Synthesis of Tryptamines from Radical Cyclization of 2-Iodoaryl Allenyl Amines and Coupling with 2-Azallyls.

An efficient synthesis of tryptamines is developed. Indole structures were constructed using 2-iodoaryl allenyl amines as electron acceptors and radical cyclization precursors. Radical-radical coupling of indolyl methyl radicals and azaallyl radicals led to the tryptamine derivatives. The utility and versatility of this method are showcased by the synthesis of 22 examples of tryptamines in ≤88% yield. In each case, indole formation is accompanied by in situ removal of the Boc protecting group.

Effective-component compatibility of Bufei Yishen formula III ameliorated COPD by improving airway epithelial cell senescence by promoting mitophagy via the NRF2/PINK1 pathway.

BACKGROUND: Effective-component compatibility of Bufei Yishen formula III (ECC-BYF III) demonstrates positive effects on stable chronic obstructive pulmonary disease (COPD). PURPOSE: To investigate the mechanisms of ECC-BYF III on COPD rats from the aspect of airway epithelial cell senescence. METHODS: COPD model rats (Sprague-Dawley rat) were treated with ECC-BYF III for 8 weeks, and the efficacy was evaluated. Cigarette smoke extract (CSE)-induced senescence model of airway epithelial cells was treated with ECC-BYF III, and related enzymes and proteins involved in oxidative stress and mitophagy were detected. RESULTS: ECC-BYF III markedly rescued pulmonary function and histopathological changes, which might be associated with the amelioration of lung senescence, including the reduction of malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and matrix metalloproteinase (MMP)-9 levels, increase of the level in total superoxide dismutase (T-SOD), and decease in the p21 level in the airways. Furthermore, ECC-BYF III suppressed p16 and p21 expressions and senescence-associated ß-galactosidase (SA-ß-Gal) in CSE-induced airway epithelial cells. Moreover, ECC-BYF III upregulated mitophagy-related proteins, including the co-localizations of TOM20 and LC3B, PINK1 and PARK2, and improved mitochondrial function by upregulating mitochondrial mitofusin (MFN)2 and reducing dynamin-related protein 1 (DRP1) expression. ECC-BYF III enhanced the activities of T-SOD and GSH-PX by up-regulating NRF2, thus inhibiting oxidative stress. After intervention with NRF2 inhibitor, the regulation effects of ECC-BYF III on oxidative stress, mitophagy and senescence in airway epithelial cells were significantly suppressed. CONCLUSIONS: ECC-BYF III exerts beneficial effects on COPD rats by ameliorating airway epithelial cell senescence, which is mediated by inhibiting oxidative stress and subsequently enhancing mitophagy through the activation of NRF2 signaling.

Dual Photoredox/Nickel-Promoted Alkylation of Heteroaryl Halides with Redox-Active Esters.

Herein a method for the radical alkylation of heteroaryl halides that relies upon the combination of photoredox and nickel catalysis is described. The use of aliphatic N-(acyloxy)phthalimides as redox-active esters affords primary and secondary radicals for the decarboxylative dual cross-coupling with pyrimidine and pyridine heteroaryl chlorides, bromides, and iodides. The method provides an additional synthetic tool for the incorporation of medicinally relevant heterocyclic motifs.

Metal-Free Synthesis of Phenol-Aryl Selenides via Dehydrogenative C-Se Coupling of Aryl Selenoxides with Phenols.

Herein, we disclose the synthesis of diaryl selenides through an unexpected C-Se coupling between aryl benzyl selenoxides and phenols. The synthetic significance of the method is that it provides a mild, rapid, and metal-free access to organoselenides in high yields with excellent functional group tolerance. This coupling of aryl benzyl selenoxides reveals a completely new reaction possibility compared with aryl sulfoxides. We also probed the reaction mechanism of this unexpected transformation through experimental studies and revealed a special Se(IV)-Se(III)-Se(II) reaction pathway.

Synthesis of Benzofuran Derivatives through Cascade Radical Cyclization/Intermolecular Coupling of 2-Azaallyls.

Benzofurans are among the most popular structural units in bioactive natural products, however, the synthesis of such structures by radical cyclization cascade reactions is rare. Herein, we report a mild and broadly applicable method for the construction of complex benzofurylethylamine derivatives through a unique radical cyclization cascade mechanism. Single-electron transfer (SET) from 2-azaallyl anions to 2-iodo aryl allenyl ethers initiates a radical cyclization that is followed by intermolecular radical-radical coupling. This expedient approach enables the synthesis of a range of polycyclic benzofurans that would otherwise be difficult to prepare.

Ligand-Promoted RhIII -Catalyzed Thiolation of Benzamides with a Broad Disulfide Scope.

A ligand-promoted RhIII -catalyzed C(sp2 )-H activation/thiolation of benzamides has been developed. Using bidentate mono-N-protected amino acid ligands led to the first example of RhIII -catalyzed aryl thiolation reactions directed by weakly coordinating directing amide groups. The reaction tolerates a broad range of amides and disulfide reagents.

Cation-π Interactions in the Benzylic Arylation of Toluenes with Bimetallic Catalysts.

A method to directly arylate toluene derivatives with aryl bromides to generate diarylmethanes, which are important building blocks in drug discovery, is described. In this method, KN(SiMe3)2 in combination with a (NIXANTPHOS)Pd catalyst accomplished the deprotonative activation of toluene derivatives to permit cross-coupling with aryl bromides. Good to excellent yields are obtained with a range of electron-rich to neutral aryl bromides. Both electron-rich and electron-poor toluene derivatives are well tolerated, and even 2-chlorotoluene performs well, providing a platform for introduction of additional functionalization. This discovery hinges on the use of a main group metal to activate toluene for deprotonation by means of a cation-π interaction, which is secured by a bimetallic K(NIXANTPHOS)Pd assembly. Mechanistic and computational studies support acidification of toluene derivatives by the K+-cation- π interaction, which may prove pertinent in the development of other, new reaction systems.

Transition-Metal-Free Radical C(sp3)-C(sp2) and C(sp3)-C(sp3) Coupling Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-Partners.

The past decade has witnessed the rapid development of radical generation strategies and their applications in C-C bond-forming reactions. Most of these processes require initiators, transition metal catalysts, or organometallic reagents. Herein, we report the discovery of a simple organic system (2-azaallyl anions) that enables radical coupling reactions under transition-metal-free conditions. Deprotonation of N-benzyl ketimines generates semistabilized 2-azaallyl anions that behave as "super-electron-donors" (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2-azaallyl anions into persistent 2-azaallyl radicals, which capture the aryl and alkyl radicals to form C-C bonds. The radical coupling of aryl and alkyl radicals with 2-azaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogenous radical initiators or transition metal catalysts. Radical clock studies and 2-azaallyl anion coupling studies provide mechanistic insight for this unique reactivity.

Arylation of Azaarylmethylamines with Aryl Chlorides and a NiBr2/NIXANTPHOS-based Catalyst.

A nickel-catalyzed coupling of azaarylmethylamines with aryl chlorides has been achieved. NIXANTPHOS together with low cost NiBr2 was successfully developed and optimized to exhibit high reactivity at 2.5 mol % loading. Under optimized reaction conditions, aryl(azaaryl)methylamine products were afforded in good to excellent yields (22 examples, up to 98% yield).

Synthesis and cytotoxic activity of novel tetrahydrobenzodifuran-imidazolium salt derivatives.

The synthesis of a series of novel 4-substituted 2,3,6,7-tetrahydrobenzo [1,2-b;4,5-b']difuran-1H-imidazolium salts is presented. The biological properties of the compounds were evaluated in vitro against a panel of human tumor cell lines. Results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a 2-naphthylmethyl substituent or 2-naphthylacyl substituent, were important to the cytotoxic activity. Notably, 3-(2-Naphthylmethyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b']difuran-4-yl)methyl)-1H-5,6-dimethyl-benzimidazol-3-ium bromide (42) was found to be the most potent derivative against five human tumor cell lines with IC50 values of 1.06-4.34µM and more selective towards SMMC-7721, A549 and SW480 cell lines. 3-(2-Naphthylacyl)-1-((2,3,6,7-tetrahydrobenzo[1,2-b;4,5-b']difuran-4-yl)methyl)-1H-2-methyl-benzimidazol-3-ium bromide (37) showed higher selectivity to SMMC-7721 and MCF-7 cell lines with IC50 values 2.7-fold and 8.4-fold lower than DDP. Study regarding to the antitumor mechanism of action showed that compound 37 could induce cell cycle G1 phase arrest and apoptosis in SMMC-7721 cells.

Umpolung Synthesis of Diarylmethylamines via Palladium-Catalyzed Arylation of N-Benzyl Aldimines.

An umpolung synthesis of diarylmethylamine derivatives is presented. This reaction entails a Pd catalyzed arylation of 1,3-diaryl-2-azaallyl anions, in situ generated from N-benzyl aldimines. A Pd(NIXANTPHOS)-based catalyst together with hindered silylamide bases enabled the coupling of aldimines with aryl bromides in good to excellent yields without product isomerization. Moreover, regioselectivity in the arylation of unsymmetrical 1,3-diaryl-2-azaallyl anions was studied. This method is suitable for a gram scale synthesis of diarylmethylamine derivatives at room temperature without use of a glovebox.

Palladium-Catalyzed α-Arylation of Methyl Sulfonamides with Aryl Chlorides.

A Palladium-catalyzed α-arylation of sulfonamides with aryl chlorides is presented. A Buchwald type precatalyst formed with Kwong's indole-based ligand enabled this transformation to be compatible with a large variety of methyl sulfonamides and aryl chlorides in good to excellent yields. Importantly, under the optimized reaction conditions, only mono-arylated products were observed. This method has been applied to the efficient synthesis of sumatriptan, which is used to treat migraines.

Synthesis and cytotoxic activity of novel hexahydropyrrolo[2,3-b]indole imidazolium salts.

A series of novel hexahydropyrrolo[2,3-b]indole-1H-imidazolium salts were synthesized and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or 2-naphthylmethyl group, were important for the cytotoxic activity. Notably, Compound 43, bearing a 2-bromobenzyl substituent at position-3 of 5,6-dimethyl-benzimidazole, was found to possess the most potent derivative against five human tumor cell lines with IC50 values below 2.68µM and more selective towards SMMC-7721, A549 and SW480 cell lines. Compounds 25 and 39 were more selective to HL-60 and MCF-7 cell lines with IC50 values of 0.47 and 1.46µM.

Synthesis and antitumor activity of novel N-substituted tetrahydro-ß-carboline-imidazolium salt derivatives.

The synthesis of a series of novel N-substituted tetrahydro-ß-carboline-imidazolium salt derivatives is presented. The biological properties of the compounds were evaluated in vitro against a panel of human tumor cell lines. The results suggest that the benzimidazole ring and 1-(naphthalen-2-yl)ethan-1-one or 2-naphthylmethyl substituent at the imidazolyl-3-position were vital for modulating cytotoxic activity. Compound 41 was observed as a potent derivative with IC50 values of 3.24-8.78 µM and exhibited cytotoxic activity selectively against HL-60, A-549 and MCF-7 cell lines. Meanwhile, high inhibitory activities selectively against HL-60 and MCF-7 cell lines were observed for compound 51. Moreover, compound 51 was able to induce G1 phase cell cycle arrest and apoptosis in MCF-7 cells. The cytotoxicity of compound 51 against human normal lung epithelial cell line BEAS-2B was further evaluated.

Total Syntheses of (R)-Strongylodiols C and D.

The first total syntheses of two marine natural products, (R)-strongylodiols C and D, with 99% ee were achieved. The key steps of the strategy include the zipper reaction of an alkyne, the asymmetric alkynylation of an unsaturated aliphatic aldehyde catalyzed with Trost's ProPhenol ligand, and the Cadiot-Chodkiewicz cross-coupling reaction of a chiral propargylic alcohol with a bromoalkyne.

Palladium-Catalyzed C-H Arylation of α,ß-Unsaturated Imines: Catalyst-Controlled Synthesis of Enamine and Allylic Amine Derivatives.

A unique chemo- and regioselective α- and γ-arylation of palladium azapentadienyl intermediates is presented. Two distinct catalysts and sets of conditions successfully controlled the regioselectivity of the arylation. These methods provide the first umpolung C-H functionalization of azapentadienyl palladium intermediates and enable the divergent synthesis of allylic amine and enamine derivatives, which are of significant interest in the pharmaceutical industry.

Leukemia risk assessment of exposure to low-levels of benzene based on the linearized multistage model.

Objectives: To assess leukemia risk in occupational populations exposed to low levels of benzene. Methods: Leukemia incidence data from the Chinese Benzene Cohort Study were fitted using the Linearized multistage (LMS) model. Individual benzene exposure levels, urinary S-phenylmercapturic acid (S-PMA) and trans, trans-muconic acid (t, t-MA) were measured among 98 benzene-exposed workers from factories in China. Subjects were categorized into four groups by rounding the quartiles of cumulative benzene concentrations (< 3, 3-5, 5-12, ≥12 mg/m3·year, respectively). The risk of benzene-induced leukemia was assessed using the LMS model, and the results were validated using the EPA model and the Singapore semi-quantitative risk assessment model. Results: The leukemia risks showed a positive correlation with increasing cumulative concentration in the four exposure groups (excess leukemia risks were 4.34, 4.37, 4.44 and 5.52 × 10-4, respectively; Ptrend < 0.0001) indicated by the LMS model. We also found that the estimated leukemia risk using urinary t, t-MA in the LMS model was more similar to those estimated by airborne benzene compared to S-PMA. The leukemia risk estimated by the LMS model was consistent with both the Singapore semi-quantitative risk assessment model at all concentrations and the EPA model at high concentrations (5-12, ≥12 mg/m3·year), while exceeding the EPA model at low concentrations (< 3 and 3-5 mg/m3·year). However, in all four benzene-exposed groups, the leukemia risks estimated by these three models exceeded the lowest acceptable limit for carcinogenic risk set by the EPA at 1 × 10-6. Conclusion: This study demonstrates the utility of the LMS model derived from the Chinese benzene cohort in assessing leukemia risk associated with low-level benzene exposure, and suggests that leukemia risk may occur at cumulative concentrations below 3 mg/m3·year.

Afferent Renal Denervation Attenuates Sympathetic Overactivation From the Paraventricular Nucleus in Spontaneously Hypertensive Rats.

BACKGROUND: The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin-angiotensin system (RAS) pathway. METHODS: Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR. RESULTS: The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. CONCLUSIONS: These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.

Whether and how will using social media induce social anxiety? The correlational and causal evidence from Chinese society.

Background: Prior literature has well established the relationship between social media use and social anxiety, but little attention has been paid to the underlying mechanisms. Additionally, the causal evidence concerning the effect of social media use on social anxiety is scarce. Objective: Given that, two studies were conducted to examine the effect of social media use on social anxiety and the underlying mechanisms. Methods and results: In Study 1, with 470 undergraduates as participants, we applied the questionnaire survey to investigate the relationship between social media use and social anxiety. The results showed that higher social media use intensity was significantly related to higher social anxiety, and social media use was related to social anxiety via two possible mediation paths: (1) social media use → upward social comparison → social anxiety, (2) and social media use → upward social comparison → self-esteem → social anxiety. In Study 2, with 180 undergraduates as participants, we conducted a lab experiment, in which participants were assigned to the experimental (exposed to the content that undergraduates frequently access on social media) or control (exposed to landscape documentaries) condition, and then measured their upward social comparison, self-esteem and social anxiety. The results showed that participants in the experimental condition reported higher social anxiety than those in the control condition, demonstrating the causality between social media exposure and social anxiety. The subsequent mediation analysis basically replicated the findings of Study 1. That is, upward social comparison played the mediating role between social media exposure and social anxiety, and upward social comparison and self-esteem played the chain-mediating role between them. Conclusion: The current research firstly demonstrated the causality between social media use and social anxiety in Chinese society, and also revealed the mediating mechanisms between them, which would deepen our understanding of how social media use will increase social anxiety.

Effective-compounds of Jinshui Huanxian formula ameliorates fibroblast activation in pulmonary fibrosis by inhibiting the activation of mTOR signaling.

BACKGROUND: Jinshui Huanxian formula (JHF) ameliorates idiopathic pulmonary fibrosis patients. Active compounds, including icariin, isoliquiritigenin, nobiletin, peimine, and paeoniflorin, deriving from JHF were combined as effective-component compatibility ECC of JHF II (ECC-JHF II), which is an effective therapeutic strategy for pulmonary fibrosis (PF) induced by bleomycin (BLM) in rats. PURPOSE: This study aimed to explore the underlying mechanism of ECC-JHF II on pulmonary fibrosis. METHODS: A model of PF in rats was established through intratracheal instillation of BLM. Pulmonary function, pathological changes, and collagen deposition were examined. The gene and protein expressions in fibroblast activation were detected by quantitative real-time PCR and western blotting respectively. RESULTS: ECC-JHF II significantly improved BLM-induced PF in rats, manifested as decreased collagen deposition, reduced pathological damage and improved pulmonary function. Furthermore, ECC-JHF II inhibited fibroblast activation by reducing the expression of α-smooth muscle actin (α-SMA) and fibronectin. We analyzed the targets of ECC-JHF II and differentially expressed genes (DEGs) of fibroblast activation induced by transforming growth factor-ß1 (TGF-ß1) and found that ECC-JHF II might regulate fibroblast activation by EGFR, PI3K-Akt or mTOR signaling pathway. In vitro experiments, we also found that ECC-JHF II suppressed the mTOR pathway, such as downregulating the phosphorylation levels of p70S6K in fibroblast activation induced by TGF-ß1. After activating mTOR signaling, the inhibition of ECC-JHF II on fibroblast activation was blocked. These results suggested that ECC-JHF II potently ameliorated pulmonary fibrosis in rats and effectively suppressed fibroblast activation by interfering with mTOR signaling. CONCLUSION: We combined transcriptomics with the network analysis to predict the mechanism underlying ECC-JHF II suppression of fibroblast activation. In summary, ECC-JHF II improved BLM-induced pulmonary fibrosis, which might be associated with the suppression of fibroblast activation by inhibiting the mTOR signaling.