Structure-guided design and photochemical synthesis of new carbamo(dithioperoxo)thioates with improved potencies to SARS-CoV-2 3CL.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered a protracted global pandemic from 2019 to 2022, and posed a significant threat to human health. One of the non-structural proteins 3CL of SARS-CoV-2 is considered as a validated target for the development of inhibitors against the virus. Disulfiram has been reported as a covalent inhibitor of 3CL; however, its structure lacks bonding site with active pockets of 3CL and its highly symmetric structure doesn't match well with the irregular cavity of the active center, limiting its therapeutic applications.

Radical Alkynylthiolation with Visible-Light-Sensitive -Alkynylthio Sulfonates.

A novel kind of -alkynylthio sulfonate, which can be directly activated under visible-light irradiation, has been developed for the radical addition of multiple bond systems and radical coupling with diazonium salts under photocatalyst-free conditions. This strategy features a broad substrate scope, high regioselectivity, excellent tolerance of functional groups, and the late-stage modification of drugs. Experimental and theoretical mechanistic investigations gave reasonable insight into the photolysis of -alkynylthio sulfonates and C-S bond formation.

-Vinylthio Phthalimides (-VTPs): Modular Reagents for Vinylthio AIEgen Transfer.

Novel sulfur reagents -vinylthio phthalimides (-VTPs) have been employed as modular reagents for vinylthiolation, enabling the construction of aggregation-induced emission (AIE)-active tetraaryldivinyl sulfides (TADVSs) and diarylvinyl sulfides (DAVSs). Notably, TADVSs with sulfur insertion to ethene stators are reported as AIE luminogens (AIEgens) for the first time, and the corresponding photophysical properties and aggregated confirmation have been detailed for the demonstration of the AIE effect. A water-soluble TADVS with a quinolinium salt was prepared for cell imaging.

Hydroxyphenylpyruvate Dioxygenase Is a Metabolic Immune Checkpoint for UTX-deficient Colorectal Cancer.

Background & Aims: Aberrant epigenetic events mediated by histone methyltransferases and demethylases contribute to malignant progression of colorectal cancer (CRC). However, the role of the histone demethylase ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) in CRC remains poorly understood.

Methods: UTX conditional knockout mice and UTX-silenced MC38 cells were used to investigate UTX function in tumorigenesis and development of CRC.

Optimization of the expression of the main protease from SARS-CoV-2.

The main protease (M) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) plays a vital role in viral replication. To study the function of M and screen inhibitors targeting M, it is necessary to prepare high-purity and high-activity M. In this study, four types of SARS-CoV-2 Ms containing different termini were prepared, and their activities were determined successfully.

Divergent Synthesis of Fluorinated Alkenes, Allenes, and Enynes via Reaction of 2-Trifluoromethyl-1,3-enynes with Carbon Nucleophiles.

Herein, inorganic base KPO promoted divergent synthesis of CF-substituted allenes, cyclopentenes, alkynes, and fluorinated enynes via regioselective nucleophilic addition of carbon nucleophiles to 2-trifluoromethyl-1,3-enynes was developed. With the choice of different carbon nucleophiles, various fluorinated compounds could be obtained under KPO/DMF reaction system. When malononitriles were used as nucleophiles, CF-substituted allenes, cyclopentenes, and alkynes could be obtained, respectively.

Homocouplings of Sodium Arenesulfinates: Selective Access to Symmetric Diaryl Sulfides and Diaryl Disulfides.

Symmetrical diaryl sulfides and diaryl disulfides have been efficiently and selectively constructed via the homocoupling of sodium arenesulfinates. The selectivity of products relied on the different reaction systems: symmetrical diaryl sulfides were predominately obtained under the Pd(OAc) catalysis, whereas symmetrical diaryl sulfides were exclusively yielded in the presence of the reductive Fe/HCl system.

-Thiohydroxy Succinimide Esters (NTSEs): Versatile Reagents for Selective Acyl and Acylthio Transfer.

Differentiation between similarly reactive sites in molecules represents an ongoing challenge of organic synthesis. Herein we described one kind of versatile reagents, -thiohydroxy succinimide esters (NTSEs), serving as both acyl and acylthio surrogates for the diverse synthesis of ketones, thioesters, amides, and acyl disulfides by selective cleavage of similarly reactive C-S and N-S bonds.

3,4-Bisthiolated Pyrroles: Concise Construction and Their Electronic Properties.

3,4-Bisthiolated pyrroles constitute key cores in pyrrole-based semiconductors, and their electronic properties could be improved by the bisthio groups via the -effect. Herein, a convenient method for the synthesis of 3,4-bisthiolated pyrroles has been developed through the AlCl-catalyzed thiolation/cyclization of homopropargylic azides, and cyclic voltammetry and DFT calculations indicated that the desired 3,4-bisthiolated pyrroles had higher HOMO orbital energies and lower band gaps than the parent unsubstituted 2,5-diphenylpyrrole.

3-Thiolated pyrroles/pyrrolines: controllable synthesis and usage for the construction of thiolated fluorophores.

Thiolation/cyclization of homopropargylic tosylamides allowed the selective synthesis of 3-thiolated pyrroles and pyrrolines controlled by solvents. Moreover, the desired 3-thiolated pyrroles were readily transformed to organic fluorophores benzothienopyrrole and bisthiolated boron dipyrromethene (S-BODIPY).

Rh(I)-Catalyzed Carbene Migration/Carbonylation/Cyclization: Straightforward Construction of Fully Substituted Aryne Precursors.

The Rh(I)-catalyzed cascade formation of carbenoid followed by a carbonylative cyclization of silyl diynes has been established to achieve diverse silyl-substituted phenolics, enabling access to fully substituted aryne precursors via a one-step fluorosulfurylation. The silyl mask on the termini of alkynes is demonstrated not only to suppress the undesired oxidation but also to control the selectivity of CO insertion. Straightforward access to fully substituted arynes was comprehensively established and applied for the efficient construction of polycyclic aromatic molecules.

Chemo- and Diastereoselective Synthesis of Pyrrolidines from Aroylformates and δ-Tosylamino Enones via P(NMe)-Mediated Reductive Amination/Base-Catalyzed Michael Addition Cascade.

A novel P(NMe)-mediated tandem (1 + 4) annulation between aroylformates and δ-tosylamino enones has been developed that affords a facile synthesis of functionalized pyrrolidines in moderate to excellent yields with exclusive chemoselectivity and high diastereoselectivity. Mechanistic investigation reveals that the reaction proceeds through an unprecedented P(NMe)-mediated reductive amination/base-catalyzed Michael addition cascade. The reaction herein also represents the first study of the reactivity patterns of the Kukhtin-Ramirez adducts toward ambiphilic nucleophile-electrophiles.

Steric and stereoscopic disulfide construction for cross-linkage -dithiophthalimides.

Disulfide bonds are a significant motif in life and drug-delivery systems. In particular, steric hindrance and stereoscopic disulfide linkers are closely associated with the stability of antibody-drug conjugates, which affects the potency, selectivity, and pharmacokinetics of drugs. However, limited availability and diversity of tertiary thiols impede the construction of steric and stereoscopic disulfides for cross-linkage in biochemistry and pharmaceuticals.

Synthesis of 4-chalcogenyl pyrazoles via electrophilic chalcogenation/cyclization of α,β-alkynic hydrazones.

A facile method for the synthesis of 4-chalcogenylated pyrazoles has been developed via electrophilic chalcogenation/cyclization of α,β-alkynic hydrazones. The cyclization of α,β-alkynic aldehyde hydrazones could be induced by using either sulfenyl chloride or the S-electrophiles generated in situ from the reaction of NCS and arythiol. The developed method was successfully applied to the synthesis of the sulfenyl analogue of celecoxib.

Targeting oxidative pentose phosphate pathway prevents recurrence in mutant Kras colorectal carcinomas.

Recurrent tumors originate from cancer stem cells (CSCs) that survive conventional treatments. CSCs consist of heterogeneous subpopulations that display distinct sensitivity to anticancer drugs. Such a heterogeneity presents a significant challenge in preventing tumor recurrence.

-Alkynylthio Phthalimide: A Shelf-Stable Alkynylthio Transfer Reagent for the Synthesis of Alkynyl Thioethers.

A new kind of electrophilic alkynylthiolating reagent, called -alkynylthio phthalimide, is designed and synthesized herein. This electrophilic sulfenylating reagent can be easily prepared in three steps from commercially available phthalimide and corresponding silver acetylide. Furthermore, the -alkynylthio phthalimides are demonstrated to be efficient alkynylthio transfer reagents that can react with various C-nucleophiles, including β-ketoesters, aryl boronic acids, and Grignard reagents to afford a diverse range of alkynyl thioethers under mild conditions.

Nickel-catalyzed borrowing hydrogen annulations: access to diversified N-heterocycles.

Herein, we report an efficient nickel-catalyzed direct cyclization of amines with alcohols for the synthesis of various nitrogen containing heterocycles. These processes employ the sustainable "borrowing hydrogen" strategy and have many advantages, such as earth-abundant metal catalysts, easily available starting materials, wide synthetic versatility and harmless waste emission.

Glutamate Decarboxylase 65 Signals through the Androgen Receptor to Promote Castration Resistance in Prostate Cancer.

The transition from an androgen-dependent to a castration-resistant state is a critical event in the progression of prostate cancer. In this study, we compared metabolic pathways between isogenic human androgen-dependent and castration-resistant prostate cancer (CRPC) patient-derived xenograft models, and found consistent activation of the γ-aminobutyric acid (GABA) shunt in CRPC. This difference was the result of phosphorylation and activation of glutamate decarboxylase 65 (GAD65), which synthesizes GABA from glutamate by decarboxylation.

Synthesis of 4-Sulfenyl Isoxazoles through AlCl-Mediated Electrophilic Cyclization and Sulfenylation of 2-Alkyn-1-one O-Methyloximes.

An efficient method for the synthesis of 4-sulfenyl isoxazoles has been developed via AlCl-mediated electrophilic cyclization/sulfenylation of 2-alkyn-1-one O-methyloximes. Remarkably, N-arylsulfanylsuccinimides are employed as electrophiles for the construction of 4-arylsulfanyl isoxazoles, and 4-alkylsulfanyl isoxazoles are accessed with dialkyl disulfides as electrophiles.

Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions.

The asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes was realized in the presence of 10 mol % dinuclear zinc-AzePhenol catalysts under ambient conditions. A variety of nitroamines were obtained in good yields (up to 97%) with excellent enantioselectivities (up to 99% ee) and high diasteroselectivity (up to 14:1 dr). Our protocol combined the operational simplicity and mild reaction conditions, thus making the process amenable for technical applications.

Copper(II)-Catalyzed Four-Component Oxysulfonylation/Diazenylation: Synthesis of α-Arylhydrazo-β-keto Sulfones.

A new and convenient method for one-pot synthesis of α-arylhydrazo-β-keto sulfones is developed via Cu (II)-catalyzed oxysulfonylation/diazenylation of alkenes. This four-component cascade reaction enables a series of α-arylhydrazo-β-keto sulfone derivatives accessed from readily available alkenes, sulfinates, and diazonium salts under aerobic conditions. Furthermore, the 3-sulfonyl cinnolin-4(1 H)-one skeleton is successfully constructed from the corresponding α-arylhydrazo-β-keto sulfone product under basic conditions.

Breast cancer stem cells characterized by CD70 expression preferentially metastasize to the lungs.

Background: Cancer stem cells (CSCs) are believed to form metastases. We sought to determine whether CD70 + subpopulation in human breast cancers represents the CSCs accounting for distant metastasis.

Methods: We measured the expression levels of CD70 in breast cancer cell lines and 122 primary breast cancer samples.

Chemoselective P(NMe)-Mediated Reductive Epoxidation between Two Different Carbonyl Electrophiles: Synthesis of Highly Functionalized Unsymmetrical Epoxides.

Herein, we report a chemoselective P(NMe)-mediated reductive epoxidation of α-dicarbonyl compounds such as isatins, α-keto esters, and α-diketones with aldehydes and ketones, leading to an efficient synthesis of a wide range of highly functionalized unsymmetrical epoxides in moderate to excellent yields and diastereoselectivities. The Kukhtin-Ramirez adduct, which is exclusively generated in situ from an α-dicarbonyl compound and P(NMe), plays a key role in governing the chemoselectivity. It represents the first practical synthesis of unsymmetrical epoxides via direct reductive epoxidation of two different carbonyl electrophiles and also complements the existing methods of generating epoxides.