Susceptibility of Mitophagy-Deficient Tumors to Ferroptosis Induction by Relieving the Suppression of Lipid Peroxidation.

The identification of ferroptosis-sensitive cancers is critical for the application of ferroptosis-inducing therapies in cancer therapy. Here, patient-derived organoid screening models of colorectal cancer are established to identify tumors that are sensitive to ferroptosis-inducing therapy. This study discovers that patient-derived tumors characterized by mitophagy deficiency are hypersensitive to ferroptosis-inducing therapies.

TRPML1 triggers ferroptosis defense and is a potential therapeutic target in AKT-hyperactivated cancer.

Targeting ferroptosis for cancer therapy has slowed because of an incomplete understanding of ferroptosis mechanisms under specific pathological contexts such as tumorigenesis and cancer treatment. Here, we identify TRPML1-mediated lysosomal exocytosis as a potential anti-ferroptotic process through genome-wide CRISPR-Cas9 activation and kinase inhibitor library screening. AKT directly phosphorylated TRPML1 at Ser and inhibited K552 ubiquitination and proteasome degradation of TRPML1, thereby promoting TRPML1 binding to ARL8B to trigger lysosomal exocytosis.

Iodine(III)-Mediated Trifluoroacetylation of a C(sp)-H or C(sp)-H Bond with Masked Trifluoroacyl Reagents.

A novel strategy for incorporating a trifluoroacetyl functionality into a range of structurally varied unsaturated bonds was developed by using PhI(OCOMe) as an oxidant with a masked trifluoroacyl reagent as a trifluoroacetyl radical precursor. The oxidative decarboxylation of the masked trifluoroacyl precursor followed by a tandem radical process provides versatile access to 5-- cyclization of -arylacrylamides, direct C(sp)-H trifluoroacetylation of quinolines, isoquinoline, 2-indazole, and quinoxalin-2(1)-ones, and C(sp)-H trifluoroacetylation of alkynes. This protocol is characterized by mild reaction conditions, operational simplicity, and broad functional group compatibility.

Photoredox/Nickel Dual Catalysis-Enabled Cross-Dehydrogenative C-H Amination of Indoles with Unactivated Amine.

Herein, a direct cross-dehydrogenative C-H amination of indoles has been successfully achieved, enabled by the merger of photocatalysis with nickel catalysis. This developed process does not require stoichiometric oxidants and prefunctionalization of amine partners, providing a concise platform for C-N bond formation. Moreover, the synthetic practicality of this transformation was well revealed by its high step- and atom-economy, high reaction efficiency, and broad functional group tolerance.

Visible-Light-Induced, Catalyst-Free Monofluoromethyl Sulfonylation of Alkenes with Iodine(III) Reagent and DABSO.

A visible-light-induced radical relay strategy to access heterocycles bearing a monofluoromethylsufonyl moiety is reported, with PhI(OCOCHF) as the CHF radical precursor and DABSO as the SO source. A range of oxindoles, containing a CHFSOCH- group at the C3 position, were synthesized from -arylacrylamides in up to 97% yields. The protocol features catalyst-free photochemical tandem, mild reaction conditions, broad functional group compatibility, and good to excellent yields.

Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis.

Ferroptosis, an iron-dependent lipid peroxidation-driven programmed cell death, is closely related to cancer therapy. The development of druggable ferroptosis inducers and their rational application in cancer therapy are critical. Here, we identified Tubastatin A, an HDAC6 inhibitor as a novel druggable ferroptosis inducer through large-scale drug screening.

Photoredox-Catalyzed Deoxygenation of Hexafluoroacetone Hydrate Enables Hydroxypolyfluoroalkylation of Alkenes.

An unprecedented photoredox-catalyzed phosphine-mediated deoxygenation of hexafluoroacetone hydrate was established to accomplish the hydroxylpolyfluoroalkylation of electron-deficient alkenes. A range of bis(trifluoromethyl)carbinols were facilely accessed by using readily available hexafluoroacetone hydrate, instead of toxic gaseous hexafluoroacetone. A range of electron-deficient alkenes are tolerated, giving the corresponding hydro-hydroxylpolyfluoroalkylated products in moderate to high yields.

Regioselective Access to Vicinal Diamines by Metal-Free Photosensitized Amidylimination of Alkenes with Oxime Esters.

A metal-free photosensitized protocol for regioselective diamination of alkene feedstocks over a single step was developed based on the rationally designed bifunctional diamination reagent, thus affording a range of differentially protected 1,2-diamines in moderate to high yields. Mechanistic studies reveal that the reaction is initiated with a triplet-triplet energy transfer between thioxanthone catalyst and diamination reagent, followed by fragmentation to simultaneously generate long-lived iminyl radical and transient amidyl radical. The excellent regioselectivity presumably stems from the large reactivity difference between two different N-centered radical species.

Visible-Light-Promoted Cross-Coupling of -Aryl Oximes and Nitrostyrenes to Access Cyanoalkylated Alkenes.

A photoinduced, photocatalyst-free cyanoalkylation of nitrostyenes was explored, affording a series of cyanoalkylated alkenes in moderate to good yields. Mechanistic studies reveal that an electron donor-acceptor complex formed between -aryl oximes and DIPEA is presumably involved in this process. The excellent functional group compatibility of this newly designed synthetic protocol allows for cyanoalkylation of structurally varied substrates, which offers an eco-friendly pathway for the assembly of cyanoalkylated alkenes.

Photocatalyzed Defluorinative Dichloromethylation of α-CF Alkenes Using CHCl as the Radical Source.

A visible-light-induced defluorinative dichloromethylation of α-CF alkenes was developed with cheap and readily accessible chloroform simultaneously as a dichloromethylation reagent and reaction medium, leading to the facile preparation of new polyhalogenated scaffolds. Notably, the change from CHCl to CDCl offers a straightforward pathway for accessing the deuterated analogues with excellent degrees of D incorporation. Mechanistic studies suggested the reaction underwent a radical addition of the dichloromethyl radical with alkenes, followed by sequential single-electron transfer and defluorination.

[3 + 2] . [4 + 1] Annulation: revisiting mechanism studies on the phosphine-catalysed domino sequence of alkynoates and activated methylenes.

The mechanism of the phosphine-catalysed domino sequence of alkynoates and activated methylenes has been computationally studied. The computational results revealed that the [3 + 2] annulation sequence could be ruled out, due to a difficult Knoevenagel condensation of aromatic aldehydes and active methylenes. The reaction proceeds through a [4 + 1] annulation pathway, which involves a phosphine-catalysed MBH-type reaction followed by a [1,5]-proton shift and dehydration to afford vinyl phosphonium intermediates as four-carbon synthons in the annulation reaction.

Photoinduced Construction of a Benzothienopyridine--dioxide Framework Enabled by Polychloropyridyl Multifunctional Motifs.

Reported herein is a visible-light-induced, catalyst-free intramolecular cyclization of 4-phenylsulfonyl-2,3,5,6-tetrachloropyridine, leading to rapid assembly of a series of unprecedented benzo[4,5]thieno[3,2-]pyridine 5,5-dioxide scaffolds under mild conditions. The rational introduction of a perchloropyridin-4-yl module significantly facilitated this photoinduced process and offers a versatile platform for broad structural variation. Mechanistic studies revealed that a newly identified charge-transfer complex with carbonate is crucial to this photoinduced process.

Visible-Light-Induced, Palladium-Catalyzed 1,4-Difunctionalization of 1,3-Dienes with Bromodifluoroacetamides.

A highly modular 1,4-difunctionalization of 1,3-dienes with bromodifluoroacetamides and sulfinates/amines through a photoinduced palladium-catalyzed radical relay process is described herein. This developed protocol offers a facile and general route to access a variety of value-added CF-incorporated alkenes in moderate to good yields. The versatility and flexibility of this approach have been well illustrated by readily accessible starting materials, synthetic convenience, and wide functional group compatibility.

PKCβII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis.

The accumulation of lipid peroxides is recognized as a determinant of the occurrence of ferroptosis. However, the sensors and amplifying process of lipid peroxidation linked to ferroptosis remain obscure. Here we identify PKCβII as a critical contributor of ferroptosis through independent genome-wide CRISPR-Cas9 and kinase inhibitor library screening.

Electrochemical heterodifunctionalization of α-CF alkenes to access α-trifluoromethyl-β-sulfonyl tertiary alcohols.

An unprecedented electrochemical heterodifunctionalization of α-CF alkenes with benzenesulfonyl hydrazides was accomplished in this work, wherein a β-sulfonyl and a α-hydroxyl group were simultaneously incorporated across the olefinic double bond in a single operation. Consequently, a series of potentially medicinally valuable and densely functionalized α-trifluoromethyl-β-sulfonyl tertiary alcohols were assembled under mild conditions. Electrochemically-driven oxidative 1,2-difunctionlization of electron-deficient alkenes well obviates the need for oxidizing reagents, thus rendering this protocol more eco-friendly.

,,','-Tetramethylethylenediamine-Enabled Photoredox-Catalyzed C-H Methylation of -Heteroarenes.

Aiming at the valuable methylation process, readily available and inexpensive ,,,-tetramethylethylenediamine (TMEDA) was first identified as a new methyl source in photoredox-catalyzed transformation in this work. By virtue of this simple methylating reagent, a facile and practical protocol for the direct C-H methylation of -heteroarenes was developed, featuring mild reaction conditions, broad substrate scope, and scalability. Mechanistic studies disclosed that a sequential photoredox, base-assisted proton shift, fragmentation, and tautomerization process was essentially involved.

Photocatalytic Cyclization/Defluorination Domino Sequence to Access 3-Fluoro-1,5-dihydro-2-pyrrol-2-one Scaffold.

We herein report an unprecedented photoinduced cyclization/defluorination domino process of -allylbromodifluoroacetamide with cyclic secondary amines. Consequently, a wide array of valuable 3-fluoro-1,5-dihydro-2-pyrrol-2-ones were facilely prepared from readily available starting materials under mild conditions. Preliminary mechanistic investigations suggest that a radical chain propagation and amine-promoted defluorination pathway are presumably involved in this transformation.

Associations Between Periosteal Reaction of Proximal Tibial and Medial Compartment Knee Osteoarthritis.

Objective: To evaluate and analyze the potential relationship between periosteal reaction and medial compartment knee osteoarthritis (KOA), and to assess the independent risk factors for the development of periosteal reaction associated with medial compartment KOA.

Methods: This is a retrospective comparative study. From January 2019 to December 2019 at the Third Hospital of Hebei Medical University, a total of 363 patients (726 knees) with medial compartment KOA were enrolled in this study according to our inclusion and exclusion criteria, including 91 males and 272 females, with an mean age of 57.

-Perhalopyridin-4-yl Hydroxylamines: Amidyl-Radical Generation Scaffolds in Photoinduced Direct Amination of Heterocycles.

Reported herein is the design and synthesis of new -perhalopyridin-4-yl hydroxylamines as shelf-stable and versatile amidyl-radical precursors. The novel amination reagents can be easily prepared via a single synthetic step from inexpensive commercially available starting materials using monoprotected HONH as amino source. The synthetic potency of the developed reagents was well demonstrated by direct amination of a series of quinoxalin-2(1)-ones and their analogues under photocatalytic conditions, even without any additive and photocatalysts.

MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis.

The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis.

Arthroscopic evaluation for tibial plateau fractures on the incidence and types of cruciate ligamentous injuries following closed reduction and internal fixation.

Purpose: To evaluate the overall incidence and types of anterior cruciate ligament (ACL) injuries and posterior cruciate ligament (PCL) injuries associated with tibial plateau fractures (TPFs) following closed reduction and internal fixation (CRIF), and to identify the relationship between the incidence and types of cruciate ligamentous injuries with Schatzker classification and "three-column" classification.

Methods: From January 2016 to January 2018, 185 patients with closed TPFs who underwent CRIF were included in this retrospective study. All patients were performed with arthroscopic examination after CRIF, and then, the incidence and types of cruciate ligamentous injuries were recorded and evaluated.

Four new sesquiterpene lactones from Atractylodes macrocephala and their CREB agonistic activities.

One new bisesquiterpenoid, biepiasreorlid II (1), three new sesquiterpene lactones 8α-methoxy-epiasterolid (4), 3β-acetoxyl-8-epiasterolid (5), and 3β-acetoxyl-atractylenolide I (6), along with five known analogues (2-3 and 7-9), were obtained from rhizome of Atractylodes macrocephala Koidz. All structures were assigned on the basis of detailed spectroscopic analyses. The absolute configuration of 1 was established by the analysis of single-crystal X-ray diffraction with Ga Kα radiation, and 4-6 were elucidated by TDDFT-ECD calculations.