α,ß-Desaturation and Formal ß-C(sp3)-H Fluorination of N-Substituted Amines: A Late-Stage Functionalization Strategy Enabled by Electrochemistry.

Incorporation of C(sp3)-F bonds in biologically active compounds is a common strategy employed in medicinal and agricultural chemistry to tune pharmacokinetic and pharmacodynamic properties. Due to the limited number of robust strategies for C(sp3)-H fluorination of complex molecules, time-consuming de novo syntheses of such fluorinated analogs are typically required, representing a major bottleneck in the drug discovery process. In this work, we present a general and operationally simple strategy for site-specific ß-C(sp3)-H fluorination of amine derivatives including carbamates, amides, and sulfonamides, which is compatible with a wide range of functional groups including N-heteroarenes. In this approach, an improved electrochemical Shono oxidation is used to set the site of functionalization via net α,ß-desaturation to access enamine derivatives. We further developed a series of new transformations of these enamine intermediates to synthesize a variety of ß-fluoro-α-functionalized structures, allowing efficient access to pertinent targets to accelerate drug discovery campaigns.

Dietary Hydroxytyrosol Supplementation on Growth Performance, Gut Morphometry, and Oxidative and Inflammatory Status in LPS-Challenged Broilers.

This study assessed the effects of hydroxytyrosol (HT) on 8- to 20-day-old broilers challenged with lipopolysaccharide (LPS); 180 Cobb500™ male chicks were randomly assigned to 3 treatment groups, each comprising 10 replicates with 6 birds per replicate. Treatments included a control diet (CON), CON with LPS administration, and CON + LPS supplemented with 10 mg of HT/kg of feed. LPS was administered intraperitoneally on days 14, 16, 18, and 20. Body weight (BW), body weight gain (BWG), and the feed conversion ratio (FCR) were measured. On day 20, ten birds per treatment were slaughtered for analysis. Bursa, spleen, and liver were collected, and their respective relative weight was determined. The jejunum was destined for morphological analyses of villus height (VH), crypt depth (CD), and their ratio (VH:CD), and for mRNA expression of nuclear factor kappa B (NF-κB), catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and interleukins 10 (IL-10), 1 beta (IL-1ß), and 8 (IL-8). HT improved BW, BWG, and FCR, and reduced crypt depth (CD) while increasing the VH:CD ratio in the jejunum. Moreover, HT downregulated mRNA expression of CAT, GPx, IL-10, and IL-1ß. In conclusion, HT enhances broiler growth performance, mitigates jejunal mucosa damage from LPS, and modulates antioxidant and immune responses.

Frustrated Radical Pairs in Organic Synthesis.

Frustrated radical pairs (FRPs) describe the phenomenon that two distinct radicals─which would otherwise annihilate each other to form a closed-shell covalent adduct─can coexist in solution, owing to steric repulsion or weak bonding association. FRPs are typically formed via spontaneous single-electron transfer between two sterically encumbered precursors─an oxidant and a reductant─under ambient conditions. The two components of a FRP exhibit orthogonal chemical properties and can often act in cooperativity to achieve interesting radical reactivities. Initially observed in the study of traditional frustrated Lewis pairs, FRPs have recently been shown to be capable of homolytically activating various chemical bonds. In this Perspective, we will discuss the discovery of FRPs, their fundamental reactivity in chemical bond activation, and recent developments of their use in synthetic organic chemistry, including in C-H bond functionalization. We anticipate that FRPs will provide new reaction strategies for solving challenging problems in modern organic synthesis.

Research Note: Nitrogen-corrected apparent metabolizable energy and standardized ileal amino acid digestibility determination of high-protein dried distiller's grains and corn bran with solubles for broilers.

Metabolism and digestibility trials were performed on broiler chickens to determine 1) nitrogen-corrected apparent metabolizable energy (AMEn) using total excreta collection and 2) standardized ileal amino acid digestibility (SIAAD) using the ileal digesta collection from high-protein dried distillers' grains (HP-DDG) and corn bran with solubles (CBS). The results of the metabolism trial indicated that AMEn values for HP-DDG and CBS were 3,334 kcal/kg and 2,083 kcal/kg on dry matter (DM) basis, respectively. Concerning the HP-DDG, the digestibility trial resulted in the following SIAAD values and digestible concentrations, respectively: 80.33% and 1.09 for Lys, 85.95% and 1.44 for Met + Cys, 75.58% and 1.24 for Thr, 89.58% and 1.66 for Arg, 84.91% and 1.08 for His, 86.37% and 1.35 for Ile, 90.64% and 4.56 for Leu, 85.76% and 1.80 for Val, and 88.67% and 1.90 for Phe. Concerning the CBS, the following SIAAD values and digestible concentrations were measured, respectively: 79.29% and 0.44 for Lys, 89.57% and 0.31 for Met + Cys, 78.89% and 0.40 for Thr, 92.28% and 0.66 for Arg, 87.48% and 0.36 for His, 93.40% and 0.35 for Ile, 92.27% and 1.01 for Leu, 90.97% and 0.51 for Val, and 88.81% and 0.45 for Phe. The digestibility average of CBS is 88.45% for essential amino acids and 85.21% for nonessential amino acids, whereas the digestibility average of HP-DDG is 85.83% for essential amino acids and 83.83% for nonessential amino acids.

An Electrochemical Strategy to Synthesize Disilanes and Oligosilanes from Chlorosilanes.

Silanes are important compounds in industrial and synthetic chemistry. Here, we develop a general approach for the synthesis of disilanes as well as linear and cyclic oligosilanes via the reductive activation of readily available chlorosilanes. The efficient and selective generation of silyl anion intermediates, which are arduous to achieve by other means, allows for the synthesis of various novel oligosilanes by heterocoupling. In particular, this work presents a modular synthesis for a variety of functionalized cyclosilanes, which may give rise to materials with distinct properties from linear silanes but remain challenging synthetic targets. In comparison to the traditional Wurtz coupling, our method features milder conditions and improved chemoselectivity, broadening the functional groups that are compatible in oligosilane preparation. Computational studies support a mechanism whereby differential activation of sterically and electronically distinct chlorosilanes are achieved in an electrochemically driven radical-polar crossover mechanism.

Research Note: The influence of different isoleucine: lysine ratios on the growth performance of broiler chickens fed low-protein diets.

Two trials were carried out to assess the effects of different ratios of standardized ileal digestible isoleucine:lysine (SID Ile:Lys) on the growth performance of broiler chickens fed low-protein diets. A total of 1,320 male chickens were distributed in each trial into 6 treatments, with 10 replicates with 22 birds each. A control diet was formulated that satisfied the nutritional requirements of the broilers, and a low-protein diet was formulated with reduced protein content, meeting broiler nutritional requirements, except for the SID Ile levels. Five SID Ile:Lys ratios (56%, 61%, 66%, 71%, and 76%) were obtained by adding l-isoleucine to the low-protein diet. The body weight (BW), body weight gain (BWG), average daily feed intake (ADFI), and feed conversion ratio (FCR) were evaluated from day 1 to day 21 in trial 1, and from day 22 to day 44 in trial 2. ANOVA was performed on the data, and the treatments were compared to the control group using Dunnett's test (P ≤ 0.05). Regression analyses were performed for modeling the variables assessed and the ratios of SID Ile:Lys. There was no significant difference between the treatments on ADFI of birds (P > 0.05). The BW, BWG, and FCR showed a quadratic effect as the SID Ile:Lys ratio increased in low-protein diets in trials 1 and 2 (P ≤ 0.05). In conclusion, the recommended ratio of SID Ile:Lys in low-protein diets for growth performance is around 66% for broiler chickens from 1 to 21 d old and is around 65% for broiler chickens from 22 to 44 d old.

Deep Electroreductive Chemistry: Harnessing Carbon- and Silicon-based Reactive Intermediates in Organic Synthesis.

This Viewpoint outlines our recent contribution in electroreductive synthesis. Specifically, we leveraged deeply reducing potentials provided by electrochemistry to generate radical and anionic intermediates from readily available alkyl halides and chlorosilanes. Harnessing the distinct reactivities of radicals and anions, we have achieved several challenging transformations to construct C-C, C-Si, and Si-Si bonds. We highlight the mechanistic design principle that underpinned the development of each transformation and provide a view forward on future opportunities in growing area of reductive electrosynthesis.

Effects of Hydroxytyrosol Supplementation on Performance, Fat and Blood Parameters of Broiler Chickens.

The study aimed to evaluate the effects of dietary supplementation of hydroxytyrosol (HT) on performance, fat, and blood parameters of broilers. In total, 960 male chicks were distributed into four treatments groups with 12 replicates with 20 birds per pen, with varying HT levels (0, 5, 10, and 50 mg/kg of feed) added to the basal diet from 1 to 42 days old. Feed intake, body weight gain, and feed conversion ratio were evaluated. Enzymes related to liver injury were evaluated in blood. Fatty acid profile and malondialdehyde (MDA) concentration were determined in the breast meat. Dietary supplementation of HT did not improve broilers' performance (p > 0.05). Birds fed 50 mg HT/kg had lower AST, ALT, and GGT concentrations (p ≤ 0.05), whereas broilers fed 5, 10, and 50 mg HT/kg, had lower TBIL concentrations (p ≤ 0.05). Breast meat of broilers fed 50 mg HT/kg had lower lipid content, saturated fatty acid, unsaturated fatty acids, MDA concentrations (p ≤ 0.05), and polyunsaturated fatty acids (p < 0.0001). In summary, supplementation of 5, 10, and 50 mg HT/kg does not improve the performance of broilers, but the dose of 50 mg HT/kg helps the liver against inflammation and improves fat parameters.

The effects of arginine supplementation through different ratios of arginine:lysine on performance, skin quality and creatine levels of broiler chickens fed diets reduced in protein content.

Two trials were carried out to assess the effects of arginine supplementation through ratios of digestible arginine:lysine on growth performance, skin quality and creatine levels in muscle and serum of broiler chickens fed diets reduced in protein content. A total of 1,540 Cobb500 male chickens were distributed into 7 treatments, with 10 replicates with 22 birds each. The experimental diets were based on corn and soybean meal, and a control diet was formulated to satisfy broiler nutritional requirements. A basal diet with reduced protein content was formulated to meet broiler nutritional requirements, except for SID Arg levels. The experimental diets were obtained by adding L-arginine to basal diets, meeting 6 different SID Arg:Lys ratios (94, 100, 106, 112, 118, and 124%). Body weight, body weight gain, average daily feed intake, and feed conversion ratio were evaluated from 01 to 21 d old (trial 1) and from 22 to 44 d old (trial 2). At 21 and 44 d, in trials 1 and 2, respectively, birds were slaughtered to assess skin thickness (ST), skin strength (SS), creatine level in muscle (CRM) and serum (CRS). Data were subjected to ANOVA, and treatments were compared to the control group by Dunnett's test (P ≤ 0.05). Regression analyses were performed to model the variables assessed and the ratios of SID Arg:Lys. The SID Arg:Lys ratios did not affect ADFI of broilers in both trials (P > 0.05), whereas it linearly increased the BW, BWG, and ST, in both trials (P < 0.001). The FCR of broilers linearly decreased, in trial 1 (P = 0.038) and trial 2 (P < 0.001). The CRM of birds had a linear effect (P < 0.001) in trial 1, and a quadratic effect (P = 0.001) in trial 2. The CRS and SS of broilers linearly increased, in trial 2 (P < 0.001). In conclusion, increasing SID Arg:Lys ratios in diets reduced CP enhanced growth performance, skin quality and CR levels in muscle and serum of broiler chickens from 01 to 21 and 22 to 44 d old.

Intercepting Hydrogen Evolution with Hydrogen-Atom Transfer: Electron-Initiated Hydrofunctionalization of Alkenes.

Hydrogen-atom transfer mediated by earth-abundant transition-metal hydrides (M-Hs) has emerged as a powerful tool in organic synthesis. Current methods to generate M-Hs most frequently rely on oxidatively initiated hydride transfer. Herein, we report a reductive approach to generate Co-H, which allows for canonical hydrogen evolution reactions to be intercepted by hydrogen-atom transfer to an alkene. Electroanalytical and spectroscopic studies provided mechanistic insights into the formation and reactivity of Co-H, which enabled the development of two new alkene hydrofunctionalization reactions.

Exploring Electrochemical C(sp3)-H Oxidation for the Late-Stage Methylation of Complex Molecules.

The "magic methyl" effect, a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group, provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)-H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C-C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the "magic methyl" effect. This synthesis strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

Electrocatalysis as an enabling technology for organic synthesis.

Electrochemistry has recently gained increased attention as a versatile strategy for achieving challenging transformations at the forefront of synthetic organic chemistry. Electrochemistry's unique ability to generate highly reactive radical and radical ion intermediates in a controlled fashion under mild conditions has inspired the development of a number of new electrochemical methodologies for the preparation of valuable chemical motifs. Particularly, recent developments in electrosynthesis have featured an increased use of redox-active electrocatalysts to further enhance control over the selective formation and downstream reactivity of these reactive intermediates. Furthermore, electrocatalytic mediators enable synthetic transformations to proceed in a manner that is mechanistically distinct from purely chemical methods, allowing for the subversion of kinetic and thermodynamic obstacles encountered in conventional organic synthesis. This review highlights key innovations within the past decade in the area of synthetic electrocatalysis, with emphasis on the mechanisms and catalyst design principles underpinning these advancements. A host of oxidative and reductive electrocatalytic methodologies are discussed and are grouped according to the classification of the synthetic transformation and the nature of the electrocatalyst.

A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL.

Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific proteins in a proteasome-dependent manner. However, a major limitation of TPD is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent recruiter for the E3 ligase RNF114. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or, in some cases, inactivity. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs, and we demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing selectivity for the degradation of neo-substrate proteins.

Development of a Terpene Feedstock-Based Oxidative Synthetic Approach to the Illicium Sesquiterpenes.

The Illicium sesquiterpenes are a family of natural products containing over 100 highly oxidized and structurally complex members, many of which display interesting biological activities. This comprehensive account chronicles the evolution of a semisynthetic strategy toward these molecules from (+)-cedrol, seeking to emulate key aspects of their presumed biosynthesis. An initial route generated lower oxidation state analogs but failed in delivering a crucial hydroxy group in the final step. Insight gathered during these studies, however, ultimately led to a synthesis of the pseudoanisatinoids along with the allo-cedrane natural product 11- O-debenzoyltashironin. A second-generation strategy was then developed to access the more highly oxidized majucinoid compounds including jiadifenolide and majucin itself. Overall, one dozen natural products can be accessed from an abundant and inexpensive terpene feedstock. A multitude of general observations regarding site-selective C(sp3)-H bond functionalization reactions in complex polycyclic architectures are reported.

Contemporary Synthetic Strategies toward seco-Prezizaane Sesquiterpenes from Illicium Species.

Since the elucidation of the structure of anisatin in the late 1960s, sesquiterpene lactones from various Illicium species of plants have captivated synthetic chemists worldwide, resulting in a large body of synthetic work. In particular, Illicium sesquiterpenes containing the seco-prezizaane carbon framework have seen immense interest in recent years owing to desirable structural and medicinal attributes. This synopsis will focus on recently developed synthetic strategies to access these compact, highly oxidized terpenoids.

Formal Total Synthesis of Actinoranone: Synthesis Approaches and Cytotoxic Studies.

This article describes our efforts toward the total synthesis of actinoranone. Our synthesis strategies rely on a convergent route to connect the terpenoid and polyketide fragments, employing catalysis and powerful classical reactions for the assembly of these key fragments. A new transformation was disclosed during this work, a domino ring-opening and esterification. Initial cytotoxic studies for the selected synthesis intermediates are also presented.

Formal Total Synthesis of Actinoranone and Asymmetric Synthesis of Labda-7,13-(E)-dien-15-ol.

The syntheses of the polyketide and terpenoid fragments of actinoranone are reported in a concise fashion, relying on catalytic methods. Minimization on the use of protecting groups and redox reactions allowed the synthesis of the carbon backbone of actinoranone in 20 steps (11 steps for LLS). The asymmetric synthesis of labda-7,13-(E)-dien-15-ol is also disclosed.

Comparing the Comprehensive Stroke Ward Versus Mixed Rehabilitation Ward-The Importance of the Team in the Acute Stroke Care in a Case-Control Study.

BACKGROUND AND PURPOSE: Ischemic stroke is one of the most frequent causes of death in Brazil. Many measures have been taken to reduce this tragic outcome, and one of those is the implementation of stroke units in hospitals. The aim of the present study is to analyze the in-hospital complications for patients with ischemic stroke admitted in a comprehensive stroke ward (CSW) as compared to patients admitted in a mixed rehabilitation ward (MRW). METHODS: A retrospective interventional study with historic controls of patients admitted to the Neurology Division between January 2010 and October 2013. Patients admitted between January 2010 and September 2012 were included in the MRW group, and patients admitted from October 2012 until October 2013 were included in the CSW group. Throughout the whole study period, the same team assisted all the patients. Both groups were paired in relation to age and gender. The rate of in-hospital complications, mortality, and independency on discharge were evaluated in both groups. RESULTS: Each group was comprised of 91 patients. There were no statistically significant differences for any of the risk factors analyzed between the 2 groups nor for outcome measures-in-hospital complications, mortality, and independence on discharge. CONCLUSION: The present study demonstrated that in-hospital complications, independence on discharge, and mortality have similar rates in patients admitted to an MRW compared to patients admitted to a CSW, when the same staff provided them with specialized in-hospital care. EVIDENCE LEVEL: Case-control study-Evidence Level 3.

Estimation of optimal ratios of digestible phenylalanine + tyrosine, histidine, and leucine to digestible lysine for performance and breast yield in broilers.

Three experiments were carried out to estimate the optimal ratios of digestible phenylalanine + tyrosine (Phe + Tyr), histidine (His), and leucine (Leu) relative to digestible lysine (Lys) for performance and carcass criteria of Cobb-500 broilers from 8 to 17 d of age. In each experiment, 160 male chicks were allocated to a completely randomized experimental design with eight replicate pens, each receiving five dietary treatments. A common, semi-purified basal diet was formulated to meet all dietary recommendations except for those of the tested amino acids (i.e., Phe + Tyr, His, and Leu). Growth performance and carcass characteristics data were analyzed using various requirement-estimation models, including 95% of the quadratic regression, linear response plateau (LRP; i.e., stepwise regression), LRP-to-quadratic regression ratio; and quadratic broken line (QBL). Graded digestible Phe + Tyr ratios elicited a quadratic response (P < 0.05) in body weight gain and linear responses (P < 0.05) in breast and breast fillet weights. Linear effects (P < 0.05) were also observed when graded ratios of digestible His were fed for feed intake and weight gain, and quadratic responses (P < 0.05) were noted for feed conversion ratio and breast and breast fillet weights and yields. Graded Leu ratios elicited quadratic responses (P < 0.05) in feed intake, weight gain, and breast and breast fillet weight and yield. Based on growth and carcass parameters, the estimated ideal digestible ratios of Phe + Tyr, His, and Leu relative to digestible Lys were 112, 38, and 104%, respectively, for broiler chicks raised from 8 to 17 d of age.

Design and synthesis of cenocladamide analogues and their evaluation against breast cancer cell lines.

This work describes the total synthesis of the alkaloid cenocladamide and a concise library of nine structural analogues aiming at their evaluation against the breast cancer cell line MDA-MB-231. The most promising compound (3; IC50 = 6.6 µM) was also evaluated in a panel of seven breast cancer cell lines and two non-tumorigenic cell lines. We further conducted an initial investigation on the mechanism of action of analogue 3, which lacks the endocyclic double bond when compared to cenocladamide. The present study presents the discovery of a cenocladamide analogue with interesting cytotoxic activity, which could be useful for further optimization towards new chemotherapeutic agents for breast cancer treatment.