Multicomponent Diels-Alder Sequences of 1-Aminodendralenes

This thesis explores the use of in situ generated acyclic 1-aminodendralenes in multicomponent diene-transmissive Diels-Alder (DTDA) reaction sequences. Dendralenes have previously been shown to generate polycyclic frameworks in a step-economic manner. The 1-amino substituent is shown to promote very high levels of site selectivity in these processes. Chapter 1 reviews the Diels-Alder reactions of 1-amino-1,3-butadienes and is divided into three sections. The first two sections cover the Diels-Alder reactions of 1-amino-1,3-butadienes and 1-amino-3-siloxy-1,3-butadienes (Rawal’s dienes) generated with a stoichiometric amount of amine. The third section covers enantioselective Diels-Alder reactions involving 1-amino-1,3-butadienes generated in situ with a catalytic amount of a chiral amine. While there have been many reports of Diels-Alder reactions of 1-amino-1,3-butadienes and 1-amino-3-siloxy-1,3-butadienes, there has been only one involving a semi-cyclic 1-amino[3]dendralene. There have been few examples which combine these Diels-Alder reactions with other transformations in multicomponent reactions to generate polycyclic frameworks. Chapter 2 describes the use of acyclic 1-amino[3]dendralenes in multicomponent reactions to generate a diverse range of heterocyclic structures. The condensation/Diels- Alder reaction sequence was tolerant of a variety of amines as well as carbon and hereoatom-based dienophiles. The Diels-Alder reactions of 1-amino[3]dendralenes were highly site-selective, taking place exclusively at the amine substituted 1,3-butadiene unit. The sequence was extended to a one-pot four-component reaction by including an additional dienophile for a Diels-Alder reaction to take place at the newly generated semi-cyclic diene. These condensation/Diels-Alder/Diels-Alder cycloadducts were generated with high diastereoselectivity, the origins of which were investigated and explained with the use of density functional theory calculations (carried out by Prof Paddon-Row). By reversing the order of events, that is performing a Diels-Alder reaction on the skipped dienal precursor before the condensation/Diels-Alder reaction sequence, constitutional isomers were accessed. The second Diels-Alder reaction could be performed intramolecularly when an amine bearing an alkenyl substituent was used. This condensation/Diels-Alder/intramolecular Diels-Alder reaction sequence furnished a variety of tricyclic and tetracyclic heterocycles. Chapter 3 describes the use of acyclic 1-aminodendralenes bearing chiral amines in organocatalytic, enantioselective Diels-Alder reactions to deliver enantioenriched cycloadducts. The enantioselective Diels-Alder reaction between 1-amino[3]dendralenes, the condensation product of skipped dienals and chiral amines, and various dienophiles followed by elimination of the amine generated trienal cycloadducts in good yield and high enantioselectivity. The reaction tolerates substitution on the skipped dienal as well as dienophiles possessing an aldehyde substituent at the α position. Extension of this methodology by performing Wittig and Diels-Alder reactions on the trienal cycloadducts enabled access to enantioenriched polycyclic products. By using a diene-dialdehyde as the starting precursor, it is anticipated that the Horeau principle would operate in the twofold condensation/Diels-Alder/elimination reaction sequence would furnish the cycloadduct in high enantioselectivity. A preliminary attempt successfully generated the desired cycloadduct as the major product

Current trends in drug metabolism and pharmacokinetics.

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug-drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice

Redox modulation of muscle mass and function

Muscle mass and strength are very important for exercise performance. Training-induced musculoskeletal injuries usually require periods of complete immobilization to prevent any muscle contraction of the affected muscle groups. Disuse muscle wasting will likely affect every sport practitioner in his or her lifetime. Even short periods of disuse results in significant declines in muscle size, fiber cross sectional area, and strength. To understand the molecular signaling pathways involved in disuse muscle atrophy is of the utmost importance to develop more effective countermeasures in sport science research. We have divided our review in four different sections. In the first one we discuss the molecular mechanisms involved in muscle atrophy including the main protein synthesis and protein breakdown signaling pathways. In the second section of the review we deal with the main cellular, animal, and human atrophy models. The sources of reactive oxygen species in disuse muscle atrophy and the mechanism through which they regulate protein synthesis and proteolysis are reviewed in the third section of this review. The last section is devoted to the potential interventions to prevent muscle disuse atrophy with especial consideration to studies on which the levels of endogenous antioxidants enzymes or dietary antioxidants have been tested

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

A multi-country test of brief reappraisal interventions on emotions during the COVID-19 pandemic.

The COVID-19 pandemic has increased negative emotions and decreased positive emotions globally. Left unchecked, these emotional changes might have a wide array of adverse impacts. To reduce negative emotions and increase positive emotions, we tested the effectiveness of reappraisal, an emotion-regulation strategy that modifies how one thinks about a situation. Participants from 87 countries and regions (n = 21,644) were randomly assigned to one of two brief reappraisal interventions (reconstrual or repurposing) or one of two control conditions (active or passive). Results revealed that both reappraisal interventions (vesus both control conditions) consistently reduced negative emotions and increased positive emotions across different measures. Reconstrual and repurposing interventions had similar effects. Importantly, planned exploratory analyses indicated that reappraisal interventions did not reduce intentions to practice preventive health behaviours. The findings demonstrate the viability of creating scalable, low-cost interventions for use around the world

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

An enantioconvergent halogenophilic nucleophilic substitution (SN2X) reaction

Bimolecular nucleophilic substitution (SN2) plays a central role in organic chemistry. In the conventionally accepted mechanism, the nucleophile displaces a carbon-bound leaving group X, often a halogen, by attacking the carbon face opposite the C–X bond. A less common variant, the halogenophilic SN2X reaction, involves initial nucleophilic attack of the X group from the front and as such is less sensitive to backside steric hindrance. Herein, we report an enantioconvergent substitution reaction of activated tertiary bromides by thiocarboxylates or azides that, on the basis of experimental and computational mechanistic studies, appears to proceed via the unusual SN2X pathway. The proposed electrophilic intermediates, benzoylsulfenyl bromide and bromine azide, were independently synthesized and shown to be effective.Ministry of Education (MOE)Nanyang Technological UniversityWe acknowledge support from Nanyang Technological University (M4011663 and M4080946); Ministry of Education, Singapore (MOE2016-T2-1-087); and Singapore University of Technology and Design (T1MOE1706 and IDG31800104) as well as computational resources from National Supercomputing Centre (Singapore)

Kinetic and Dynamic Kinetic Resolution of Racemic Tertiary Bromides by Pentanidium‐Catalyzed Phase‐Transfer Azidation

We have developed a method to afford enantiomerically enriched tertiary azides and bromides through pentanidium-catalyzed kinetic resolution (KR) of racemic tertiary bromides under base-free conditions. We found that the absence of water is crucial to attain a high selectivity factor (s). On the other hand, new experimental observations and DFT modeling led us to propose that enantioconvergent azidation of tertiary bromides proceeded through dynamic kinetic resolution (DKR). The investigations particularly identified the crucial roles of base and water in the enantioconvergent process, thus supporting the proposal that the tertiary bromide isomerizes in the presence of base and water through a SN2X pathway.Ministry of Education (MOE)We gratefully acknowledge financial support from Nanyang Technological University through Tier 1 grant 2019-T1-001-107 and the Ministry of Education (Singapore) through Tier 2 grants MOE2016-T2-1-087 and MOE2019-T2-1-091. We also acknowledge financial support from Singapore University of Technology and Design for SUTD-MIT IDC grants T1MOE1706 and IDG31800104

Multicomponent Diene-Transmissive Diels-Alder Sequences Featuring Aminodendralenes

1-Aminodecalins were prepared from acyclic precursors by combining the powerful twofold diene-transmissive Diels-Alder chemistry of [3]dendralenes with the simplicity of enamine formation. On mixing at ambient temperature, a simple dienal condenses with a primary or secondary amine to generate the enamine, a 1-amino-[3]dendralene in situ, and this participates as a double diene in a sequence of two Diels-Alder events with separate dienophiles. Overall, four C-C bonds and one C-N bond are formed. Mechanistic insights into these reactions are provided by means of density functional theory calculations