Solvent-Dependent C(sp3)-CF3 Reductive Elimination from Neutral Four-Coordinate Cu(III) Complexes.

A solvent dependent C(sp3)-CF3 bond-forming reductive elimination from neutral four-coordinate Cu(III) complexes [(L)Cu(CF3)2(CH2CO2tBu)] (L = pyridine or its derivatives) is described. Reactions in less polar solvent ClCH2CH2Cl proceed via a concerted bond breaking/bond forming process along with the reorientation of the ligand, while reaction in polar solvent DMF occurs via a rate limiting ligand-dissociation, followed by C(sp3)-CF3 reductive elimination from the resulting three-coordinate intermediate. These mechanistic proposals are supported by kinetic studies that included ligand and temperature effects, as well as DFT calculations.

BrCFCN for photocatalytic cyanodifluoromethylation.

Considering the unique electronic properties of the CF and the CN groups, the CFCN group has significant potential in drug and agrochemical development, as well as material sciences. However, incorporating a CFCN group remains a considerable challenge. In this work, we disclose a use of bromodifluoroacetonitrile (BrCFCN), a cost-effective and readily available reagent, as a radical source for cyanodifluoromethylation of alkyl alkenes, aryl alkenes, alkynes, and (hetero)arenes under photocatalytic conditions.

Chemodivergent, enantio- and regioselective couplings of alkynes, aldehydes and silanes enabled by nickel/N-heterocyclic carbene catalysis.

Divergent synthesis of valuable molecules through common starting materials and metal catalysis represents a longstanding challenge and a significant research goal. We here describe chemodivergent, highly enantio- and regioselective nickel-catalyzed reductive and dehydrogenative coupling reactions of alkynes, aldehydes, and silanes. A single chiral Ni-based catalyst is leveraged to directly prepare three distinct enantioenriched products (silyl-protected trisubstituted chiral allylic alcohols, oxasilacyclopentenes, and silicon-stereogenic oxasilacyclopentenes) in a single chemical operation.

LncRNAs chaperoning dynamic protein condensates in cancer cells.

In this issue of Molecular Cell, Sun et al. reveal that the long non-coding RNA (lncRNA) DNAJC3-AS1 plays a dual role in maintaining the rRNA processing function of fibrillarin (FBL) in cancer cells. It promotes FBL condensation while preventing abnormal aggregation, offering new therapeutic insights for cancer treatment by targeting lncRNAs involved in the regulation of FBL condensation.

Yatakemycin biosynthesis requires two deoxyribonucleases for toxin self-resistance.

The highly active natural product yatakemycin (YTM) from sp. TP-A0356 is a potent DNA damaging agent with antimicrobial and antitumor properties. The YTM biosynthesis gene cluster () contains several toxin self-resistance genes.

Stereoselective chemical N-glycoconjugation of amines via CO incorporation.

Chemical N-glycoconjugation can provide a unique way to tailor the properties of the ubiquitous amines for further expending their diverse functions and applications. Nevertheless, effective methodology for glycoconjugation of amines remains largely underdeveloped. Inspired by a biotransformation pathway of amine-containing drugs in vivo, we have developed an effective protocol that enables one-step chemical N-glycoconjugation of amines in high stereoselectivity under mild conditions.

Ligand-enabled Ni-catalysed dicarbofunctionalisation of alkenes with diverse native functional groups.

The transition metal-catalysed dicarbofunctionalisation of unactivated alkenes normally requires exogenous strong coordinated directing groups, thus reducing the overall reaction efficiency. Here, we report a ligand-enabled Ni(II)-catalysed dicarbofunctionalisation of unactivated alkenes with aryl/alkenyl boronic acids and alkyl halides as the coupling partners with a diverse range of native functional groups as the directing group. This dicarbofunctionalisation protocol provides an efficient and direct route towards vicinal 1,2-disubstituted alkanes using primary, secondary, tertiary amides, sulfonamides, as well as secondary and tertiary amines under redox-neutral conditions that are challenging to access through conventional methods.

Photochemical 1,3-boronate rearrangement enables three-component N-alkylation for α-tertiary hydroxybenzylamine synthesis.

Hydroxybenzylamines are prevalent in drugs and bioactive molecules, including various antimalarial and anticancer drugs. α-tertiary alkylation of amines impacts drug-target interactions significantly through their influence on basicity and lipophilicity. Traditional N-alkylation methods, especially for α-tertiary amines, suffer from limitations due to high energy barriers from steric hindrance.

A biomimetic phosphor that can build a rigid microenvironment for its long-lived afterglow in aqueous medium.

Organic phosphorescent materials have great prospects for application, whose performance particularly depends on the preparation method. Inspired by nature's wisdom, we report a phosphor that can utilize monomers in its environment by polymerization to construct a rigid microenvironment under light illumination, leading to a glow-in-the-dark emulsion with a phosphorescence lifetime of 1 s in water. This phosphor can achieve active growth of the aqueous emulsion with the introduction of more monomers.

Emerging roles of palmitoylation in pyroptosis.

Pyroptosis is a lytic, proinflammatory type of programmed cell death crucial for the immune response to pathogen infections and internal danger signals. Gasdermin D (GSDMD) acts as the pore-forming protein in pyroptosis following inflammasome activation. While recent research has improved our understanding of pyroptosis activation and execution, many aspects regarding the molecular mechanisms controlling inflammasome and GSDMD activation remain to be elucidated.

Discovery of the first selective and potent PROTAC degrader for the pseudokinase TRIB2.

Pseudokinase TRIB2, a member of the CAMK Ser/Thr protein kinase family, regulates various cellular processes through phosphorylation-independent mechanisms. Dysregulation of TRIB2 has been implicated in promoting tumor growth, metastasis, and therapy resistance, making it a promising target for cancer treatment. In this study, we designed and synthesized a series of TRIB2 PROTAC degraders by conjugating a TRIB2 binder 1 with VHL or CRBN ligands via linkers of varying lengths and compositions.

Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression.

It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death.

The crucial quality marker of Panax ginseng: Glycosylated modified ribonuclease-like storage protein.

Panax ginseng C.A.Mey is a famous natural herbal medicine worldwide.

Selective monodeuteration enabled by bisphosphonium catalyzed ring opening processes.

The selective incorporation of a deuterium atom into small molecules with high selectivity is highly valuable for medical and chemical research. Unfortunately, this remains challenging due to the complete deuteration caused by commonly used hydrogen isotope exchange strategies. We report the development of a photocatalytic selective monodeuteration protocol utilizing C-C bond as the unconventional functional handle.

Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway.

Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear.

Molecular Basis of the Recognition of the Active Rab8a by Optineurin.

Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism.

Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition.

Cyclin-dependent kinases 12/13 play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Biallelic CDK12 loss has been documented in various malignancies. Here, we develop a selective CDK12/13 PROTAC degrader, YJ9069, which effectively inhibits proliferation in subsets of prostate cancer cells preferentially over benign immortalized cells.

Electrochemical deconstruction of alkyl substituted boron clusters to produce alkyl boronate esters.

-Hexaborate (-BH) can engage in nucleophilic substitution reactions with a wide variety of alkyl electrophiles. The resulting functionalized boron clusters undergo oxidative electrochemical deconstruction, selectively cleaving B-B bonds while preserving B-C bonds in these species. This approach allows the conversion of multinuclear boron clusters into single boron site organoboranes.