Chemoselective deoxygenative α-arylation of carboxylic acids, amides, and esters: synthesis of anesthetic and anti-inflammatory compounds.

A metal-free strategy has been developed for the α-arylation of carboxylic acids, secondary amides, and esters employing arenes as key reagents. This process entails the Lewis-acid catalyzed reductive Friedel-Crafts alkylation of arenes utilizing α-ketoacids, facilitated by silane in HFIP solvent. The transformation exhibits exceptional functional group tolerance, enabling late-stage functionalization of natural products. This one-step protocol has been successfully used to synthesize commercially available drugs, such as adiphenine, piperidolate, derivatives of ketoprofen, ibuprofen, flurbiprofen, and the pesticide bromopropylate.

Synthesis of tetralone and indanone derivatives via cascade reductive Friedel-Crafts alkylation/cyclization of keto acids/esters.

We disclose herein a metal-free cascade reductive Friedel-Crafts alkylation/cyclization of keto acids/esters for the synthesis of tetralones and indanones. Owing to the simple reaction conditions and setup, this protocol features broad substrate generality, facile scalability, and remarkable functional group tolerance, including the synthesis of bioactive molecule sertraline.

Grains in a Modern Time: A Comprehensive Review of Compositions and Understanding Their Role in Type 2 Diabetes and Cancer.

Globally, type 2 diabetes (T2D) and Cancer are the major causes of morbidity and mortality worldwide and are considered to be two of the most significant public health concerns of the 21st century. Over the next two decades, the global burden is expected to increase by approximately 60%. Several observational studies as well as clinical trials have demonstrated the health benefits of consuming whole grains to lower the risk of several chronic non-communicable diseases including T2D and cancer. Cereals grains are the primary source of energy in the human diet. The most widely consumed pseudo cereals include (quinoa, amaranth, and buckwheat) and cereals (wheat, rice, and corn). From a nutritional perspective, both pseudo cereals and cereals are recognized for their complete protein, essential amino acids, dietary fibers, and phenolic acids. The bran layer of the seed contains the majority of these components. Greater intake of whole grains rather than refined grains has been consistently linked to a lower risk of T2D and cancer. Due to their superior nutritional compositions, whole grains make them a preferred choice over refined grains. The modulatory effects of whole grains on T2D and cancer are also likely to be influenced by several mechanisms; some of these effects may be direct while others involve altering the composition of gut microbiota, increasing the abundance of beneficial bacteria, and lowering harmful bacteria, increasing insulin sensitivity, lowering solubility of free bile acids, breaking protein down into peptides and amino acids, producing short-chain fatty acids (SCFAs), and other beneficial metabolites that promote the proliferation in the colon which modulate the antidiabetic and anticancer pathway. Thus, the present review had two aims. First, it summarized the recent knowledge about the nutritional composition and bioactive acids in pseudo cereals (quinoa, amaranth, and buckwheat) and cereals (wheat, rice, and corn); the second section summarized and discussed the progress in recent human studies, such as observational (cross-sectional studies, case-control studies, and cohort studies) and intervention studies to understand their role in T2D and cancer including the potential mechanism. Overall, according to the scientific data, whole grain consumption may reduce the incidence of T2D and cancer. Future studies should carry out randomized controlled trials to validate observational results and establish causality. In addition, the current manuscript encourages researchers to investigate the specific mechanisms by which whole grains exert their beneficial effects on health by examining the effects of different types of specific protein, dietary fibers, and phenolic acids that might help to prevent or treat T2D and cancer.

Composition of Whole Grain Dietary Fiber and Phenolics and Their Impact on Markers of Inflammation.

Inflammation is an important biological response to any tissue injury. The immune system responds to any stimulus, such as irritation, damage, or infection, by releasing pro-inflammatory cytokines. The overproduction of pro-inflammatory cytokines can lead to several diseases, e.g., cardiovascular diseases, joint disorders, cancer, and allergies. Emerging science suggests that whole grains may lower the markers of inflammation. Whole grains are a significant source of dietary fiber and phenolic acids, which have an inverse association with the risk of inflammation. Both cereals and pseudo-cereals are rich in dietary fiber, e.g., arabinoxylan and ß-glucan, and phenolic acids, e.g., hydroxycinnamic acids and hydroxybenzoic acids, which are predominantly present in the bran layer. However, the biological mechanisms underlying the widely reported association between whole grain consumption and a lower risk of disease are not fully understood. The modulatory effects of whole grains on inflammation are likely to be influenced by several mechanisms including the effect of dietary fiber and phenolic acids. While some of these effects are direct, others involve the gut microbiota, which transforms important bioactive substances into more beneficial metabolites that modulate the inflammatory signaling pathways. Therefore, the purpose of this review is twofold: first, it discusses whole grain dietary fiber and phenolic acids and highlights their potential; second, it examines the health benefits of these components and their impacts on subclinical inflammation markers, including the role of the gut microbiota. Overall, while there is promising evidence for the anti-inflammatory properties of whole grains, further research is needed to understand their effects fully.

Enhancing biofilm penetration and antibiofilm efficacy with protein nanocarriers against pathogenic biofilms.

Nanocarriers play an important role in enhancing the efficacy of antibiotics against biofilms by improving their penetration and prolonging retention in pathogenic biofilms. Herein, the multifunctional nanocarriers including nanospheres (NS) and nanotubes (NT) with a high biocompatibility and biodegradability were prepared through self-assembly of partially hydrolyzed α-lactalbumin. The effects of these two different shaped nanocarriers on the delivery of antibiotics for biofilm treatment were examined by conducting in vitro antibiofilm experiment and in vivo infected wound model. The strong affinity of NS and NT for the bacterial surface allows antibiotics to be concentrated in the bacteria. Notably, the high permeability of NT into biofilms facilitates deeper penetration and the easier diffusion of loaded antibiotics within the biofilm. Furthermore, the acidic biofilm environment triggers the release of antibiotics from the NT, resulting in the accumulation of high local antibiotic concentrations. Therefore, NT could efficiently clean and inhibit the biofilm formation while also destroying the mature biofilms. In a S. aureus infected wound animal model, treatment with antibiotic-loaded NT demonstrated accelerated healing of S. aureus infected wounds when compared to free antibiotic treatment. These findings indicate that NT nanocarrier strategy is promising for treating bacterial biofilm infections, offering the potential for lower antibiotics dosages and preventing the overuse of antibiotics.

Silyl Cation-Initiated, Brønsted Acid-Catalyzed Strategy toward Unsymmetrical 3,3-Disubstituted 2-Oxindoles and Azonazine Cores.

Herein, a mild, metal-free, robust approach for synthesizing valuable and sterically demanding unsymmetrical 3,3-disubstituted 2-oxindoles via reductive cyclization of α-ketoamides is reported. This operationally simple protocol is initiated by a silyl cation and further catalyzed by a Brønsted acid. We have utilized a wide range of arenes, amines, and thiols as coupling partners with various α-ketoamides. The products were afforded in excellent regioselectivity and good functional group tolerance. This procedure provides easy access to the scaffolds of azonazine and its derivatives with an excellent syn-diastereoselectivity bearing all-carbon quaternary stereocenters.

Brookhart's Acid-Catalyzed Switchable Regioselective N-Alkylation of Arylamines/Heterocyclic Amines with Cyclopropylcarbinols by Temperature Regulation.

An unprecedented, Brookhart's acid-catalyzed temperature-switchable regioselective divergent approach for N-alkylation of arylamines and heterocyclic amines by utilising cyclopropylcarbinols is presented herein. The reaction offers N-alkylated cyclopropyl derivatives and homoallyl amines by employing 2.5 mol% catalyst loading at different temperatures in excellent regioselectivity and yields. This method has shown to be relevant with a wide range of cyclopropylcarbinols, including aliphatic ones. Several control experiments and spectroscopic studies have been performed to gain insight into the reaction mechanism. Further, the synthetic utility of the protocol has also been described.

Catalyst-Switchable Divergent Synthesis of Bis(indolyl)alkanes and 3-Alkylated Indoles from Styrene Oxides.

A novel and effective Brønsted acid-catalyzed chemoselective synthesis of bis(indolyl)alkanes and 3-alkyl indoles is reported. The selectivity of two significant indole derivatives is attained by allowing the same substrates to go through divergent reaction routes catalyzed by different catalysts. Furthermore, this mild approach is applicable to a wide range of substrates and has high efficacy in large-scale reactions. A plausible mechanism is provided based on the control experiments and spectroscopic studies.

Rapid Access to Arylated and Allylated Cyclopropanes via Brønsted Acid-Catalyzed Dehydrative Coupling of Cyclopropylcarbinols.

A regioselective protocol for the synthesis of cyclopropyl derivatives that relies on Brookhart acid-catalyzed dehydrative coupling over substituted cyclopropylcarbinols without rearrangement is reported herein. The reactions proceed promptly at 25 °C with only 2.0 mol % catalyst loading and produce the cyclopropyl derivatives in excellent yields. This method is well tolerated with a vast range of cyclopropylcarbinols including aliphatic cyclopropylcarbinols, where no elimination product was obtained, demonstrating the protocol's utility. Further, the Hammett correlation suggested the formation of a cyclopropylcarbinyl cation followed by a coupling reaction. An extremely effective gram-scale reaction has also been demonstrated with a high turnover number.

Brønsted Acid-Catalysed Epoxide Ring-Opening Using Amine Nucleophiles: A Facile Access to ß-Amino Alcohols.

A mild, efficient, and metal-free synthetic protocol for the synthesis of ß-amino alcohols is reported. The reaction proceeds at room temperature with only 0.5 mol % catalyst loading and affords ß-amino alcohol derivatives in excellent yield. This protocol is well-tolerated by a wide range of styrene oxide and aniline derivatives. A notably efficacious gram-scale synthesis is also reported with a high TON=842. Further, the Hammett correlation study was also performed to identify the rate-determining step.

Overview of the Composition of Whole Grains' Phenolic Acids and Dietary Fibre and Their Effect on Chronic Non-Communicable Diseases.

Chronic non-communicable diseases are the major cause of death globally. Whole grains are recommended in dietary guidelines worldwide due to increasing evidence that their consumption can improve health beyond just providing energy and nutrients. Epidemiological studies have suggested that the incorporation of whole grains, as part of a healthy diet, plays a key role in reducing one's risk for cardiovascular diseases (CVDs), obesity, type 2 diabetes (T2D) and cancer. Phenolic acids and dietary fibre are important components found in whole grains that are largely responsible for these health advantages. Both phenolic acids and dietary fibre, which are predominantly present in the bran layer, are abundant in whole-grain cereals and pseudo-cereals. Several studies indicate that whole grain dietary fibre and phenolic acids are linked to health regulation. The main focus of this study is two-fold. First, we provide an overview of phenolic acids and dietary fibres found in whole grains (wheat, barley, oats, rice and buckwheat). Second, we review existing literature on the linkages between the consumption of whole grains and the development of the following chronic non-communicable diseases: CVDs, obesity, T2D and cancer. Altogether, scientific evidence that the intake of whole grains reduces the risk of certain chronic non-communicable disease is encouraging but not convincing. Based on previous studies, the current review encourages further research to cover the gap between the emerging science of whole grains and human health.

Lambert Salt-Initiated Development of Friedel-Crafts Reaction on Isatin to Access Distinct Derivatives of Oxindoles.

Herein, a mild metal-free and efficacious route for the synthesis of biologically important 3-aryl oxindole derivatives is described. Using Lambert salt-initiated hydroarylation of isatin, a diverse array of monoarylated products, symmetrical/unsymmetrical double-arylated products, and deoxygenated hydroarylated products could be synthesized from the single starting substrate in good to excellent yields. A preliminary mechanistic study revealed that the reaction proceeds via a monoarylated product followed by a nucleophilic attack by another electron-rich arene nucleophile under mild conditions. The potential of newly synthesized symmetric/unsymmetric 3,3-disubstituted oxindole, 3-substituted 3-hydroxy oxindoles, 3,3-di(indolyl)indolin-2-ones, and α-aryl oxindoles as valuable building blocks is further illustrated.

Sugar- and Artificially Sweetened Beverages Consumption Linked to Type 2 Diabetes, Cardiovascular Diseases, and All-Cause Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

Although studies have examined the association between habitual consumption of sugar- (SSBs) and artificially sweetened beverages (ASBs) and health outcomes, the results are inconclusive. Here, we conducted a dose-response meta-analysis of prospective cohort studies in order to summarize the relationship between SSBs and ASBs consumption and risk of type 2 diabetes (T2D), cardiovascular diseases (CVDs), and all-cause mortality. All relevant articles were systematically searched in PubMed, Embase, and Ovid databases until 20 June 2020. Thirty-four studies met the inclusion criteria and were eligible for analysis. Summary relative risks (RRs) and 95% confidence intervals (95% CI) were estimated using random effects or fixed-effects model for highest versus lowest intake categories, as well as for linear and non-linear relationships. With each additional SSB and ASB serving per day, the risk increased by 27% (RR: 1.27, 95%CI: 1.15-1.41, I2 = 80.8%) and 13% (95%CI: 1.03-1.25, I2 = 78.7%) for T2D, 9% (RR: 1.09, 95%CI: 1.07-1.12, I2 = 42.7%) and 8% (RR: 1.08, 95%CI: 1.04-1.11, I2 = 45.5%) for CVDs, and 10% (RR: 1.10, 95%CI: 0.97-1.26, I2 = 86.3%) and 7% (RR: 1.07, 95%CI: 0.91-1.25, I2 = 76.9%) for all-cause mortality. Linear relationships were found for SSBs with T2D and CVDs. Non-linear relationships were found for ASBs with T2D, CVDs, and all-cause mortality and for SSBs with all-cause mortality. The findings from the current meta-analysis indicate that increased consumption of SSBs and ASBs is associated with the risk of T2D, CVDs, and all-cause mortality.

A Novel Machine Learning Strategy for the Prediction of Antihypertensive Peptides Derived from Food with High Efficiency.

Strategies to screen antihypertensive peptides with high throughput and rapid speed will doubtlessly contribute to the treatment of hypertension. Food-derived antihypertensive peptides can reduce blood pressure without side effects. In the present study, a novel model based on the eXtreme Gradient Boosting (XGBoost) algorithm was developed and compared with the dominating machine learning models. To further reflect on the reliability of the method in a real situation, the optimized XGBoost model was utilized to predict the antihypertensive degree of the k-mer peptides cutting from six key proteins in bovine milk, and the peptide-protein docking technology was introduced to verify the findings. The results showed that the XGBoost model achieved outstanding performance, with an accuracy of 86.50% and area under the receiver operating characteristic curve of 94.11%, which were better than the other models. Using the XGBoost model, the prediction of antihypertensive peptides derived from milk protein was consistent with the peptide-protein docking results, and was more efficient. Our results indicate that using the XGBoost algorithm as a novel auxiliary tool is feasible to screen for antihypertensive peptides derived from food, with high throughput and high efficiency.