Molecular chirality is a cornerstone of modern chemistry and it has a profound impact on biological activity, chemical reactivity and physical property. Developing asymmetric synthesis methods to efficiently and precisely produce chiral molecules remains a challenging issue in organic chemistry. In recent years, transition-metal-catalyzed enantioselective C-H activation has emerged as an efficient strategy for the rapid access to valuable chiral compounds from readily available feedstocks in an atom- and step-economic manner. Here we report a rhodium(III)-catalyzed C-H activation/annulation of ketones with alkynes. This method features mild conditions, wide substrate scope, and perfect atom economy, affording a series of chiral tertiary indenols in excellent yields and enantioselectivity (up to 98% yield and 99% ee). Combined experimental and computational studies revealed the turnover-limiting step of the reaction and the origins of enantioselectivity and regioselectivity.

Organofluorine compounds, owing to their unique physicochemical properties, play an increasingly crucial role in fields such as medicine, pesticides, and advanced materials. Fluorinated reagents are indispensable for developing efficient synthetic methods for organofluorine compounds and serve as the cornerstone of organofluorine chemistry. Equally important are fluorinated functional molecules, which contribute specific properties necessary for applications in pharmaceuticals, agrochemicals, and materials science. However, information about these agents' structure, properties, and functions is scattered throughout vast literature, making it inconvenient for synthetic chemists to access and utilize them effectively. Recognizing the need for a dedicated and organized resource, we present FluoBase-a comprehensive fluorinated agents database designed to streamline access to key information about fluorinated agents. FluoBase aims to become the premier resource for information related to fluorine chemistry, serving the scientific community and anyone interested in the applications of fluorine chemistry and machine learning for property predictions. FluoBase is freely available at https://fluobase.siochemdb.com.

Recently, researchers have been committed to boosting the environmental friendliness and functional performance of multifunctional additives. In this study, an eco-friendly methylbenzotriazole-amide derivative (MeBz-2-C18) was designed and synthesized, with ethylamine serving as the linkage between methylbenzotriazole and the oleoyl chain. The structure of MeBz-2-C18 was characterized by nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HR-MS), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). Subsequently, the storage stability and tribological behavior of MeBz-2-C18 and the commercial benzotriazole oleamide salt (T406) were comparatively evaluated. The covalently-bonded MeBz-2-C18 exhibits superior thermal stability, along with boosted storage stability and tribological performance in the synthetic base oil. Specifically, 0.5 wt.% addition of MeBz-2-C18 and T406 can reduce the average wear scar diameter (ave. WSD) by 21.6% and 13.9%, respectively. To further explore the micro-mechanism, the electrostatic potential (ESP) and worn surfaces were analyzed with scanning electron microscope-energy dispersive spectrometer (SEM-EDS), X-ray photoelectron spectroscopy (XPS), and density functional theory (DFT) calculations. The results show that MeBz-2-C18 possesses stronger adsorption on the metal surface, and its amide bond preferentially breaks during friction. This reduces the interfacial shear force and promotes the film formation of iron oxides, thus resulting in superior tribological performance.

While synthesizing circular polymers with telechelic polyolefin building blocks recently emerged as a promising strategy for addressing conventional polyethylenes' sustainability challenges, the lack of telechelic iPP (tPP) with sufficient difunctional purity for polycondensation has been limiting the development of circular polypropylenes with iPP-like structures and properties. Here we described a combined approach of coordinative chain transfer polymerization and transition-metal-catalyzed quenching reaction with various acyl chlorides, affording tPPs with a high difunctional ratio (up to similar to 99%) and broad end functional group scope. The steric effect of polymeryl-Zn species and the role of Pd catalyst were revealed by DFT. This method also solved the low difunctional ratio challenge for telechelic polyethylenes. Ester-linked iPPs with iPP-like structure and thermomechanical properties and PE/iPP multiblock copolymers were synthesized by the resulting tPPs.

ROR1 has been identified as a pseudokinase, functioning as an allosteric regulator in tumor progression. Aberrant overexpression of ROR1 has been observed in various malignancies, highlighting its potential as therapeutic target for cancer therapy. Modulation of ROR1 by proteolysis targeting chimera degrader instead of traditional inhibitor could offer great efficiency in blocking its kinase-independent regulatory function. Here, we report the first potent ROR1 degraders constructed by connecting the E3 ligand to a ROR1 binder. One representative compound 11d exhibited remarkable efficacy in depleting ROR1 protein with a DC50 value of 40.88 nM and Dmax of 93.7 %. Mechanistic investigations illuminated that compound 11d triggers ROR1 protein degradation in a ubiquitin proteasome system (UPS)-dependent manner. Additionally, compound 11d displayed a significantly enhanced ability to inhibit ROR1 signaling, induce apoptosis, and suppress proliferation in lung cell lines compared to the warhead ROR1 binder. These findings underscore the substantial potential of ROR1 degrader for the treatment of non-small cell lung cancer (NSCLC) cells.

Proto-oncogene RET is overexpressed in many cancers, and its expression level is positively related to the size and malignancy of the tumors. Effective inhibition of its overexpression can be used to potentially treat cancers. A guanine-rich GC-boxes (I-V) sequence in its promoter region folds into noncanonical G-quadruplex (G4) DNA structures, negatively regulating its expression by interactions with small molecules. Previously, we reported that RET20T in GC-boxes II-V formed parallel G4 only at low concentrations of K+ solutions, and that RET-21mer in GC-boxes I-IV folded into different mixed parallel / antiparallel G4s in 50 mM K+ or 100 mM Na+ solutions. These data implied high complexity in producing G4 topology by cation type. Here, mainly by nuclear magnetic resonance (NMR), we demonstrated that RET20T formed slightly different, but rarely reported inter-convertible mixed parallel / antiparallel G4s dependent on Na+ concentration. Unclassical base-pairs G3 center dot G6 and G14 center dot T20 and ternary plane G3 center dot C5 center dot G6 stabilized these two RET20T G4 structures. These structural evidences enhanced our understanding that generation of a unimolecular G4 structure could be significantly affected by cation concentration and type in buffer, and the oligo sequence. Conformational switch of G4s should be noted before anticancer drug screening in future.

Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson's disease (PD), alpha-synuclein (alpha-syn), as an example of protein aggregates, we find that aspirin is able to reduce alpha-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the alpha-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

Background: Depression is a widely recognized neuropsychiatric disorder. Recent studies have shown a potential correlation between bile acid disorders and depression, highlighting the importance of maintaining bile acid balance for effective antidepressant treatment. Schisandrol B (SolB), a primary bioactive compound from Schisandra chinensis (Turcz.) Baill. or Schisandra sphenanthera Rehd.etWils, is pivotal in regulating bile acid homeostasis via pregnane X receptor (PXR) in cholestasis. However, the potential of SolB in alleviating depression-like symptoms, its pharmacological effects, and the underlying mechanisms remain to be fully elucidated. Methods: We confirmed the effect of SolB against depression induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS) in mice. The role of SolB in bile acid homeostasis in depression was analyzed using the metabolomic. Gene analyses and 16S rRNA sequencing were employed to investigate the involvement of PXR. Experiments with Pxr- /- mice were conducted to confirm the essential role of the PXR pathway in SolB's antidepressant effects. Results: SolB treatment significantly increased sucrose consumption in the SPT and the locomotor activity in the OFT, while decreasing immobility time in the FST and TST in mice exposed to CRS and CUMS. Additionally, SolB treatment significantly preserved the integrity of the dendritic spine, elevated synaptic protein PSD95 levels, and augmented CREB/BDNF expression. Metabolomic and gene analyses indicated that SolB treatment significantly facilitated bile acid metabolism, promoted intestinal bile acid efflux, decreased hippocampal levels of the secondary bile acids DCA and TLCA, and upregulated expression of the PXR target proteins CYP3A11, SULT2A1, MRP2, and OATP1B1 in the liver, and MRP2 and MDR1 in hippocampus, which are integral to bile acid homeostasis. 16S rRNA sequencing revealed that SolB reduced the abundance of the bile salt hydrolase (BSH)producing bacteria Lactobacillus johnsonii and Bacteroides fragilis and subsequently decreased the production of TLCA and DCA. Moreover, SolB failed to protect against depression induced by CRS in Pxr-null mice, suggesting that the antidepressant effect of SolB was PXR-dependent. Conclusions: These results provide direct evidence of the antidepressant effect of SolB via activation of PXR to regulate bile acid homeostasis in the brain-liver-gut axis, suggesting that SolB may serve as a novel potential target for preventing and treating depression.