A Radical Smiles Rearrangement Promoted by Neutral Eosin Y as a Direct Hydrogen Atom Transfer Photocatalyst.

A visible-light-mediated radical Smiles rearrangement has been achieved using neutral eosin Y as a direct hydrogen atom transfer (HAT) photocatalyst. Novel N-heterocycles as single diastereomers featuring an isothiazolidin-3-one 1,1-dioxide moiety are directly accessed by this method. A wide range of functional groups can be incorporated in the products by employing diverse aldehydes and N-(hetero)arylsulfonyl propiolamides. The transformation proceeds through a cascade of visible-light-induced HAT, 1,4-addition, Smiles rearrangement, 5-endo-trig cyclization, and a reverse HAT process. Preliminary biological studies of the highly functionalized heterocyclic compounds suggest potential anticancer activity with some of the synthesized compounds.

Pd-Catalyzed Annulation of 1-Halo-8-arylnaphthalenes and Alkynes Leading to Heptagon-Embedded Aromatic Systems.

A palladium-catalyzed heptagon-forming annulation reaction between 1-halo-8-arylnaphthalene and diarylacetylene is reported. The reaction is promoted using a catalytic system comprised of Pd(OAc)2 , moderately electron-deficient triarylphosphine P(4-ClC6 H4 )3 , and Ag2 CO3 to afford benzo[4,5]cyclohepta[1,2,3-de]naphthalene derivatives in moderate to good yields, in preference to fluoranthene as a competing byproduct. Twofold annulation can also be achieved to access a novel heptagon-embedded polycyclic aromatic hydrocarbon compound.

Synthesis and decreasing Aß content evaluation of arctigenin-4-yl carbamate derivatives.

A series of arctigenin-4-yl carbamate derivatives were synthesized and evaluated for potency in reducing ß-amyloid (Aß) content in HEK293-APPswe cells. Most of the arctigenin-4-yl aralkyl or aryl carbamate derivatives showed improved potency in reducing Aß content. Among the synthesized compounds, arctigenin-4-yl (3-chlorophenyl)carbamate (20) exhibited the strongest potency with 78.7% Aß content reduction at 20µM. Furthermore, the effect of arctigenin-4-yl (4-chlorophenyl)carbamate (19) and arctigenin-4-yl (3-chlorophenyl)carbamate (20) on lowing Aß content was better than arctigenin under the concentrations of 1, 10 and 20µM.

Arctigenin effectively ameliorates memory impairment in Alzheimer's disease model mice targeting both ß-amyloid production and clearance.

Alzheimer's disease (AD) chiefly characterizes a progressively neurodegenerative disorder of the brain, and eventually leads to irreversible loss of intellectual abilities. The ß-amyloid (Aß)-induced neurodegeneration is believed to be the main pathological mechanism of AD, and Aß production inhibition or its clearance promotion is one of the promising therapeutic strategies for anti-AD research. Here, we report that the natural product arctigenin from Arctium lappa (L.) can both inhibit Aß production by suppressing ß-site amyloid precursor protein cleavage enzyme 1 expression and promote Aß clearance by enhancing autophagy through AKT/mTOR signaling inhibition and AMPK/Raptor pathway activation as investigated in cells and APP/PS1 transgenic AD model mice. Moreover, the results showing that treatment of arctigenin in mice highly decreased Aß formation and senile plaques and efficiently ameliorated AD mouse memory impairment strongly highlight the potential of arctigenin in anti-AD drug discovery.

Risk factors and survival prediction of young breast cancer patients with liver metastases: a population-based study.

Background: The risk and prognosis of young breast cancer (YBC) with liver metastases (YBCLM) remain unclear. Thus, this study aimed to determine the risk and prognostic factors in these patients and construct predictive nomogram models. Methods: This population-based retrospective study was conducted using data of YBCLM patients from the Surveillance, Epidemiology, and End Results database between 2010 and 2019. Multivariate logistic and Cox regression analyses were used to identify independent risk and prognostic factors, which were used to construct the diagnostic and prognostic nomograms. The concordance index (C-index), calibration plot, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to assess the performances of the established nomogram models. Propensity score matching (PSM) analysis was used to balance the baseline characteristics between the YBCLM patients and non-young patients with BCLM when comparing overall survival (OS) and cancer-specific survival (CSS). Results: A total of 18,275 YBC were identified, of whom 400 had LM. T stage, N stage, molecular subtypes, and bone, lung, and brain metastases were independent risk factors for LM developing in YBC. The established diagnostic nomogram showed that bone metastases contributed the most risk of LM developing, with a C-index of 0.895 (95% confidence interval 0.877-0.913) for this nomogram model. YBCLM had better survival than non-young patients with BCLM in unmatched and matched cohorts after propensity score matching analysis. The multivariate Cox analysis demonstrated that molecular subtypes, surgery and bone, lung, and brain metastases were independently associated with OS and CSS, chemotherapy was an independent prognostic factor for OS, and marital status and T stage were independent prognostic factors for CSS. The C-indices for the OS- and CSS-specific nomograms were 0.728 (0.69-0.766) and 0.74 (0.696-0.778), respectively. The ROC analysis indicated that these models had excellent discriminatory power. The calibration curve also showed that the observed results were consistent with the predicted results. DCA showed that the developed nomogram models would be effective in clinical practice. Conclusion: The present study determined the risk and prognostic factors of YBCLM and further developed nomograms that can be used to effectively identify high-risk patients and predict survival outcomes.

"AMP plus": Immunostimulant-Inspired Design Based on Chemotactic Motif-(PhHAhPH)n.

Ability to stimulate antimicrobial immunity has proven to be a useful therapeutic strategy in treating infections, especially in the face of increasing antibiotic resistance. Natural antimicrobial peptides (AMPs) exhibiting immunomodulatory functions normally encompass complex activities, which make it difficult to optimize their therapeutic benefits. Here, a chemotactic motif was harnessed as a template to design a series of AMPs with immunostimulatory activities plus bacteria-killing activities ("AMP plus"). An amphipathic peptide ((PhHAhPH)n) was employed to improve the antimicrobial impact and expand the therapeutic potential of the chemotactic motif that lacked obvious bacteria-killing properties. A total of 18 peptides were designed and evaluated for their structure-activity relationships. Among the designed, KWH2 (1) potently killed bacteria and exhibited a narrow antimicrobial spectrum against Gram-negative bacteria and (2) activated macrophages (i.e., inducing Ca2+ influx, cell migration, and reactive oxygen species production) as a macrophage chemoattractant. Membrane permeabilization is the major antimicrobial mechanism of KWH2. Furthermore, the mouse subcutaneous abscess model supported the dual immunomodulatory and antimicrobial potential of KWH2 in vivo. The above results confirmed the efficiency of KWH2 in treating bacterial infection and provided a viable approach to develop immunomodulatory antimicrobial materials with desired properties.

Stepwise on-demand functionalization of multihydrosilanes enabled by a hydrogen-atom-transfer photocatalyst based on eosin Y.

Organosilanes are of vital importance for modern human society, having found widespread applications in functional materials, organic synthesis, drug discovery and life sciences. However, their preparation remains far from trivial, and on-demand synthesis of heteroleptic substituted silicon reagents is a formidable challenge. The generation of silyl radicals from hydrosilanes via direct hydrogen-atom-transfer (HAT) photocatalysis represents the most atom-, step-, redox- and catalyst-economic pathway for the activation of hydrosilanes. Here, in view of the green characteristics of neutral eosin Y (such as its abundance, low cost, metal-free nature, absorption of visible light and excellent selectivity), we show that using it as a direct HAT photocatalyst enables the stepwise custom functionalization of multihydrosilanes, giving access to fully substituted silicon compounds. By exploiting this strategy, we realize preferable hydrogen abstraction of Si-H bonds in the presence of active C-H bonds, diverse functionalization of hydrosilanes (for example, alkylation, vinylation, allylation, arylation, deuteration, oxidation and halogenation), and remarkably selective monofunctionalization of di- and trihydrosilanes.

The glucotoxicity protecting effect of honokiol in human hepatocytes via directly activating AMPK.

Introduction: Sustained hyperglycemia causes glucotoxicity, which has been regarded as a contributor to hepatocyte damage in type 2 diabetes (T2D) and its metabolic comorbidities. Honokiol is a natural biphenolic component derived from the dietary supplement Magnolia officinalis extract. This study aimed to investigate the effects of honokiol on glucose metabolism disorders and oxidative stress in hepatocytes and the underlying mechanisms. Methods: HepG2 cells were treated with glucosamines (18 mM) to induce glucotoxicity as a diabetic complication model in vitro. Results and discussion: Honokiol significantly increased glucose consumption, elevated 2-NBDG uptake, and promoted GLUT2 translocation to the plasma membrane in glucosamine-treated HepG2 cells, indicating that honokiol ameliorates glucose metabolism disorders. Furthermore, glucosamine-induced ROS accumulation and loss of mitochondrial membrane potential were markedly reduced by honokiol, suggesting that honokiol alleviated glucotoxicity-induced oxidative stress. These effects were largely abolished by compound C, an AMPK inhibitor, suggesting an AMPK activation-dependent manner of honokiol function in promoting glucose metabolism and mitigating oxidative stress. Molecular docking results revealed that honokiol could interact with the amino acid residues (His151, Arg152, Lys243, Arg70, Lys170, and His298) in the active site of AMPK. These findings provide new insights into the antidiabetic effect of honokiol, which may be a promising agent for the prevention and treatment of T2D and associated metabolic comorbidities.

Bromine radical as a visible-light-mediated polarity-reversal catalyst.

Polarity-reversal catalysts enable otherwise sluggish or completely ineffective reactions which are characterized by unfavorable polar effects between radicals and substrates. We herein disclose that when irradiated by visible light, bromine can behave as a polarity-reversal catalyst. Hydroacylation of vinyl arenes, a three-component cascade transformation and deuteration of aldehydes were each achieved in a metal-free manner without initiators by using inexpensive N-bromosuccinimide as the precatalyst. Light is essential to generate and maintain the active bromine radical during the reaction process. Another key to success is that HBr can behave as an effective hydrogen donor to turn over the catalytic cycles.

Divergent functionalization of aldehydes photocatalyzed by neutral eosin Y with sulfone reagents.

While aldehydes represent a classic class of electrophilic synthons, the corresponding acyl radicals are inherently nucleophilic, which exhibits umpolung reactivity. Generation of acyl radicals typically requires noble metal catalysts or excess oxidants to be added. Herein, we report a convenient and green approach to access acyl radicals, capitalizing on neutral eosin Y-enabled hydrogen atom transfer (HAT) photocatalysis with aldehydes. The generated acyl radicals underwent SOMOphilic substitutions with various functionalized sulfones (X-SO2R') to deliver value-added acyl products. The merger of eosin Y photocatalysis and sulfone-based SOMOphiles provides a versatile platform for a wide array of aldehydic C-H functionalizations, including fluoromethylthiolation, arylthiolation, alkynylation, alkenylation and azidation. The present protocol features green characteristics, such as being free of metals, harmful oxidants and additives; step-economic; redox-neutral; and amenable to scale-up assisted by continuous-flow technology.

Phenanthrene Synthesis via Chromium-Catalyzed Annulation of 2-Biaryl Grignard Reagents and Alkynes.

A chromium/2,2'-bipyridine-catalyzed annulation reaction of 2-biarylmagnesium reagents with alkynes is reported. The reaction is applicable to a variety of aryl- and/or alkyl-substituted internal alkynes as well as 2-biaryl and related Grignard reagents, thus affording phenanthrene derivatives in moderate to good yields. The reaction proceeds at the expense of excess alkyne as a hydrogen acceptor and thus does not need an external oxidant. Deuterium-labeling experiments shed light on the reaction mechanism, which likely involves multiple intramolecular C-H activation processes on chromium.

Gold-Catalyzed Cycloisomerization and Diels-Alder Reaction of 1,6-Diyne Esters with Alkenes and Diazenes to Hydronaphthalenes and -cinnolines.

A method for the efficient preparation of hydronaphthalene and -cinnoline derivatives by Au(I)-catalyzed cycloisomerzation of 1,6-diyne esters followed by a Diels-Alder reaction with alkenes or diazenes under mild conditions at room temperature with catalyst loadings as low as 1 mol % is described.