Radical Decarboxylation-Initiated SH2' Reaction of ß,ß-Difluoroenol Sulfonates: Access to α,α-Difluoroketones.

Reported herein is a novel radical decarboxylation-initiated SH2' reaction of ß,ß-difluoroenol sulfonates. This transformation is characterized by mild reaction conditions, a broad substrate scope, and late-stage modification of drug molecules, providing general and mechanistically distinct access to bioactive and synthetically versatile α,α-difluoroketones. Preliminary mechanistic studies demonstrate that this reaction proceeds through a succession of silver-mediated decarboxylative radical generation and radical-addition-induced ß-elimination of the sulfonyl radical.

Multi-substituted trifluoromethyl alkene construction via gold-catalyzed fluoroarylation of gem-difluoroallenes.

An unprecedented fluoroarylation of 1,1-difluoroallenes with a cost-effective nucleophilic fluoride reagent and aryldiazonium salts is reported. This visible light promoted gold-catalyzed reaction allows a stereo- and regioselective incorporation of both the fluorine atom and aryl group, enabling a straightforward construction of multi-substituted trifluoromethyl alkenes. Under the mild reaction conditions, a nice tolerance of diverse functional groups is achieved. The high regioselectivity for fluorine-incorporation is rationalized by considering the thermodynamic driving force of trifluoromethyl group formation, whereas the counterintuitive stereoselectivity that aryl is installed on the side of the bulkier γ-substituent is interpreted by alleviating the increasing 1,3-allylic interaction in the gold-coordinated allene intermediate en route to the product.

Achieving Strong Circularly Polarized Luminescence through Cascade Cationic Insertion in Lead-free Hybrid Metal Halides.

Generating circularly polarized luminescence (CPL) with simultaneous high photoluminescence quantum yield (PLQY) and dissymmetry factor (glum) is difficult due to usually unmatched electric transition dipole moment (µ) and magnetic transition dipole moment (m) of materials. Herein we tackle this issue by playing a "cascade cationic insertion" trick to achieve strong CPL (with PLQY of ~100 %) in lead-free metal halides with high glum values reaching -2.3×10-2 without using any chiral inducers. Achiral solvents of hydrochloric acid (HCl) and N, N-dimethylformamide (DMF) infiltrate the crystal lattice via asymmetric hydrogen bonding, distorting the perovskite structure to induce the "intrinsic" chirality. Surprisingly, additional insertion of Cs+ cation to substitute partial (CH3)2NH2 + transforms the chiral space group to achiral but the crystal maintains chiroptical activity. Further doping of Sb3+ stimulates strong photoluminescence as a result of self-trapped excitons (STEs) formation without disturbing the crystal framework. The chiral perovskites of indium-antimony chlorides embedded on LEDs chips demonstrate promising potential as CPL emitters. Our work presents rare cases of chiroptical activity of highly luminescent perovskites from only achiral building blocks via spontaneous resolution as a result of symmetry breaking.

Programmable synthesis of difluorinated hydrocarbons from alkenes through a photocatalytic linchpin strategy.

The introduction of difluoromethylene moieties into organic molecules has garnered significant attention due to their profound influence on the physicochemical and biological properties of compounds. Nonetheless, the existing approaches for accessing difluoroalkanes from readily available feedstock chemicals remain limited. In this study, we present an efficient and modular protocol for the synthesis of difluorinated compounds from alkenes, employing the readily accessible reagent, ClCF2SO2Na, as a versatile "difluoromethylene" linchpin. By means of an organophotoredox-catalysed hydrochlorodifluoromethylation of alkenes, followed by a ligated boryl radical-facilitated halogen atom transfer (XAT) process, we have successfully obtained various difluorinated compounds, including gem-difluoroalkanes, gem-difluoroalkenes, difluoromethyl alkanes, and difluoromethyl alkenes, with satisfactory yields. The practical utility of this linchpin strategy has been demonstrated through the successful preparation of CF2-linked derivatives of complex drugs and natural products. This method opens up new avenues for the synthesis of structurally diverse difluorinated hydrocarbons and highlights the utility of ligated boryl radicals in organofluorine chemistry.

Multi-omics analysis reveals BDE47 induces depression-like behaviors in mice by interfering with the 2-arachidonoyl glycerol-associated microbiota-gut-brain axis.

2,2',4,4'-tetrabromodiphenyl ether (BDE47) is a foodborne environmental risk factor for depression, but the pathogenic mechanism has yet to be fully characterized. In this study, we clarified the effect of BDE47 on depression in mice. The abnormal regulation of the microbiome-gut-brain axis is evidenced closely associated with the development of depression. Using RNA sequencing, metabolomics, and 16s rDNA amplicon sequencing, the role of the microbiome-gut-brain axis in depression was also explored. The results showed that BDE47 exposure increased depression-like behaviors in mice but inhibited the learning memory ability of mice. The RNA sequencing analysis showed that BDE47 exposure disrupted dopamine transmission in the brain of mice. Meanwhile, BDE47 exposure reduced protein levels of tyrosine hydroxylase (TH) and dopamine transporter (DAT), activated astrocytes and microglia cells, and increased protein levels of NLRP3, IL-6, IL-1ß, and TNF-α in the brain of mice. The 16 s rDNA sequencing analysis showed that BDE47 exposure disrupted microbiota communities in the intestinal contents of mice, and faecalibaculum was the most increased genus. Moreover, BDE47 exposure increased the levels of IL-6, IL-1ß, and TNF-α in the colon and serum of mice but decreased the levels of tight junction protein ZO-1 and Occludin in the colon and brain of mice. In addition, the metabolomic analysis revealed that BDE47 exposure induced metabolic disorders of arachidonic acid and neurotransmitter 2-Arachidonoyl glycerol (2-AG) was one of the most decreased metabolites. Correlation analysis further revealed gut microbial dysbiosis, particularly faecalibaculum, is associated with altered gut metabolites and serum cytokines in response to BDE47 exposure. Our results suggest that BDE47 might induce depression-like behavior in mice through gut microbial dysbiosis. The mechanism might be associated with the inhibited 2-AG signaling and increased inflammatory signaling in the gut-brain axis.

Prenatal exposure to phthalates and polybrominated diphenyl ethers on neonatal health: A birth cohort study in Guangxi, China.

Few epidemiological studies have focused on prenatal phthalates (PAEs) and polybrominated diphenyl ethers (PBDEs) exposure to neonatal health in China. This study aimed to assess the associations between prenatal PAEs and PBDEs exposure and neonatal health in Guangxi, a Zhuang autonomous region of China. Concentrations of 4 PAEs metabolites (mPAEs) and 5 PBDEs congeners were measured in the serum of 267 healthy pregnant women. Birth outcomes and clinical data of neonates were collected after delivery. Mono-(2-Ethylhexyl) phthalate (MEHP) (81.52%) and BDE47 (35.21%) were the mPAEs and PBDEs congeners with the highest detection rate in serum. Prenatal exposures to mono-n-butyl phthalate (MBP), MEHP, and ΣmPAEs were negatively associated with birth weight (BW), birth length (BL), and gestational age (GA). Higher exposures to MBP, MEHP, and ΣmPAEs were associated with an increased odds ratio (OR) for low birth weight (LBW), but exposure to BDE28 exhibited the opposite effect. Moreover, higher exposures to MBP, MEHP, ΣmPAEs, BDE99, and ΣPBDEswere associated with an increased OR for premature birth (PTB) (P < 0.05). In contrast to MBP exposure, BDE28 exposure was associated with a higher OR for neonatal jaundice (NNJ) (P < 0.05). The interaction analysis showed a positive interaction between monoethyl phthalate (MEP) and BDE28 on the risk of NNJ and positive interaction between ΣmPAEs and BDE47 on the risk of NNJ. In addition, there are ethnicity-specific associations of prenatal PBDEs exposure with neonatal health in individuals of Zhuang and Han nationalities, and boy neonates were more sensitive to prenatal PBDEs exposure than girl neonates. The results revealed that prenatal exposure to mPAEs and PBDEs might have adverse effects on neonatal development, and the effects might be ethnicity- and sex-specific.

Difluoromethylation of Unactivated Alkenes Using Freon-22 through Tertiary Amine-Borane-Triggered Halogen Atom Transfer.

The application of abundant and inexpensive fluorine feedstock sources to synthesize fluorinated compounds is an appealing yet underexplored strategy. Here, we report a photocatalytic radical hydrodifluoromethylation of unactivated alkenes with an inexpensive industrial chemical, chlorodifluoromethane (ClCF2H, Freon-22). This protocol is realized by merging tertiary amine-ligated boryl radical-induced halogen atom transfer (XAT) with organophotoredox catalysis under blue light irradiation. A broad scope of readily accessible alkenes featuring a variety of functional groups and drug and natural product moieties could be selectively difluoromethylated with good efficiency in a metal-free manner. Combined experimental and computational studies suggest that the key XAT process of ClCF2H is both thermodynamically and kinetically favored over the hydrogen atom transfer pathway owing to the formation of a strong boron-chlorine (B-Cl) bond and the low-lying antibonding orbital of the carbon-chlorine (C-Cl) bond.

Ethyl acetate extract of Caesalpinia sappan L. inhibited acute myeloid leukemia via ROS-mediated apoptosis and differentiation.

BACKGROUND: The dried heartwood of Caesalpinia sappan L. is traditionally prescribed in the formula of traditional Chinese medicine (TCM) for the treatment of acute myeloid leukemia (AML), while nothing is yet known of the active fractions and the underlying mechanisms. PURPOSE: This study aims to investigate the effect of the ethyl acetate extract of the dried heartwood of Caesalpinia sappan L. (C-A-E) on induction of apoptosis and promotion of differentiation in vitro and anti-AML activity in vivo. STUDY DESIGN/METHODS: The aqueous extract was sequentially separated with solvents of increasing polarity and the active fraction was determined through the inhibition potency. The inhibition of the active fraction on cell viability, proliferation and colony formation was performed in different AML cells. Induction of apoptosis and the promotion of differentiation were further determined. Then, the level of the reactive oxygen species (ROS) and its potential role were assessed. Finally, anti-AML activity was evaluated in NOD/SCID mice. RESULTS: C-A-E exhibited the highest inhibition on the cell viability of HL-60 cells. Meanwhile, C-A-E significantly suppressed the proliferation and the colony formation ability of HL-60 and Kasumi-1 cells. Moreover, C-A-E significantly induced the apoptosis, which was partially reversed by Z-VAD-FMK. C-A-E also reduced the level of mitochondrial membrane potential, promoted the release of cytochrome C, decreased the Bcl-2/Bax ratio, and promoted the cleavage of caspase-9 and -3. In addition, Mdivi-1 (mitochondrial fission blocker) remarkably reduced the apoptosis caused by C-A-E. Meanwhile, C-A-E also induced the expression of Mff and Fis1 and increased the location of Drp1 in mitochondria. Furthermore, C-A-E obviously promoted the differentiation of AML cells characterized by the typic morphological changes, the increased NBT positive cells, as well as the increased CD11b and CD14 levels. Notably, C-A-E significantly enhanced the intracellular ROS level. Moreimportantly, C-A-E-mediated apoptosis and differentiation of HL-60 cells was significantly mitigated by NAC. Additionally, C-A-E also exhibited an obvious anti-AML effect in NOD/SCID mice with the injection of HL-60 cells. CONCLUSIONS: C-A-E exhibited an inhibitory effect on AML cells by inducing mitochondrial apoptosis and promoting differentiation, both of which were highly correlated to the activation of ROS.

Metformin inhibits the proliferation of rheumatoid arthritis fibroblast-like synoviocytes through IGF-IR/PI3K/AKT/m-TOR pathway.

Rheumatoid arthritis (RA) is a chronic autoimmune disease in which synovial fibroblast-like cells (FLSs) play an important role in RA development and is known to be lack of effective therapy. Thus, novel therapeutic strategies are greatly needed for treatment of RA. Metformin, a first-line drug for the treatment of type 2 diabetes, has been reported to inhibit the proliferation of a variety of tumor cells. In this study, we demonstrated that metformin could inhibit the RA-FLS proliferation in dose- and time-dependent manner. Our cell viability MTT test and 5-ethynyl-2-deoxyuridine incorporation assay showed that metformin inhibited the RA-FLSs proliferation with a time- and concentration-dependent increase. More importantly, metformin induced G2/M cell cycle phase arrest in RA-FLS via the IGF-IR/PI3K/AKT/ m-TOR pathway and inhibited m-TOR phosphorylation through both the IGF-IR/PI3K/AKT signaling pathways thereby further upregulating and down-regulating p70s6k and 4E-BP1 phosphorylation, respectively; however, metformin was found not to induce apoptosis in RA-FLSs. In summary, these results demonstrate that metformin can effectively inhibit RA-FLS proliferation through inducing cell cycle and upregulating and down-regulating p70s6k and 4E-BP1 phosphorylation. Moreover, IGF-IR/PI3K/AKT m-TOR signaling pathway can be regulated by metformin. Our results indicate that metformin may provide a new way of thinking for the treatment of RA.

Fluorine Effects on Group Migration via a Rhodium(V) Nitrenoid Intermediate.

An unprecedented rhodium(III)-catalyzed hydroarylation of α,α-difluoromethylene alkynes with N-pivaloxyl aroylamides through sequential C-H activation and aryl migration is detailed herein. A large array of α,α-difluoromethylene alkynes and N-pivaloxyl aryl amides were amenable to this transformation, thus providing a novel synthetic protocol for the construction of difluorinated 2-alkenyl aniline derivatives in high yields and with excellent regioselectivity. Notably, unique fluorine effects were found to underlie the thus unconventional reaction manifold.

C-F Bond Cleavage Enabled Redox-Neutral [4+1] Annulation via C-H Bond Activation.

Using α,α-difluoromethylene alkyne as a nontraditional one-carbon reaction partner, a synthetically novel method for the construction of isoindolin-1-one derivatives via Rh(III)-catalyzed [4+1] annulation reaction is reported. The 2-fold C-F bond cleavage not only enables the generation of desired product under an overall oxidant-free condition but also results in a net migration of carbon-carbon triple bond. In addition, the present reaction protocol exhibits a tolerance of a wide spectrum of functional groups due to the mild reaction conditions employed.

Redox-Neutral Rhodium-Catalyzed [4+1] Annulation through Formal Dehydrogenative Vinylidene Insertion.

A synthetic protocol for the expedient construction of 5-methylene-1H-pyrrol-2(5H)-one derivatives through rhodium-catalyzed [4+1] annulation with gem-difluoroacrylate as the C1 component was reported. By taking advantage of the twofold C-F bond cleavage occurring during the annulation, this reaction not only allows the synthesis of these heterocyclic compounds under overall oxidant-free conditions but also renders the transformation stereospecific. The very mild reaction conditions employed ensure compatibility with a wide variety of synthetically useful functional groups.

F- Nucleophilic-Addition-Induced Allylic Alkylation.

Herein we present a novel strategy based on palladium-catalyzed allylic alkylation by taking advantage of the nucleophilic addition of external fluoride onto gem-difluoroalkenes as the initiation step. The merit of this protocol is highly appealing, as it enables a formal allylation of trifluoroethylarene derivatives through the in situ generation of ß-trifluorocarbanions, which otherwise are deemed to be problematic in deprotonative allylation. Furthermore, this strategy distinguishes itself by high modularity, operational simplicity, and wide substrate scope with respect to allyl carbonates, giving rise to a broad array of homoallyltrifluoromethane derivatives, which otherwise would not be easily obtained using existing synthetic methods.

Copper-Catalyzed Vicinal Oxyazidation and Diazidation of Styrenes under Mild Conditions: Access to Alkyl Azides.

A novel and efficient copper-catalyzed oxyazidation and diazidation of styrenes is described. The stable azidoiodine(III) reagent is used as an efficient azide radical source in this reaction. A variety of synthetically useful functional groups are compatible with the mild reaction conditions. This protocol enables the straightforward synthesis of various functionalized azides in good-to-excellent yields.

[Comparative study on pharmacokinetics of curcumin extract of rhizoma curcumae longae and rhizoma wenyujin concisum in rats].

OBJECTIVE: To compare the pharmacokinetics of curcumin extracted from Rhizoma Curcumae Longe and Rhizoma Wenyujin Concisum in rats. METHODS: Sprague Dawley rats were administrated extracts of Rhizoma Curcumae Longae and Rhizoma Wenyujin Concisum. The pharmacokinetic parameters were calculated with 3P97 program. RESULTS: The plasma concentration-time curves of curcumin that extracted from Rhizoma Curcumae Longae and Rhizoma Wenyujin Concisum were fitted with one-compartment model respectively. The AUC and Cmax of curcumin extracted from Rhizoma Curcumae Longae were much greater than of extracted from Rhizoma Wenyujin Concisum. CONCLUSION: There were significantly difference in pharmacokinetic parameters of curcumin in Rhizoma Curcumae Longae and Rhizoma Wenyujin Concisum in rats.

[Impacts of combined supplementation with ascorbic acid and thiamine on certain biochemical and morphologic indexes of testes in mice treated by lead].

OBJECTIVE: To investigate the impacts of the combined administration of ascorbic acid and thiamine on certain biochemical and morphologic indexes of testes in mice exposed to lead. METHOD: s 75 male mice were divided into control groups, groups received with 0.2% lead acetate and groups treated by the same lead acetate dose in combination with ascorbic acid and thiamine (subdivided into:low, middle and high-dose) ad libitum with 15 mice in each. 5 mice in each group were sacrificed at 2, 4 and 6 weeks respectively, and then testes were separated from mice. To evaluate the lead toxicity in testis, the levels of TGFbeta1 and Caspase-3 were detected by immunohistochemistry, apoptotic cell was determined by terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick end labeling (TUNEL); DNA damage of germ cells was assessed by single cell gel electrophoresis (SCGE or Comet assay). RESULTS: The levels of TGFbeta1 and Caspase-3, apoptotic index were significantly higher in groups given by lead than those in control groups( P < 0.05 ). After intervention of low and middle-dose vitamins, DNA damage and the number of apoptotic cell in testis were obviously lower than those of groups exposed to lead( P < 0.05 ) . Also, the impaired tissues were markedly ameliorated under light microscope. Groups administrated with vitamins at the highest dose, however, promoted testicular cell apoptosis via elevated expression of TGFP, and Caspase-3, percentage of tail cell and tail length were reduced significantly. CONCLUSION: Thiamine and ascorbic acid could antagonize the action of certain toxicity of testes in mice treated by lead acetate.