Transition-Metal-Free Hydrodefluoroamination of Trifluoromethyl Enones for the Synthesis of α-Fluoroenamides.

A three-component strategy was developed to enable hydrodefluoroamination of ß-trifluoromethyl enones by selectively activating two C(sp3)-F bonds in the trifluoromethyl group. The method involved a sequence of carbonyl reduction, hydrodefluorination, and defluoroamination under transition-metal-free conditions. Synthetically useful (E)-stereospecific α-fluoroenamides were obtained in good yields with diverse functional group tolerance, which could be easily transformed into valuable organofluorides and heterocycles. The carbonyl auxiliary exerts both electronic and steric impacts on the CF3-alkenes, allowing for controllable and selective defluorination.

Association between Perceived Stress and Motoric Cognitive Risk Syndrome in an Elderly Population: Rugao Longevity and Aging Study.

INTRODUCTION: Previous studies have indicated a correlation between perceived stress and cognitive decline. However, it remains unknown whether high levels of perceived stress can result in motoric cognitive risk (MCR) syndrome. This study investigated the relationship between perceived stress and MCR in a community-based population. METHODS: The study cohort comprised 852 elderly individuals from the Rugao Longitudinal Aging Cohort. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10), while MCR was defined as the coexistence of subjective memory complaints (SMCs) and slow gait speed. RESULTS: The average age of the study participants is 79.84 ± 4.34 years. The mean score of PSS-10 among participants is 10.32 (range = 0-33; [SD] = 5.71), with a median score of 10.00 (6.00, 14.00). The prevalence of MCR is 9.3%. In the logistic regression analysis, for each 1-SD (5.71) increase in the global PSS-10 score, the risk of MCR increased by 40% (95% CI 1.09-1.80). Additionally, in the aspect of two components of MCR, with a 1-SD increase (5.71) in the global PSS-10 score, there was a 50% (95% CI 1.29-1.75) increase in the risk of SMCs and a 27% (95% CI 1.04-1.55) increase in the risk of slow gait speed. In terms of specific walking speed, there was a reverse correlation between the global PSS-10 score and walking speed (r = -0.14, p < 0.001). CONCLUSIONS: This study provided preliminary evidence that high levels of perceived stress were associated with the risk of MCR in a community-dwelling population.

Hydroxylation of Aryl Sulfonium Salts for Phenol Synthesis under Mild Reaction Conditions.

Hydroxylation of aryl sulfonium salts could be realized by utilizing acetohydroxamic acid and oxime as hydroxylative agents in the presence of cesium carbonate as a base, leading to a variety of structurally diverse hydroxylated arenes in 47-95% yields. In addition, the reaction exhibited broad functionality tolerance, and a range of important functional groups (e.g., cyano, nitro, sulfonyl, formyl, keto, and ester) could be well amenable to the mild reaction conditions.

Palladium-Catalyzed Esterification of Aryl Fluorosulfates with Aryl Formates.

An efficient palladium-catalyzed carbonylation of aryl fluorosulfates with aryl formates for the facile synthesis of esters was developed. The cross-coupling reactions proceeded effectively in the presence of a palladium catalyst, phosphine ligand, and triethylamine in DMF to produce the corresponding esters in moderate to good yields. Of note, functionalities or substituents, such as nitro, cyano, methoxycarbonyl, trifluoromethyl, methylsulfonyl, trifluoromethoxy, fluoro, chloro, bromo, methyl, methoxy, N,N-dimethyl, and [1,3]dioxolyl, were well-tolerated in the reactions, which could be kept for late-stage modification. The reactions employing readily available and relatively robust aryl fluorosulfates as coupling electrophiles could potentially serve as an attractive alternative to traditional cross-couplings with the use of aryl halides and pseudohalides as substrates.

Desulfonylation via Radical Process: Recent Developments in Organic Synthesis.

As the "chemical chameleon", sulfonyl-containing compounds and their variants have been merged with various types of reactions for the efficient construction of diverse molecular architectures by taking advantage of their incredible reactive flexibility. Currently, their involvement in radical transformations, in which the sulfonyl group typically acts as a leaving group via selective C-S, N-S, O-S, S-S, and Se-S bond cleavage/functionalization, has facilitated new bond formation strategies which are complementary to classical two-electron cross-couplings via organometallic or ionic intermediates. Considering the great influence and synthetic potential of these novel avenues, we summarize recent advances in this rapidly expanding area by discussing the reaction designs, substrate scopes, mechanistic studies, and their limitations, outlining the state-of-the-art processes involved in radical-mediated desulfonylation and related transformations. With a specific emphasis on their synthetic applications, we believe this review will be useful for medicinal and synthetic organic chemists who are interested in radical chemistry and radical-mediated desulfonylation in particular.

Elevated HMGB1 and sRAGE levels in cerebrospinal fluid of aneurysmal subarachnoid hemorrhage patients.

BACKGROUND: Neuroinflammation after aneurysmal subarachnoid hemorrhage (aSAH) leads to poor outcome of patients. High mobility group box 1 (HMGB1) contributes to inflammation through binding to receptors for advanced glycation end-products (RAGE) in various diseases. We aimed to determine the production of these two factors after aSAH and their relationship with clinical features. METHODS: HMGB1 and soluble RAGE (sRAGE) levels in cerebrospinal fluid (CSF) of aSAH patients and controls were measured, and their temporal courses were observed. The correlation between early concentrations (days 1-3) and clinical symptoms assessed by disease severity scores, neuroinflammation estimated by CSF IL-6 levels, as well as prognosis evidenced by delayed cerebral ischemia (DCI) and 6-month adverse outcome was investigated. Finally, combined analysis of early levels for predicting prognosis was confirmed. RESULTS: CSF HMGB1 and sRAGE levels were higher in aSAH patients than in controls (P < 0.05), and the levels decreased from higher early to lower over time. Their early concentrations were positively associated with disease severity scores, IL-6 levels, DCI and 6-month poor outcome (P < 0.05). HMGB1 ≥ 6045.5 pg/ml (OR = 14.291, P = 0.046) and sRAGE ≥ 572.0 pg/ml (OR = 13.988, P = 0.043) emerged as independent predictors for DCI, while HMGB1 ≥ 5163.2 pg/ml (OR = 7.483, P = 0.043) and sRAGE ≥ 537.3 pg/ml (OR = 12.653, P = 0.042) were predictors for 6-month poor outcome. Combined analysis of them improved predictive values of adverse prognosis. CONCLUSION: CSF HMGB1 and sRAGE levels of aSAH patients were increased early and then varied dynamically, which might act as potential biomarkers for poor outcome, especially when co-analyzed.

Nickel-Catalyzed Direct Cross-Coupling of Diaryl Sulfoxide with Aryl Bromide.

The direct cross-couplings of diaryl sulfoxides with aryl bromides via C-S bond cleavage could be readily accomplished using nickel(II) as the catalyst, 1,2-bis(diphenylphosphino)ethane (dppe) as the ligand, and magnesium turnings as the reducing metal in THF, leading to the corresponding biaryls in moderate to good yields. The reaction exhibited a broad substrate scope and could be applied to a gram-scale synthesis. The "one-pot" reaction, which avoids the utility of presynthesized and moisture-labile organometallic compounds, is operationally simple and step-economic.

Association of cerebrospinal fluid advanced oxidation protein products levels with early brain injury and prognosis of aneurysmal subarachnoid hemorrhage: A preliminary prospective study.

OBJECTIVES: In this study, we investigated the time course in the cerebrospinal fluid (CSF) advanced oxidation protein products (AOPPs) levels in patients with aneurysmal subarachnoid hemorrhage (aSAH), and ascertained the relationship between the levels of AOPPs and early brain injury (EBI), hydrocephalus and prognosis of patients with aSAH. METHODS: We measured the CSF AOPPs levels in 50 patients with aSAH at 1-3 d, 4-6 d, 7-9 d, and 10-12 d after hemorrhage. The modified Fisher grades, Hunt-Hess grades, CSF IL-6 levels, peripheral blood count of white blood cells, cerebral edema scores and hydrocephalus were used to assess the severity of brain injury. Modified Rankin Scale (mRS) scores were used to assess the prognosis. Patients with mRS scores greater than 2 were considered to have a poor outcome. RESULTS: CSF AOPPs levels were significantly higher in patients with aSAH with poor prognosis, compared to patients with good prognosis and peaked in the early stage. Among patients with aSAH, the levels of CSF AOPPs on days 1-3 were significantly correlated with modified Fisher grades, Hunt-Hess grades, CSF IL-6 levels, peripheral blood count of white blood cells, and cerebral edema scores. Also, in patients with hydrocephalus, early CSF AOPPs levels were significantly elevated. Levels of CSF AOPPs in aSAH patients on days 1-3, 4-6, and 7-9 were independently associated with poor prognosis at the 90-day follow-up, and the optimal area under the curve (AUC) values for CSF AOPPs levels were found on days 1-3. CONCLUSIONS: AOPPs may serve as the potential biomarker to assess the severity of EBI and prognosis in patients with aSAH.

Titanium(IV)-Mediated Ring-Opening/Dehydroxylative Cross-Coupling of Diaryl-Substituted Methanols with Cyclopropanol Derivatives.

A titanium(IV)-mediated ring-opening/dehydroxylative cross-coupling of diaryl-substituted methanols with a cyclopropanol derivative was developed. The reactions proceeded efficiently to provide synthetically useful γ,γ-diaryl esters in moderate to good yields, which could be applied to the functionalization of complex molecules derived from bioactive fenofibrate and isoxepac and the synthesis of a precursor of Zoloft.

Three-Component Bisannulation for the Synthesis of Trifluoromethylated Tetracyclic Aza-Aromatics through Six C(sp3)-F Bond Cleavage and Four C-N Bond Formation.

An unprecedented and expeditious tandem bisannulation of polyfluoroalkylated tetralones with benzamidines to access various fluoroalkyl tetracyclic [1,3]-diazepines through multiple C-N bond formation and C(sp3)-F bond cleavage is reported. The process features high regio-/chemoselectivities, broad substrate scope, good functional group tolerance, procedural simplicity, mild reaction conditions, and scale-up synthesis. Mechanistic studies showed that the distinctive fluorine effect of polyfluoroalkyl tetralone plays a vital role for the aza-tetracycle construction.

Metal-free [3 + 2 + 1] annulation of allylic alcohols, ketones, and ammonium acetate: radical-involving synthesis of 2,3-diarylpyridine derivatives.

A three-component [3 + 2 + 1] annulation strategy for the synthesis of biologically and pharmaceutically active 2,3-diarylpyridine derivatives by using a series of allylic alcohols, ketones, and ammonium acetate as substrates has been developed. The method proceeds efficiently under metal-free conditions, and the desired heterocycles could be obtained in a site-specific selectivity manner with good functional group tolerance.

Research progress on the treatment of advanced prostate cancer with Olaparib.

Prostate cancer (PCa) is one of the most common malignancies in men worldwide, and metastatic castrate-resistant prostate cancer (mCRPC) has shown a poor prognosis. Although chemotherapy and androgen deprivation therapy (ADT) have improved clinical outcomes, the median survival (MS) of patients with mCRPC is still less than 2 years. With the development of poly adenosine diphosphate-ribose polymerase inhibitor (PARPi), the treatment strategy for patients with mCRPC has markedly evolved. Olaparib, a type of PARPi that can selectively induce synthetic lethality in cancer cells with homologous recombination (HR) deficiencies, was the first type of PARPi approved for treating patients with mCRPC harboring mutations in HR repair (HRR) genes. This review discusses and summarizes the latest progress on therapeutic mechanisms, monotherapy, combination therapy, and adverse events of Olaparib.

The Combination of Bacillus Thuringiensis and Its Engineered Strain Expressing dsRNA Increases the Toxicity against Plutella Xylostella.

RNA interference (RNAi) has been developed and used as an emerging strategy for pest management. Here, an entomopathogen Bacillus thuringiensis (Bt) was used to express the dsRNA for the control of Plutella xylostella. A vector containing a 325-bp fragment of the conserved region of P. xylostella arginine kinase gene (PxAK) flanking in two ends with the promoter Pro3α was developed and transferred into Bt 8010 and BMB171, and consequently engineered Bt strains 8010AKi and BMB171AKi expressing dsRNA of PxAK were developed. The two engineered Bt strains were separately mixed with Bt 8010 in a series of ratios, and then fed to the P. xylostella larvae. We found that 8010:8010AKi of 9:1 and 8010:BMB171AKi of 7:3 caused a higher mortality than Bt 8010. PxAK expression levels in the individuals treated with the mixtures, 8010AKi and BMB171Aki, were lower than that in the control. The intrinsic rate of increase (r) and net reproductive rate (R0) of the population treated with 8010:8010AKi of 9:1 were lower than those of the population treated with Bt 8010 or 8010AKi. We developed a Bt-mediated insect RNAi for the control of P. xylostella and demonstrated a practical approach to integrating the entomopathogen with RNAi technique for the pest management.

Frailty index is associated with increased risk of elevated BNP in an elderly population: the Rugao Longevity and Ageing Study.

BACKGROUND AND AIMS: To explore whether frailty, defined by frailty index (FI), is associated with the risk of elevated B-type natriuretic peptide (BNP), a surrogate endpoint of cardiovascular events. METHODS: Data of 1382 community-dwelling elders who had no documented cardiovascular diseases aged 70-84 years from the ageing arm of the Rugao Longevity and Ageing Study was used. Traditional risk factor index (TI) was constructed using eight established cardiovascular-related risk factors. FI was constructed using 36 health deficits. Elevated BNP was defined as BNP ≥ 100pg/mL. Cardiovascular events include incident major cardiovascular events and cardiovascular death. RESULTS: During a 3-year follow-up period, 97 participants had cardiovascular events. TI was not associated with the risk of elevated BNP, but was associated with cardiovascular events (HR = 1.16, 95% CI 1.01-1.34). Frailty index was not only associated with cardiovascular events (HR = 1.32, 95% CI 1.06-1.64), but also associated with elevated BNP with an OR of 1.22 (95% CI 1.02-1.47) for each 0.1 increment. Further, both frailty (OR = 1.93, 95% CI 1.67-3.17) and pre-frailty (OR = 1.54, 95% CI 1.06-2.25) were associated with increased risk of elevated BNP. CONCLUSION: FI is associated with increased risks of both cardiovascular events and surrogated endpoint of cardiovascular disease-elevated BNP. Frailty may be a non-traditional risk factor of cardiovascular diseases and frailty index may be a measurement for early identifying high risk elderly individuals of cardiovascular abnormities.

Depressive symptoms are associated with incident frailty in a Chinese population: the Rugao Longevity and Aging Study.

BACKGROUND AND AIMS: This study aimed at investigating whether depression symptoms are associated with prevalent and incident physical frailty in Chinese older population. METHODS: We analyzed data of 1168 older Chinese adults aged 70 and above in the aging arm of the Rugao Longevity and Aging Study (RuLAS). Depressive symptoms (Geriatric Depression Scale ≥ 6) were assessed by the Geriatric Depression Scale. Frailty was defined using Fried phenotype criteria at baseline and 3-year survey. RESULTS: At baseline, 8.9% of the participants had depression symptoms. The prevalence of pre-frailty and frailty were 34.5% and 5.9%, respectively. The percentages of depressive symptoms increase from robust (5.3%) to pre-frail (11.2%), and then to frail (31.9%) groups. After adjustments of multiple covariates, depressive symptoms were associated with both prevalent pre-frailty (OR = 1.75, 95% CI 1.08-2.84) and prevalent frailty (OR = 5.64, 95% CI 2.85-11.14) at baseline. At 3-year survey, 9.3% participants reported the development of frailty. After multiple adjustments, depressive symptoms were associated with a 2.79-fold (95% CI 1.09-7.10) increased risk of 3-year incident frailty. CONCLUSION: Depressive symptoms are associated with prevalent and incident frailty in Chinese older population. Together with the observations of the European populations, depressive symptoms may be a candidate risk factor of frailty.

Frailty and incident depressive symptoms in a Chinese sample: the Rugao Longevity and Ageing Study.

BACKGROUND: To explore the cross-sectional and longitudinal associations between frailty and incident depressive symptoms in a Chinese elderly sample. METHODS: We analysed data of 1264 older Chinese elders aged 70-87 years in the Rugao Longevity and Ageing Study. The frailty phenotype was assessed using the Fried criteria and depression symptoms was measured by the Geriatric Depression Scale. RESULTS: At baseline, 10.6% of participants had depressive symptoms and 9.0% had frailty. In cross-sectional analysis, both pre-frailty (odds ratio (OR) = 2.18, 95% CI 1.35-3.51) and frailty (OR = 4.64, 95% CI 2.49-8.66) were associated with depressive symptoms. In longitudinal analyses, frailty (OR = 2.12, 95% CI 1.17-3.83), instead of pre-frailty, was associated with 1.5-year incident depressive symptoms in a full-adjusted model among participants free of baseline depressive symptoms. In the components of frailty, lower grip strength was associated with increased risk of depressive symptoms onset (OR = 1.56, 95% CI 1.06-2.29). CONCLUSIONS: Frailty and lower grip strength were associated with incident depressive symptoms in a Chinese elderly sample. Interventions designed to prevent depressive symptoms may be useful by utilising physical aspects of the elderly population.

Counterion-Dictated Self-Cleaning Behavior of Polycation Coating upon Water Action: Macroscopic Dissection of Hydration of Anions.

The counterions of polydiallyldimethylammonium (PDADMA) coatings were altered by incubation in aqueous solutions of different electrolytes. Oil de-wetting on the resulting polycationic surfaces upon water action exhibited a straightforward connection with the Jones-Dole viscosity B-coefficient (Bη) sign of surface counteranions. Upon water action, surface counteranions with negative Bη render PDADMA coatings oil-adhering, but those with positive Bη furnish PDADMA coatings with excellent self-cleaning. The oil-adhering PDADMA surfaces can become self-cleaning upon water action in response to the Bη of surface counteranions sign-switching with increasing water temperature. Courtesy of surface counter-anions with Bη>0, self-cleaning PDADMA coatings enable not only conversion of conventional meshes into self-cleaning membranes for oil/water separation, but also regioselective maneuver of oil flow on polycationic surfaces according to the Bη sign of surface counteranions patterned atop.

Preparation of Alkyl Indium Reagents by Iodine-Catalyzed Direct Indium Insertion and Their Applications in Cross-Coupling Reactions.

An efficient method for the synthesis of alkyl indium reagent by means of an iodine-catalyzed direct indium insertion into alkyl iodide in THF is reported. The thus-generated alkyl indium reagents effectively underwent Pd-catalyzed cross-coupling reactions with various aryl halides, exhibiting good compatibility to a variety of sensitive functional groups. By replacing THF with DMA and using 0.75 equiv of iodine, less reactive alkyl bromide could be used as substrate for indium insertion with equal ease.

Lead-Mediated Highly Diastereoselective Allylation of Aldehydes with Cyclic Allylic Halides.

Lead was found to efficiently mediate the allylation reactions of carbonyl compounds with cyclic allylic halides in the presence of stoichiometric amounts of lithium chloride and a catalytic amount of GaCl3 (20 mol %), leading to the desired homoallylic alcohols in modest to high yields with excellent diastereocontrol (>99:1 syn/anti) and good functional group tolerance. In contrast, the use of either 2-pyridinecarboxaldehyde as the carbonyl substrate or ( E)-cinnamyl bromide as the allylating agent produced the corresponding product with reversed diastereoselectivity (>99:1 anti/syn).

Chromium(III)-Catalyzed Addition of Water and Alcohol to α,ß-Unsaturated Ketones for the Synthesis of ß-Hydroxyl and ß-Alkoxyl Ketones in Aqueous Media.

An efficient chromium(III) chloride-catalyzed Michael-type reaction of water or alcohol with α,ß-unsaturated ketones is developed. A variety of α,ß-unsaturated ketones effectively reacted with either water or alcohols to give the corresponding ß-hydroxyl ketones or ß-alkoxyl ketones in modest to high yields with excellent compatibility to various functional groups. The approach was further utilized for the preparation of synthetically useful compounds containing tetrahydrofuran skeleton.