A force-sensitive adhesion GPCR is required for equilibrioception.

Equilibrioception (sensing of balance) is essential for mammals to perceive and navigate the three-dimensional world. A rapid mechanoelectrical transduction (MET) response in vestibular hair cells is crucial for detecting position and motion. Here, we identify the G protein-coupled receptor (GPCR) LPHN2/ADGRL2, expressed on the apical membrane of utricular hair cells, as essential for maintaining normal balance.

Design, Synthesis, and Biological Evaluation of Thieno[3,2-]pyrimidine Derivatives as the First Bifunctional PI3Kδ Isoform Selective/Bromodomain and Extra-Terminal Inhibitors.

The concomitant inhibition of PI3Kδ and bromodomain and extra-terminal (BET) that exerts a synergistic effect on the B-cell receptor signaling pathway provides a new strategy for the treatment of aggressive diffuse large B-cell lymphoma (DLBCL). Herein, a merged pharmacophore strategy was utilized to discover a series of thieno[3,2-]pyrimidine derivatives as the first-in-class bifunctional PI3Kδ-BET inhibitors. Through optimization, a highly potent compound () was identified to possess excellent and balanced activities against PI3Kδ [inhibitory concentration (IC) = 112 ± 8 nM] and BRD4-BD1 (IC = 19 ± 1 nM) and exhibited strong antiproliferative activities in DLBCL cells.

HFIP-driven Schmidt-type reaction enables chromone-3-carbonitriles and its applications.

Chromone-3-carbonitrile has been extensively studied in a panel of high-value transformations. However, existing protocols for the synthesis of this scaffold are often constrained by the structure of the starting materials and harsh conditions. To address these issues, we present a novel strategy that HFIP (hexafluoroisopropanol)-driven strategy, enables chromone-3-carbonitriles synthesis without undesirable side reactions.

Discovery and optimization of novel 4-morpholinothieno[3,2-d]pyrimidine derivatives as potent BET inhibitors for cancer therapy.

The identification of structurally novel and potently active BET inhibitors represents a significant advancement in the field of anticancer therapeutics. In the present investigation, leveraging the outcomes of previous screening endeavors, we successfully optimized and synthesized a novel series of bromodomain and extra-terminal (BET) inhibitors with a 4-morpholinothieno[3,2-d]pyrimidine structure. Among the synthesized compounds, compound 6c emerged as a promising candidate, exhibiting exceptional inhibitory activities against various BET isoform proteins, with IC values ranging from 3.

Copper-Catalyzed Radical Sulfonylation: Divergent Construction of C(sp)-Sulfonyl Bonds with Sulfonylhydrazones.

Sulfonylhydrazones have been proven to be versatile synthetic intermediates in a panel of transformations. However, radical sulfonylation with sulfonylhydrazone as sulfonyl radical source is relatively rare. Here, we found that sulfonylhydrazone can serve as a new sulfonyl radical precursor to couple various partners such as arylacetic acids, ene-yne-ketones, and -quinone methides under copper catalysis and microwave irradiation.

Adipose stem cell-derived exosomes in the treatment of wound healing in preclinical animal models: a meta-analysis.

Background: Wound healing has always been a serious issue for doctors and primary health care systems. In addition, adipose stem cell-derived exosomes have been proven to play a positive and effective role in tissue repair and regeneration. A systematic review of these preclinical studies was performed to assess the efficacy of adipose stem cell-derived exosomes (ADSC-Exos) in treating wounds.

Lewis Acid-Driven Multicomponent Reactions Enable 2-Alkyl Chromanones with Anticancer Activities.

2-Alkyl chromanone scaffold has become prominent in pharmaceuticals and natural compounds. Consequently, devising robust strategies for synthesizing 2-alkyl chromanones remains crucial. Here, multicomponent reactions were employed to synthesize 2-alkyl chromanones containing an oxazole moiety using 3-formylchromones, amines, and -propargylamides as reactants.

Tandem Vinylogous Aldol and Intramolecular [2 + 2] Cycloaddition toward Benzocyclobutenes by UV Light Photocatalysis.

A facile and efficient radical tandem vinylogous aldol and intramolecular [2 + 2] cycloaddition reaction for direct synthesis of cyclobutane-containing benzocyclobutenes (BCBs) under extremely mild conditions without using any photocatalysts is reported. This approach exhibited definite compatibility with functional groups and afforded new BCBs with excellent regioselectivity and high yields. Moreover, detailed mechanism studies were carried out both experimentally and theoretically.

The role of traffic conflicts in roundabout safety evaluation: A review.

The roundabout is one type of at-grade intersection commonly seen in many countries. The evaluation of roundabout safety is usually counted on conflict analysis of the roundabout traffic due to random and limited records of real accidents. This paper surveyed published papers and reports that investigate the role of traffic conflicts in roundabout safety evaluation.

Metal-Free Catalyzed Oxidation/Decarboxylative [3+2] Cycloaddition Sequences of 3-Formylchromones to Access Pyrroles with Anti-Cancer Activity.

An efficient and direct approach to pyrroles was successfully developed by employing 3-formylchromones as decarboxylative coupling partners, and facilitated by microwave irradiation. The protocol utilizes easily accessible feedstocks, a catalytic amount of DBU without any metals, resulting in high efficiency and regioselectivity. Notably, all synthesized products were evaluated against five different cancer cell lines and compound selectively inhibited the proliferation of HCT116 cells with an IC value of 10.

NSUN2 is a glucose sensor suppressing cGAS/STING to maintain tumorigenesis and immunotherapy resistance.

Glucose metabolism is known to orchestrate oncogenesis. Whether glucose serves as a signaling molecule directly regulating oncoprotein activity for tumorigenesis remains elusive. Here, we report that glucose is a cofactor binding to methyltransferase NSUN2 at amino acid 1-28 to promote NSUN2 oligomerization and activation.

Silver-Catalyzed Decarboxylative Acylation of Isocyanides Accesses to α-Ketoamides with Air as a Sole Oxidant.

α-Ketoamide moieties, as privileged units, may represent a valuable option to develop compounds with favorable biological activities, such as low toxicity, promising PK and drug-like properties. An efficient silver-catalyzed decarboxylative acylation of α-oxocarboxylic acids with isocyanides was developed to derivatize the α-ketoamide functional group via a multicomponent reaction (MCR) cascade sequence in one pot. A series of α-ketoamides was synthesized with three components of isocyanides, aromatic α-oxocarboxylic acid analogues and water in moderate yields.

Unexpected Cascade Sequence Forming the C(sp)-N/C(sp)-C(sp) Bond: Direct Access to γ-Lactam-Fused Pyridones with Anticancer Activity.

An unexpected Ugi cascade reaction was developed for the facile construction of γ-lactam-fused pyridone derivatives with high tolerance of substrates. A C(sp)-N bond and a C(sp)-C(sp) bond were formed together, accompanied by a chromone ring-opening in Ugi adducts, under the basic conditions without any metal catalyst for the whole process. Screening data of several difficult-to-inhibit cancer cell lines demonstrated that displayed a high cytotoxicity against HCT116 cells (IC = 5.

Deafness-Associated ADGRV1 Mutation Impairs USH2A Stability through Improper Phosphorylation of WHRN and WDSUB1 Recruitment.

The ankle-link complex (ALC) consists of USH2A, WHRN, PDZD7, and ADGRV1 and plays an important role in hair cell development. At present, its architectural organization and signaling role remain unclear. By establishing Adgrv1 Y6236fsX1 mutant mice as a model of the deafness-associated human Y6244fsX1 mutation, the authors show here that the Y6236fsX1 mutation disrupts the interaction between adhesion G protein-coupled receptor V subfamily member 1 (ADGRV1) and other ALC components, resulting in stereocilia disorganization and mechanoelectrical transduction (MET) deficits.

Correction: An intramolecular hydrogen bond-promoted "green" Ugi cascade reaction for the synthesis of 2,5-diketopiperazines with anticancer activity.

[This corrects the article DOI: 10.1039/D2RA04958A.].

Acid-Promoted Direct C-H Carbamoylation at the C-3 Position of Quinoxalin-2(1)-ones with Isocyanide in Water.

Described herein is a concise and practical direct amidation at the C-3 position of quinoxalin-2(1)-ones through an acid-promoted carbamoylation with isocyanide in water. In this conversion, environmentally friendly water and commercial inexpensive isocyanide were used as a solvent and carbamoylation reagent, respectively. This study not only provides a green and efficient strategy for the construction of 3-carbamoylquinoxalin-2(1)-one derivatives that can be applied to the synthesis of druglike structures but also expands the application of isocyanide in organic chemistry.

An intramolecular hydrogen bond-promoted "green" Ugi cascade reaction for the synthesis of 2,5-diketopiperazines with anticancer activity.

We report a "green chemistry"-based Ugi cascade reaction to furnish a series of 2,5-diketopiperazines (through nucleophilic attack of amides upon ketones in Ugi adducts) at moderate-to-good yields. Investigation with the MTT assay revealed compound (±) 5c to exhibit potent anticancer activities against acute myeloid leukaemia (MV411; IC = 1.7 μM) and acute T lymphocyte leukaemia (Jurkat; IC = 5.

Ugi Cascade Sequence for the Construction of 3-Pyrrolin-2-one Scaffolds: Anti-proliferation in Prostate Cancer Cells.

Herein, a small series of 3-pyrrolin-2-ones was efficiently synthesized through a three-step Ugi cascade sequence. This method features readily available substrates, simple aqueous workup procedures and good yields, dramatically improving generality of reaction. Importantly, the newly product N-benzyl-2-(3-(4-chlorophenyl)-4-methyl-2-oxo-2,5-dihydro-1H-pyrrol-1-yl)-2-phen-ylacetamide exhibited potent anti-proliferation in prostate cancer cell line through G1/S cell cycle arrest and targeted in PI3K/AKT/TSC2 signal pathway.

[Distribution of bioactive compounds in different tissues of Paeonia lactiflora roots by DESI-MSI and UPLC].

The quality of Paeoniae Radix Alba and Paeoniae Radix Rubra is evaluated by root thickness, and paeoniflorin serves as a common quality indicator of them. However, the correlation between the content of bioactive compounds and the root size is still unclear. Therefore, this study characterized the distribution patterns and content of seven bioactive compounds including paeoniflorin in different tissues of Paeonia lactiflora roots, analyzed the correlation between the root size and the content of bioactive compounds based on the xylem-to-bark ratio, and further determined the index components for quality assessment.

Zn(OTf)-Promoted Isocyanide-Based Three-Component Reaction: Direct Access to 2-Oxazolines and β-Amino Amides.

An efficient one-pot reaction of propargylamides, isocyanides, and water catalyzed by zinc was developed for the rapid construction of 2-oxazolines with a wide functional group tolerance. The methylene-3-oxazoline was proven to play a vitally important role to start the tandem cascade transformation through unfunctionalized alkynes with sequential nucleophilic addition approaches of isocyanide and water. Notably, with a slight alteration of the reaction temperature and the addition of one molecule of water, various β-amino amide derivatives were synthesized in good to excellent yields.

Discovery of fused benzimidazole-imidazole autophagic flux inhibitors for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) with the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 ptotein, is the highly aggressive subtype of breast cancer that exhibits poor prognosis and high tumor recurrence. It is vital to develop effective agents regulating the core molecular pathway of TNBC. Through a medium throughput screening and iterative medicinal chemistry optimization, we identified compound 7h as an autophagic flux inhibitor, which showed potent activities against human TNBC (MDA-MB-231 and MDA-MB-468) cell lines with IC values of 8.

Identification of myo-inositol-binding proteins by using the biotin pull-down strategy in cultured cells.

Metabolites are not only substrates in metabolic reactions, but they also serve as signaling molecules to regulate diverse biological functions. Identification of the binding proteins for the metabolites helps in the understanding of their functions beyond the classic metabolic pathways in which they are involved. We provide the protocol for synthesizing the biotin-labeled myo-inositol, which is used to identify its binding proteins by using biotin pull-down assay, given there is no available tool for the rapid screening of inositol-binding proteins in cells and systems.

Facile synthesis and biological evaluation of tryptamine-piperazine-2,5-dione conjugates as anticancer agents.

A facile and efficient route to synthesize N-heterocyclic fused tryptamine-piperazine-2,5-dione conjugates was developed a post-Ugi cascade reaction. The targeted compounds were prepared by means of a mild reaction and simple operation procedure, which could be applied to a broad scope of starting materials. Compound 6h was demonstrated to induce significant growth inhibition of AsPC-1 and SW1990 human pancreatic cancer cell lines (IC = 6 ± 0.