The development of a series of shelf-stable monofluoroalkylated sulfonium ylide reagents and their reactions with a variety of O-nucleophiles including phenols, sulfonic acids, carboxylic acids, 1-hydroxy-benzotrizoles, amino acids was described. In general, monofluoroakylated sulfonium ylides were synthesized in three steps from commercially available starting materials including thiophenols, alkyl halides and dimethyl 2-diazomalonate. Reactions with the O-nucleophiles occurred under mild conditions and afforded the corresponding monofluoroalkylated ethers, sulfonates, and esters in good to excellent yields, thus providing a robust approach for the preparation of these compounds. Further expansion of monofluoroalkylation of C-terminus of peptides potentially provided modified drug-like peptides.

Rubriflordilactone B is a Schisandra bisnortriterpenoid with a unique 5/5/7/6/5/5-hexacyclic framework that includes a characteristic tetrasubstituted aromatic ring. Herein, we report a convergent, enantioselective total synthesis of this natural product by a bioinspired skeletal reorganization approach. Key transformations include a chelation-controlled [2,3]-Wittig-Still rearrangement to assemble the western cyclohexenyl fragment with complete diastereocontrol, a Cu(II)-catalyzed tandem acyloin acylation-Wittig olefin to build the eastern butanolide fragment, a Friedel-Crafts cyclization to construct the seven-membered ring, and an E1cB reaction/transesterification/oxa-Michael addition cascade to forge the pivotal 5/5-fused bicyclic lactone. This work vividly demonstrates that bioinspired skeletal reorganization is a useful strategy for simplifying the retrosynthetic analysis of structurally complex natural products.

Selectivity control of the reactions of propargylic and/or allenylic radicals remains particularly elusive. Here, a visible light-mediated Cu-catalyzed protocol for the highly selective syntheses of tri- and tetra-substituted allenols from alkynol derivatives has been developed. The synthetic potential of the products has been demonstrated. The control experiments, Stern-Volmer quenching, and cyclic voltammetry studies support a reaction pathway involving the generation of allenyl radicals via photo-mediated N-O bond scission, an intramolecular 1,5-HAT process, the resonance to propargylic radicals, and coupling. A non-common intramolecular 1,6-HAT process has also been observed.

CuI/6-hydroxy picolinohydrazide-catalyzed coupling of (hetero)aryl chlorides with anilines proceeded well at 100 degrees C to afford biaryl amines in a diverse manner, which represents the first example of Cu-catalyzed biaryl amines under milder conditions. The same catalytic system could make the coupling of (hetero)aryl bromides with anilines work at room temperature, giving the corresponding products with an excellent reaction scope.

The di-ferrous [2Fe-2S]0 state is the least understood oxidation level of the [2Fe-2S] unit, which is the smallest module of iron-sulfur clusters in enzymes. Reported synthetic models of the [2Fe-2S]0 state utilize bulky anionic ligands to achieve their stabilization, and their highly reducing nature renders detailed structural and spectroscopic studies difficult. Herein, we report the stabilization of the di-ferrous [2Fe-2S]0 state by using N-heterocyclic carbene (NHC) moieties as supporting ligands. The charge-neutral cluster [Fe2(mu-S)2(ICy)4] (1, ICy = 1,3-bis-cyclohexyl-imidazol-2-ylidene) is synthesized from the reaction of the iron(0) precursor [(ICy)2Fe(eta 2-CH2 00000000 00000000 00000000 00000000 11111111 00000000 11111111 00000000 00000000 00000000 CHSiMe3)] with SPPh3. The attenuated reducing power of 1 as compared to those clusters supported by anionic ligands allows its isolation in pure form. Further spectroscopic and theoretical studies established its S = 0 ground state resulting from anti-ferromagnetic coupling of two high-spin ferrous sites with an exchange-coupling constant J = -208 cm-1. The NHC ligand is also capable of stabilizing the mixed-valent complex [Fe2(mu-S)2(ICy)4][BPh4] (2), which is synthesized from the reaction of 1 with [Cp2Fe][BPh4] and identified as a Robin-Day Class II complex with an S = 1/2 ground state.

While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC50 value of 2.8 nM, and was much less active against BaF3-FGFR1 and parental BaF3 cells with IC50 values of >1000 nM. Kinase selectivity profiling revealed that BW710 completely abolished FGFR2 enzymatic activity and was selective against other 75 tyrosine kinases including FGFR1, FGFR3, and FGFR4 at 1 mu M. The covalent binding mode between BW710 and FGFR2 was confirmed by MS spectrometry. Further evaluation showed that BW710 potently suppressed the FGFR2 signaling and selectively inhibited FGFR2-driven cancer cell proliferation. Additionally, BW710 also displayed reasonable pharmacokinetic properties with an oral bioavailability of 29 % in mice. Taken together, this study provides a potent, selective and orally bioavailable FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.

Molecules containing fluoroalkyl and arylthio groups play a pivotal role in pharmaceutical and agrochemical development. The simultaneous introduction of these functional groups through the 1,2-difunctionalization of alkenes is an efficient strategy. Fluoroalkyl phenyl sulfones serve as accessible fluoroalkyl radical precursors; however, their tendency to interact with thiophenol via the electron donor-acceptor interaction mechanism can impede the desired transformation. Through meticulous selection of solvent and base, we successfully utilized copper catalysis to facilitate an alkene-involved three-component reaction. Our work unveils a photoredox copper-catalyzed fluoroalkylation-thiolation of alkenes using various fluoroalkyl phenyl sulfones (such as perfluoroethyl, tetrafluoroethyl, trifluoromethyl, difluoromethyl, difluoroalkyl, and difluorobenzyl). The efficacy of this approach is exemplified by the synthesis of Kengreal derivatives.

Tree shrews (TSs) possess a highly developed visual system. Here, we establish an age-related single-cell RNA sequencing atlas of retina cells from 15 TSs, covering 6 major retina cell classes and 3 glial cell types. An age effect is observed on the cell subset composition and gene expression pattern. We then verify the cell subtypes and identify specific markers in the TS retina including CA10 for bipolar cells, MEGF11 for H1 horizontal cells, and SLIT2, RUNX1, FOXP2, and SPP1 for retinal ganglion cell subpopulations. The cross-species analysis elucidates the cell type-specific transcriptional programs, different cell compositions, and cell communications. The comparisons also reveal that TS cones and subclasses of bipolar and amacrine cells exhibit the closest relationship with humans and macaques. Our results suggests that TS could be used as a better disease model to understand age-dependent cellular and genetic mechanisms of the retina, particularly for the retinal diseases associated with cones.

BACKGROUND: Heart failure (HF), which is the terminal stage of many cardiovascular diseases, is associated with low survival rates and a severe financial burden. The mechanisms, especially the molecular mechanism combined with new theories, underlying the pathogenesis of HF remain elusive. We demonstrate that phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 (hematopoietic progenitor kinase 1-interacting protein of 55 kDa) protects against HF. METHODS: Fluorescence recovery after photobleaching assay, differential interference contrast analysis, pull-down assay, immunofluorescence, and immunohistochemical analysis were used to investigate the liquid-liquid phase separation capacity of HIP-55 and its dynamic regulation in vivo and in vitro. Mice with genetic deletion of HIP-55 and mice with cardiac- specific overexpression of HIP-55 were used to examine the role of HIP-55 on beta-adrenergic receptor hyperactivationinduced HF. Mutation analysis and mice with specific phospho-resistant site mutagenesis were used to identify the role of phosphorylation-regulated dynamic liquid-liquid phase separation of HIP-55 in HF. RESULTS: Genetic deletion of HIP-55 aggravated HF, whereas cardiac-specific overexpression of HIP-55 significantly alleviated HF in vivo. HIP-55 possesses a strong capacity for phase separation. Phase separation of HIP-55 is dynamically regulated by AKT-mediated phosphorylation at S269 and T291 sites, failure of which leads to impairment of HIP-55 dynamic phase separation by formation of abnormal aggregation. Prolonged sympathetic hyperactivation stress induced decreased phosphorylation of HIP-55 S269 and T291, dysregulated phase separation, and subsequent aggregate formation of HIP55. Moreover, we demonstrated the important role of dynamic phase separation of HIP-55 in inhibiting hyperactivation of the beta-adrenergic receptor-mediated P38/MAPK (mitogen-activated protein kinase) signaling pathway. A phosphorylation-deficient HIP-55 mutation, which undergoes massive phase separation and forms insoluble aggregates, loses the protective activity against HF. CONCLUSIONS: Our work reveals that the phosphorylation-regulated dynamic phase separation of HIP-55 protects against sympathetic/adrenergic system-mediated heart failure.