The Certainty of a Few Good Reactions.

The impact of click chemistry was recently recognized with the 2022 Nobel Prize in Chemistry. The breadth of areas where click chemistry has accelerated discovery is prodigal. In one of the most written about subjects in chemistry over recent years, this short perspective zones in on a small fragment of what we, the authors, consider are some of the most critical developments in synthetic chemistry, which have expanded access to the click chemistry toolbox.

Stereoretentive enantioconvergent reactions.

Enantioconvergent reactions are pre-eminent in contemporary asymmetric synthesis as they convert both enantiomers of a racemic starting material into a single enantioenriched product, thus avoiding the maximum 50% yield associated with resolutions. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate's stereochemical information, thus limiting the potential substrate scope to molecules that contain labile stereogenic units. Here we present an alternative approach to enantioconvergent reactions that can proceed with full retention of the racemic substrate's configuration.

Modular synthesis of functional libraries by accelerated SuFEx click chemistry.

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines.

Protocol for producing phosphoramidate using phosphorus fluoride exchange click chemistry.

Phosphorus fluoride exchange (PFEx) is a catalytic click reaction that involves exchanging high oxidation state P-F bonds with alcohol and amine nucleophiles, reliably yielding P-O- and P-N-linked compounds. Here, we describe steps for preparing a phosphoramidic difluoride and performing two sequential PFEx reactions to yield a phosphoramidate through careful catalyst selection. We then detail procedures for handling and quenching potentially toxic P-F-containing compounds to ensure user safety when conducting PFEx reactions.

Inhibition of mitochondrial metabolism by (-)-jerantinine A: synthesis and biological studies in triple-negative breast cancer cells.

A concise semi-synthesis of the alkaloids, (-)-jerantinine A and (-)-melodinine P, and derivatives thereof, is reported. The novel compounds were shown to have potent activity against MDA-MB-231 triple-negative breast cancer cells. Furthermore, unbiased metabolomics and live cell reporter assays reveal (-)-jerantinine A alters cellular redox metabolism and induces oxidative stress that coincides with cell cycle arrest.

Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant (VRE), methicillin-resistant (MRSA), as well as vancomycin-resistant (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis.

Sulfur fluoride exchange.

Sulfur Fluoride Exchange (SuFEx) is a click reaction par excellence that has revolutionized multiple research fields. In this Primer, we delve into the essential elements of SuFEx operation, catalysis, and SuFExable connective hubs. We also explore the cutting-edge applications of SuFEx in drug development, polymer science, and biochemistry.

TORPEdO: A phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in oropharyngeal cancer.

•There is a lack of prospective level I evidence for the use of PBT for most adult cancers including oropharyngeal squamous cell carcinoma (OPSCC).•TORPEdO is the UK's first PBT clinical trial and aims to determine the benefits of PBT for OPSCC.•Training and support has been provided before and during the trial to reduce variations of contouring and radiotherapy planning.

A Rapid Review of Collision Avoidance and Warning Technologies for Mining Haul Trucks.

Given the recent focus on powered haulage incidents within the US mining sector, an appraisal of collision avoidance/warning systems (CXSs) through the lens of the available research literature is timely. This paper describes a rapid review that identifies, characterizes, and classifies the research literature to evaluate the maturity of CXS technology through the application of a Technology Readiness Assessment. Systematic search methods were applied to three electronic databases, and relevant articles were identified through the application of inclusion and exclusion criteria.

Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors.

Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core "SuFExable" hubs-exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)-enabling the modular assembly of compounds through multiple reaction pathways.

Methodology for the development of National Multidisciplinary Management Recommendations using a multi-stage meta-consensus initiative.

Background: Methods for developing national recommendations vary widely. The successful adoption of new guidance into routine practice is dependent on buy-in from the clinicians delivering day-to-day patient care and must be considerate of existing resource constraints, as well as being aspirational in its scope. This initiative aimed to produce guidelines for the management of head and neck squamous cell carcinoma of unknown primary (HNSCCUP) using a novel methodology to maximise the likelihood of national adoption.

Reducing opioid use disorder and overdose deaths in the United States: A dynamic modeling analysis.

Opioid overdose deaths remain a major public health crisis. We used a system dynamics simulation model of the U.S.

Programmatic Efforts Increase Adoption of Genomic Precision Medicine in Cancer Care in a Community Cancer Center.

Purpose: The adoption of precision medicine (PMed) depends on the critical curation of data and interpretation of genomic results. Herein, we sought to study the effect of a coordinated multidisciplinary program to assess results in a community cancer center clinic.

Methods: In a retrospective review from July 2018 to July 2021, we analyzed the implementation of a multidisciplinary PMed program in a tertiary referral community cancer center.

Modeling the evolution of the US opioid crisis for national policy development.

The opioid crisis is a major public health challenge in the United States, killing about 70,000 people in 2020 alone. Long delays and feedbacks between policy actions and their effects on drug-use behavior create dynamic complexity, complicating policy decision-making. In 2017, the National Academies of Sciences, Engineering, and Medicine called for a quantitative systems model to help understand and address this complexity and guide policy decisions.

Impact of Maternal Health Behaviours and Social Conditions on Infant Diet at Age 1-Year: Results from a Prospective Indigenous Birth Cohort in Ontario, Canada.

Background: Understanding the impact of maternal health behaviours and social conditions on childhood nutrition is important to inform strategies to promote health during childhood. Objective: To describe how maternal health sociodemographic factors (e.g.

Accelerated SuFEx Click Chemistry For Modular Synthesis.

SuFEx click chemistry is a powerful method designed for the selective, rapid, and modular synthesis of functional molecules. Classical SuFEx reactions form stable S-O linkages upon exchange of S-F bonds with aryl silyl-ether substrates, and while near-perfect in their outcome, are sometimes disadvantaged by relatively high catalyst loadings and prolonged reaction times. We herein report the development of accelerated SuFEx click chemistry (ASCC), an improved SuFEx method for the efficient and catalytic coupling of aryl and alkyl alcohols with a range of SuFExable hubs.