified and characterized the inhibitory mechanisms of TH37, a small molecule derived from traditional Chinese medicine, which selectively targets AML blasts and LSCs.

MYC/TET3-Regulated TMEM65 Activates OXPHOS-SERPINB3 Pathway to Promote Progression and Cisplatin Resistance in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective targeted therapeutics. Mitochondrial metabolism is intimately linked to TNBC progression and therapeutic resistance and is an attractive therapeutic target for TNBC. Here, it is first reported that human transmembrane protein 65 (TMEM65), a poorly characterized mitochondrial inner-membrane protein-encoding gene in human cancer, acts as a novel oncogene in TNBC to promote tumor growth, metastasis, and cisplatin resistance both in vivo and in vitro.

Kinesin-like protein KIFC2 stabilizes CDK4 to accelerate growth and confer resistance in HR+/HER2- breast cancer.

Hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer (HR+/HER2- BC) is the most common subtype, with a high risk of long-term recurrence and metastasis. Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is a standard treatment for advanced/metastatic HR+/HER2- BC, but resistance remains a major clinical challenge. We report that kinesin family member C2 (KIFC2) was amplified in approximately 50% of patients with HR+/HER2- BC, and its high expression was associated with poor disease outcome, increased tumor protein p53 (TP53) somatic mutation, and active pyrimidine metabolism.

Catalyst-free and oxidant-free cyclocondensation of 2-aminobenzamides with glycosides under visible light.

A convenient and practical method for the mild synthesis of quinazolinones has been developed under visible light at room temperature in the absence of catalysts or additional oxidants. Under very mild reaction conditions, the quinazolinone moiety can be successfully introduced into deoxyuridine and helicid. This method afforded various 5-substituted deoxyuridine analogs and 4-substituted helicid derivatives in moderate to good yields (without column chromatography) across diverse aromatic and aliphatic aldehydes, proving effective for late-stage drug functionalization.

Secernin-2 Stabilizes Histone Methyltransferase KMT2C to Suppress Progression and Confer Therapeutic Sensitivity to PARP Inhibition in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a difficulty and bottleneck in the clinical treatment of breast cancer due to a lack of effective therapeutic targets. Herein, we first report that secernin 2 (SCRN2), an uncharacterized gene in human cancer, acts as a novel tumor suppressor in TNBC to inhibit cancer progression and enhance therapeutic sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. SCRN2 is downregulated in TNBC through chaperone-mediated autophagic degradation, and its downregulation is associated with poor patient prognosis.

Visible light-induced reductive aza-6π electrocyclization access to phenanthridines.

Visible light-induced aza-6π electrocyclization was developed for the synthesis of aza-arenes from nitroarenes with diverse aldehydes. This protocol allows the reduction of nitroarenes by Bnep and subsequent 6π-electrocyclization of the formed imine under visible light. An array of 6- and multi-substituted phenanthridines were constructed in moderate to good yields under purple LEDs at room temperature.

The DRAP1/DR1 Repressor Complex Increases mTOR Activity to Promote Progression and Confer Everolimus Sensitivity in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Transcriptional dysregulation is a hallmark of cancer, and several transcriptional regulators have been demonstrated to contribute to cancer progression. In this study, we identified an upregulation of the transcriptional corepressor downregulator of transcription 1-associated protein 1 (DRAP1) in TNBC, which was closely associated with poor recurrence-free survival in patients with TNBC.

SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1.

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins.

Visible light-induced metal-free cascade denitrogenative borylation and iodination of nitroarenes.

An efficient method was developed for the one-pot construction of C-B and C-I visible light-induced transformation of nitroarenes. This protocol relies on the photochemical properties of nitroarenes under visible light, followed by reduction with Bpin and diazotization with BuONO. An array of arylboronates and iodobenzenes were constructed smoothly after excitation with purple LEDs at room temperature.

Spermatid perinuclear RNA-binding protein promotes UBR5-mediated proteolysis of Dicer to accelerate triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with no targeted therapy. Spermatid perinuclear RNA binding protein (STRBP), a poorly characterized RNA-binding protein (RBP), has an essential role in normal spermatogenesis and sperm function, but whether and how its dysregulation contributing to cancer progression has not yet been explored. Here, we report that STRBP functions as a novel oncogene to drive TNBC progression.

An Expanded EDA Complex Profile: Construction of Aza-arenes and Their Synthetic Application as Fluorescence Probes.

We developed a visible-light-driven expanded EDA complex profile for the synthesis of aza-arenes via aza-6π electrocyclization of 2-styrylanilines with aromatic aldehydes. This protocol relies on the EDA complexes of AlCl with imine to induce the absorption red-shift to visible light from ultraviolet light. An array of 2,3-disubstituted quinolines were constructed smoothly after excitation with blue-light-emitting diodes at room temperature.

Construction and evaluation of DNA vaccine encoding Crimean Congo hemorrhagic fever virus nucleocapsid protein, glycoprotein N-terminal and C-terminal fused with LAMP1.

Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe hemorrhagic fever in humans and is mainly transmitted by ticks. There is no effective vaccine for Crimean-Congo hemorrhagic fever (CCHF) at present. We developed three DNA vaccines encoding CCHFV nucleocapsid protein (NP), glycoprotein N-terminal (Gn) and C-terminal (Gc) fused with lysosome-associated membrane protein 1 (LAMP1) and assessed their immunogenicity and protective efficacy in a human MHC (HLA-A11/DR1) transgenic mouse model.

Destabilization of microrchidia family CW-type zinc finger 2 via the cyclin-dependent kinase 1-chaperone-mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule-targeting agents.

Background: Microtubule-targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges.

Methods: Immunoblotting and RT-qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis.

MYC-driven U2SURP regulates alternative splicing of SAT1 to promote triple-negative breast cancer progression.

Triple-negative breast cancer (TNBC), although highly lethal, lacks validated therapeutic targets. Here, we report that U2 snRNP-associated SURP motif-containing protein (U2SURP), a poorly defined member of the serine/arginine rich protein family, was significantly upregulated in TNBC tissues, and its high expression was associated with poor prognosis of TNBC patients. MYC, a frequently amplified oncogene in TNBC tissues, enhanced U2SURP translation through an eIF3D (eukaryotic translation initiation factor 3 subunit D)-dependent mechanism, resulting in the accumulation of U2SURP in TNBC tissues.

Iridium-Catalyzed Direct -C-H Amidation of α-Ketoesters with Sulfonyl Azides Using a Transient Directing Group Strategy.

Direct C-H amidation of α-ketoesters was accomplished using various organic azides as the amino source through the combination of transient directing group strategy and iridium catalysis. Excellent functional group tolerance and wide substrate scope were explored under simple and mild conditions. Importantly, it was found that the steric hindrance of the ester moiety played a pivotal role for the reaction efficacy.

Dynamic SUMOylation of MORC2 orchestrates chromatin remodelling and DNA repair in response to DNA damage and drives chemoresistance in breast cancer.

SUMOylation regulates a plethora of biological processes, and its inhibitors are currently under investigation in clinical trials as anticancer agents. Thus, identifying new targets with site-specific SUMOylation and defining their biological functions will not only provide new mechanistic insights into the SUMOylation signaling but also open an avenue for developing new strategy for cancer therapy. MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme with an emerging role in the DNA damage response (DDR), but its regulatory mechanism remains enigmatic.

Protein Phosphatase 1 Subunit PPP1R14B Stabilizes STMN1 to Promote Progression and Paclitaxel Resistance in Triple-Negative Breast Cancer.

Unlabelled: Triple-negative breast cancer (TNBC) represents the most lethal subtype of breast cancer due to its aggressive clinical features and the lack of effective therapeutic targets. To identify novel approaches for targeting TNBC, we examined the role of protein phosphatases in TNBC progression and chemoresistance. Protein phosphatase 1 regulatory subunit 14B (PPP1R14B), a poorly defined member of the protein phosphatase 1 regulatory subunits, was aberrantly upregulated in TNBC tissues and predicted poor prognosis.

Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy.

ATP-dependent chromatin-remodeling complexes can reorganize and remodel chromatin and thereby act as important regulator in various cellular processes. Based on considerable studies over the past two decades, it has been confirmed that the abnormal function of chromatin remodeling plays a pivotal role in genome reprogramming for oncogenesis in cancer development and/or resistance to cancer therapy. Recently, exciting progress has been made in the identification of genetic alteration in the genes encoding the chromatin-remodeling complexes associated with tumorigenesis, as well as in our understanding of chromatin-remodeling mechanisms in cancer biology.

Poly(ADP-ribosyl)ation of acetyltransferase NAT10 by PARP1 is required for its nucleoplasmic translocation and function in response to DNA damage.

Background: N-acetyltransferase 10 (NAT10), an abundant nucleolar protein with both lysine and RNA cytidine acetyltransferase activities, has been implicated in Hutchinson-Gilford progeria syndrome and human cancer. We and others recently demonstrated that NAT10 is translocated from the nucleolus to the nucleoplasm after DNA damage, but the underlying mechanism remains unexplored.

Methods: The NAT10 and PARP1 knockout (KO) cell lines were generated using CRISPR-Cas9 technology.

Direct Assembly of Diverse Unsymmetrical Tertiary 9-Fluorenols via Transient Directing Group-Enabled Palladium-Catalyzed Dual C-H Bond Activation of α-Ketoesters.

An expeditious construction of an unsymmetrical tertiary 9-fluorenol skeleton was accomplished starting from readily available α-ketoester and aryl iodide. Inexpensive commercially available substituted aniline was utilized as a potent monodentate transient directing group (TDG) to assist palladium-catalyzed direct ortho-C-H arylation and tandem dual C-H activation of α-ketoesters to form two carbon-carbon bonds. To demonstrate practical applications, the reaction was enlarged to the gram scale, and subsequent one-step derivatization allowed facile access to structurally diversified useful derivatives.