Search

Optimization of chemical reactions requires a thorough analysis of reaction products and intermediates over a given time course. Chemical reactions are often analyzed by liquid chromatography-mass spectrometry (LC-MS), but generating LC-MS samples and data analysis is time-consuming and produces a significant amount of waste. We sought to remove the sample preparation and data analysis steps by implementing an iChemExplorer/Agilent LC-MS instrument as our reactor and analysis tool, coupled with an automated report generator of reaction progress over time. Herein, we show that our easy-to-use walk-up automated reaction profiling (WARP) system can sample chemical reactions multiple times to produce a data-rich report of reaction progress over time.

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up)., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Chemical spills in surface waters pose a significant threat to public health and the environment. This study investigates the public health impacts associated with organic chemical spill emergencies and explores timely countermeasures deployable by drinking water facilities. Using a dynamic model of a typical multi-sourced New England drinking water treatment facility and its distribution network, this study assesses the impacts of various countermeasure deployment scenarios, including source switching, enhanced coagulation via poly‑aluminum chloride (PACl), addition of powdered activated carbon (PAC), and temporary system shutdown. This study reveals that the deployment of multiple countermeasures yields the most significant reduction in total public health impacts, regardless of the demand and supply availability. With the combination PAC deployed first with other countermeasures proving to be the most effective strategies, followed by the combination of facility shutdowns. By understanding the potential public health impacts and evaluating the effectiveness of countermeasures, authorities can develop proactive plans, secure additional funding, and enhance their capacity to mitigate the consequences of such events. These insights contribute to safeguarding public health and improving the resilience of drinking water systems in the face of the ever-growing threat of chemical spills., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The synthesis of quaternary carbons often requires numerous steps and complex conditions or harsh reagents that act on heavily engineered substrates. This is largely a consequence of conventional polar-bond retrosynthetic disconnections that in turn require multiple functional group interconversions, redox manipulations, and protecting group chemistry. Here, we report a simple catalyst and reductant combination that converts two types of feedstock chemicals, carboxylic acids and olefins, into tetrasubstituted carbons through quaternization of radical intermediates. An iron porphyrin catalyst activates each substrate by electron transfer or hydrogen atom transfer, and then combines the fragments using a bimolecular homolytic substitution (S H 2) reaction. This cross-coupling reduces the synthetic burden to procure numerous quaternary carbon---containing products from simple chemical feedstocks.

Introduction: Optimal management of transverse sacral fractures (TSF) remains inconclusive. These injuries may present with neurological deficits including cauda equina syndrome. We present our series of laminectomy for acute TSF with cauda equina compression., Methods: This was a retrospective chart review of all patients that underwent sacral laminectomy for treatment of cauda equina compression in acute TSF at our institution between 2007 through 2023., Results: A total of 9 patients (5 male and 4 female) underwent sacral laminectomy to decompress the cauda equina in the setting of acute high impact trauma. Surgeries were done early within a mean time of 5.9 days. All but one patient had symptomatic cauda equina syndrome. In one instance surgery was applied due to significant canal stenosis present on imaging in a patient with diminished mental status not allowing proper neurological examination. Torn sacral nerve roots were repaired directly when possible. All patients regained their neurological function related to the sacral cauda equina on follow up. The rate of surgical site infection (SSI) was 33%., Conclusion: Acute early sacral laminectomy and nerve root repair as needed was effective in recovering bowel and bladder function in patients after high impact trauma and TSF with cauda equina compression. A high SSI rate may be reduced by delaying surgery past 1 week from trauma, but little data exists at this time for clear recommendations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes 1 . This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges 2-4 . Although this approach forms the basis of undergraduate curriculum in organic chemistry 5 and strategic applications of most synthetic methods 6 , the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography 3,4,7 . Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface 8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO 3 , proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.

Simple access to aryl sulfinates from aryl iodides and bromides is reported using an inexpensive Ni-electrocatalytic protocol. The reaction exhibits a broad scope, uses stock solution of simple SO 2 as sulfur source, and can be scaled up in batch and recycle flow settings. The limitations of this reaction are clearly shown and put into context by benchmarking with state-of-the-art Pd-based methods., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Protein mapping distributes many copies of different molecular probes on the surface of a target protein in order to determine binding hot spots, regions that are highly preferable for ligand binding. While mapping of X-ray structures by the FTMap server is inherently static, this limitation can be overcome by the simultaneous analysis of multiple structures of the protein. FTMove is an automated web server that implements this approach. From the input of a target protein, by PDB code, the server identifies all structures of the protein available in the PDB, runs mapping on them, and combines the results to form binding hot spots and binding sites. The user may also upload their own protein structures, bypassing the PDB search for similar structures. Output of the server consists of the consensus binding sites and the individual mapping results for each structure - including the number of probes located in each binding site, for each structure. This level of detail allows the users to investigate how the strength of a binding site relates to the protein conformation, other binding sites, and the presence of ligands or mutations. In addition, the structures are clustered on the basis of their binding properties. The use of FTMove is demonstrated by application to 22 proteins with known allosteric binding sites; the orthosteric and allosteric binding sites were identified in all but one case, and the sites were typically ranked among the top five. The FTMove server is publicly available at https://ftmove.bu.edu., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Nitrous oxide (N2O) has been used nationally as an analgesic in many clinical settings. While neuraxial analgesia is still the most commonly used labor analgesic in the United States, there is increasing use of N2O in labor. Given the reduction in the partial pressure of gases at a higher altitude, N2O has been reported to have reduced analgesic properties. However, there is no study to date evaluating the impact of altitude on labor analgesia and N2O., Methods: We conducted a multicenter retrospective data analysis of a N2O registry collected from 4 institutions over a 3-year period. We compared the impact of altitude on 50% N2O administration for labor analgesia, conversion rates to another analgesic modality, as well as collected side effect frequencies and conversion predictors. Multivariable regression models were used to compare clinical characteristics and outcomes between parturients at high and low altitudes, while adjusting for race, ethnicity, education, and age (logistic and linear regressions for categorical and quantitative outcomes, respectively)., Results: A total of 1856 laboring parturients (age 18-50) were included in the analysis. The odds of converting from 50% N2O to another analgesic modality had no statistically significant difference between high- versus low-altitude institutions (adjusted odds ratio [aOR], 1.13; 95% confidence interval [CI], 0.90-1.42; P = .3). Yet, when parturients at low altitude converted from N2O, they were more likely (aOR, 3.03; 95% CI, 1.59-5.88) to choose neuraxial analgesia instead of another analgesic modality when compared to high-altitude parturients. This is possibly due to higher epidural rates at the low-altitude institutions. When parturients at high altitude did convert into another modality, they were more likely (aOR, 2.19; 95% CI, 1.14-4.21) to convert due to inadequate pain relief compared to low-altitude parturients; however, missing data may have affected this finding. Laboring individuals at low altitude were significantly more likely to experience side effects (aOR, 2.13; 95% CI, 1.45-3.12). Those requiring labor augmentation, assisted vaginal, or cesarean delivery converted to neuraxial analgesia significantly more often than those that delivered via spontaneous vaginal delivery (P < .05) in both high- and low-altitude groups., Conclusions: This is the first study evaluating 50% N2O as a labor analgesic at high altitude. As expected, we found lower side effects at high altitude, likely due to the lower partial pressure of N2O. However, there was not a statistically significant increase in conversion from N2O to another analgesic modality at high altitude and no clinically significant differences in neonatal outcomes., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

The development of a versatile platform for the synthesis of 1,2-difunctionalized bicyclo[1.1.1]pentanes to potentially mimic ortho / meta -substituted arenes is described. The syntheses of useful building blocks bearing alcohol, amine, and carboxylic acid functional handles have been achieved from a simple common intermediate. Several ortho- and meta -substituted benzene analogs, as well as simple molecular matched pairs, have also been prepared using this platform. The results of in-depth ADME (absorption, distribution, metabolism, and excretion) investigations of these systems are presented, as well as computational studies which validate the ortho- or meta -character of these bioisosteres., Competing Interests: The authors declare no competing interest.

Abstract: Dilated cardiomyopathy is a form of heart failure characterized by left ventricular dilation with impaired systolic function. Causes may include ischemic heart disease, hypertensive heart disease, valvular heart disease, endocrine disorders, substance use, and viral diseases. This case report describes a patient with new-onset heart failure, initially diagnosed as idiopathic dilated cardiomyopathy with pericarditis secondary to a virus but later found to be secondary to hyperthyroidism., (Copyright © 2021 American Academy of Physician Assistants.)

The RADx SM Tech initiative required a massive mobilization of the biomedical community. It was chartered with the extremely ambitious goal of rapidly developing and deploying innovative tests to detect people infected with the SARS-CoV-2 virus. It needed to do so at a scale and with urgency to get the country back to daily activities such as school and work as soon as possible. It required forming and supporting a diversity of teams with members from around the country and beyond. These teams collaborated in complex workflows that needed to be carefully monitored and tracked. This paper describes the key elements of the secure, web-based infrastructure that was configured to enable the efficient and effective operation of RADx Tech's key processes and address its unique and urgent challenges. One such challenge was to manage the flow of applications through a multi-stage, interactive selection process (using the CoLab platform) and another was to support and facilitate the progress of projects selected for support and funding through an accelerated commercialization program (using the GAITS platform)., (This work is licensed under a Creative Commons Attribution 4.0 License. For more information, see https://creativecommons.org/licenses/by/4.0/.)

Indazoles represent a privileged motif in drug discovery. However, the formation of highly substituted indazoles can require the execution of lengthy synthetic routes with minimal opportunities to introduce diversity. In this report, we disclose the development of a late-stage diversification strategy for the 4- and 5-positions of 4,5,6-trisubstituted indazoles. A regioselective C-H functionalization and subsequent nucleophilic aromatic substitution provide two sequential points of diversification. The synthetic sequence delivers rapid access to an array of 4,5,6-trisubstituted indazoles in only four steps from readily available starting materials.

Introduction: Women desire safe and effective choices for pain management during labor. Currently, neuraxial and opioid analgesia are the most common methods used in the United States. The purpose of this study was to investigate demographic characteristics, safety, and satisfaction in a cohort of parturients who used inhaled nitrous oxide (N 2 O) analgesia and to determine predictors of conversion from N 2 O to neuraxial analgesia., Methods: This was a prospective chart review study. Individuals aged at least 18 years who used inhaled N 2 O during the first or second stage of labor between March 1, 2016, and July 23, 2017, on the labor and delivery unit of one academic medical center (N = 463) and their neonates were included. Data describing maternal and neonatal factors are reported. Logistic regression and chi-square tests were used to model the effects of oxytocin augmentation, labor induction, parity, prior cesarean birth, pre-N 2 O cervical dilatation, and post-N 2 O cervical dilatation on the odds of conversion from N 2 O to neuraxial analgesia., Results: In this cohort, 31% who chose N 2 O for analgesia did not convert to any other analgesic method. Significant positive predictors for conversion from N 2 O to neuraxial analgesia included labor induction (odds ratio [OR], 2.9; 95% CI, 1.7-5.0), oxytocin augmentation (OR, 3.1; 95% CI, 1.6-6.0), and labor after cesarean (OR, 6.4; 95% CI, 2.5-16.5). Multiparity (OR, 0.4; 95% CI, 0.2-0.6) and post-N 2 O cervical dilatation (OR, 0.8; 95% CI, 0.7-0.9) were negative predictors. Adverse effects related to N 2 O use during labor were rare (8%) and were not a significant reason for conversion to neuraxial analgesia. Parturients had moderately high satisfaction with N 2 O for pain management (11-point scale, mean [SD], 7.4 [2.9]). Five-minute Apgar scores were 7 or greater in 97.8% of the newborns., Discussion: Understanding predictors of conversion from inhaled N 2 O to neuraxial analgesia may assist perinatal care providers in their discussions with women about analgesia options during labor. N 2 O is a useful, safe option for labor analgesia in the United States., (© 2020 by the American College of Nurse-Midwives.)

Hindered ethers are of high value for various applications; however, they remain an underexplored area of chemical space because they are difficult to synthesize via conventional reactions 1,2 . Such motifs are highly coveted in medicinal chemistry, because extensive substitution about the ether bond prevents unwanted metabolic processes that can lead to rapid degradation in vivo. Here we report a simple route towards the synthesis of hindered ethers, in which electrochemical oxidation is used to liberate high-energy carbocations from simple carboxylic acids. These reactive carbocation intermediates, which are generated with low electrochemical potentials, capture an alcohol donor under non-acidic conditions; this enables the formation of a range of ethers (more than 80 have been prepared here) that would otherwise be difficult to access. The carbocations can also be intercepted by simple nucleophiles, leading to the formation of hindered alcohols and even alkyl fluorides. This method was evaluated for its ability to circumvent the synthetic bottlenecks encountered in the preparation of 12 chemical scaffolds, leading to higher yields of the required products, in addition to substantial reductions in the number of steps and the amount of labour required to prepare them. The use of molecular probes and the results of kinetic studies support the proposed mechanism and the role of additives under the conditions examined. The reaction manifold that we report here demonstrates the power of electrochemistry to access highly reactive intermediates under mild conditions and, in turn, the substantial improvements in efficiency that can be achieved with these otherwise-inaccessible intermediates.

Rh-catalyzed C-H functionalization of O -pivaloyl benzhydroxamic acids with propene gas provides access to 4-methyl-substituted dihydroisoquinolones. Good to excellent levels of regioselectivity are achieved using [Cp t RhCl 2 ] 2 as a precatalyst under optimized conditions. Thorough examination of aryl/heteroaryl O -pivaloyl hydroxamic acid substrates, ligand effects on C-H site selectivity, alkene scope, and demonstration of scale are discussed within.

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.

The direct union of primary, secondary, and tertiary carboxylic acids with a chiral glyoxylate-derived sulfinimine provides rapid access into a variety of enantiomerically pure α-amino acids (>85 examples). Characterized by operational simplicity, this radical-based reaction enables the modular assembly of exotic α-amino acids, including both unprecedented structures and those of established industrial value. The described method performs well in high-throughput library synthesis, and has already been implemented in three distinct medicinal chemistry campaigns., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Many of the small drinking water systems in the US that utilize simple filtration and chlorine disinfection or chlorine disinfection alone are facing disinfection byproduct (DBP) noncompliance issues, which need immediate upgrades. In this study, four potential upgrade scenarios, namely the GAC, ozone, UV30, and UV186 scenarios, were designed for a typical small drinking water systems and compared in terms of embodied energy, carbon footprint, and life cycle cost. These scenarios are designed to either reduce the amount of DBP precursors using granular activated carbon filtration (the GAC scenario) or ozonation (the ozone scenario), or replace the chlorine disinfection with the UV disinfection at different intensities followed by chloramination (the UV30 and UV186 scenarios). The UV30 scenario was found to have the lowest embodied energy (417 GJ/year) and life cycle cost ($0.25 million US dollars), while the GAC scenario has the lowest carbon footprint (21 Mg CO 2 e/year). The UV186 scenario consistently presents the highest environmental and economic impacts. The major contributors of the economic and environmental impacts of individual scenarios also differ. Energy and/or material consumptions during the operation phase dominate the environmental impacts of the four scenarios, while the infrastructure investments have a noticeable contribution to the economic costs. The results are sensitive to changes in water quality. An increase of raw water quality, i.e., an increase in organic precursor content, could potentially result in the ozone scenario being the least energy intensive scenario, while a decrease of water quality could greatly reduce the overall competitiveness of the GAC scenario., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp 2 )-C(sp 3 ) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Critical care clinicians may be called on to care for a laboring woman. Comprehension of the anatomic changes associated with pregnancy, and labor and birth, is essential. A working knowledge of the current options for pain management in labor, both pharmacologic and nonpharmacologic, is necessary to facilitate patient-centered care. Pharmacologic options include intravenous or intramuscular agents, inhalational agents, and neuraxial anesthesia. Each modality has contraindications, risks, and benefits that must be considered when choosing the most appropriate method., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Driven by the ever-increasing pace of drug discovery and the need to push the boundaries of unexplored chemical space, medicinal chemists are routinely turning to unusual strained bioisosteres such as bicyclo[1.1.1]pentane, azetidine, and cyclobutane to modify their lead compounds. Too often, however, the difficulty of installing these fragments surpasses the challenges posed even by the construction of the parent drug scaffold. This full account describes the development and application of a general strategy where spring-loaded, strained C-C and C-N bonds react with amines to allow for the "any-stage" installation of small, strained ring systems. In addition to the functionalization of small building blocks and late-stage intermediates, the methodology has been applied to bioconjugation and peptide labeling. For the first time, the stereospecific strain-release "cyclopentylation" of amines, alcohols, thiols, carboxylic acids, and other heteroatoms is introduced. This report describes the development, synthesis, scope of reaction, bioconjugation, and synthetic comparisons of four new chiral "cyclopentylation" reagents.

Global health is centered on promoting health equity for all populations. There is a growing need for midwives to receive education in the field of global health in order to be equipped to care for diverse populations within the United States and internationally. Midwifery students benefit from the opportunity to complete global health coursework and a global health practicum, as these experiences help them learn how to reduce local and global health disparities through interdisciplinary collaboration and international partnerships. The purpose of this article is to provide an overview of how a graduate certificate in global health can be used to enhance and enrich midwifery education. The article evaluates the numerous benefits of the global health certificate for midwifery students, and it discusses the logistical challenges of implementation, including potential areas for improvement. By collaborating together, midwifery education programs can expand the breadth of global health courses and practicum experiences available to midwifery students and prepare them to engage in global health projects that improve maternal and neonatal health outcomes in the United States and around the world., (© 2016 by the American College of Nurse-Midwives.)

The risk that a newborn will develop vitamin K deficiency bleeding is 1700/100,000 (one out of 59) if vitamin K is not administered. When intramuscular vitamin K is administered, the risk of vitamin K deficiency bleeding is reduced to 1/100,000. While women may have misconceptions about vitamin K prophylaxis for their newborns, health care providers should be prepared with factual information. Prophylaxis is needed even for healthy newborns without risk factors for bleeding. Other forms of vitamin K supplementation, including oral administration of Food and Drug Administration-approved vitamin K preparations and maternal supplements during pregnancy or lactation, do not have the same effectiveness as the parenteral form. The formulations of vitamin K approved for use in the United States have not been associated with childhood leukemia or other childhood health problems. Care providers need to give accurate information to families regarding the risks and benefits of vitamin K prophylaxis. An interprofessional approach to education can be effective in increasing acceptance of vitamin K prophylaxis and decreasing the incidence of vitamin K deficiency bleeding. This article uses a case study approach to highlight common misconceptions about vitamin K prophylaxis and discuss a recent interprofessional collaboration to prevent vitamin K deficiency bleeding., (© 2016 by the American College of Nurse-Midwives.)

Lorlatinib (PF-06463922) is an ALK/ROS1 inhibitor and is in clinical trials for the treatment of ALK positive or ROS1 positive NSCLC (i.e. specific subsets of NSCLC). One of the laboratory objectives for this molecule indicated that it would be desirable to advance a molecule which was CNS penetrant in order to treat brain metastases. From this perspective, a macrocyclic template was attractive for a number of reasons. In particular, this template reduces the number of rotatable bonds, provides the potential to shield polar surface area and reinforces binding through a restricted conformation. All of these features led to better permeability for the molecules of interest and thus increased the chance for better blood brain barrier penetration. With a CNS penetrant molecule, kinase selectivity is a key consideration particularly with regard to proteins such as TrkB, which are believed to influence cognitive function. Removal of the chiral benzylic methyl substituent from lorlatinib was perceived as not only a means to simplify synthetic complexity, but also as a strategy to further truncate the molecule of interest. Examination of the NMR of the desmethyl analogues revealed that the compound existed as a mixture of atropisomers, which proved separable by chiral SFC. The individual atropisomers were evaluated through a series of in vitro assays, and shown to have a favorable selectivity profile when compared to lorlatinib. The challenge to develop such a molecule lies in the rate at which the atropisomers interchange dictated by the energy barrier required to do this. Here, we describe the synthesis of the desmethyl macrocycles, conformational studies on the atropisomers, and the kinetics of the interconversion. In addition, the corresponding conformational studies on lorlatinib are reported providing a hypothesis for why a single diastereomer is observed when the chiral benzylic methyl group is introduced., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation., (Copyright © 2016, American Association for the Advancement of Science.)

Support for women during labor encompasses the continuous presence of a person who provides psychosocial, emotional, and physical support. Providing labor support to women in the intrapartum setting is a core midwifery competency and a clinical skill that midwifery students are expected to master. Instruction on labor support is a common objective in midwifery education intrapartum courses and skills labs, yet there is no standard for teaching this skill to midwifery students. Thus, in order to accomplish this objective, we created an interprofessional simulation on labor support that involves the use of a standardized patient, a written scenario, an interprofessional team of nursing and midwifery students, faculty observations, and a reflective debrief. The goals of the labor support simulation are to allow midwifery students the opportunity to practice intrapartum labor support techniques and interprofessional communication prior to entering the clinical setting. A postsimulation structured debrief allows for student learning and reflection. This article describes the design, planning, and implementation of this unique simulation experience. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health., (© 2015 by the American College of Nurse-Midwives.)

Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,β-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.

Introduction: Many US health care and education stakeholder groups, recognizing the need to prepare learners for collaborative practice in complex care environments, have called for innovative approaches in health care education. Team-based learning is an educational method that relies on in-depth student preparation prior to class, individual and team knowledge assessment, and use of small-group learning to apply knowledge to complex scenarios. Although team-based learning has been studied as an approach to health care education, its application to midwifery education is not well described., Methods: A master's-level, nurse-midwifery, didactic antepartum course was revised to a team-based learning format. Student grades, course evaluations, and aggregate American Midwifery Certification Board examination pass rates for 3 student cohorts participating in the team-based course were compared with 3 student cohorts receiving traditional, lecture-based instruction., Results: Students had mixed responses to the team-based learning format. Student evaluations improved when faculty added recorded lectures as part of student preclass preparation. Statistical comparisons were limited by variations across cohorts; however, student grades and certification examination pass rates did not change substantially after the course revision. Although initial course revision was time-consuming for faculty, subsequent iterations of the course required less effort., Discussion: Team-based learning provides students with more opportunity to interact during on-site classes and may spur application of knowledge into practice. However, it is difficult to assess the effect of the team-based learning approach with current measures. Further research is needed to determine the effects of team-based learning on communication and collaboration skills, as well as long-term performance in clinical practice. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health., (© 2015 by the American College of Nurse-Midwives.)

The importance of ethical conduct in health care was acknowledged as early as the fifth century in the Hippocratic Oath and continues to be an essential element of clinical practice. Providers face ethical dilemmas that are complex and unfold over time, testing both practitioners' knowledge and communication skills. Students learning to be health care providers need to develop the knowledge and skills necessary to negotiate complex situations involving ethical conflict. Simulation has been shown to be an effective learning environment for students to learn and practice complex and overlapping skills sets. However, there is little guidance in the literature on constructing effective simulation environments to assist students in applying ethical concepts. This article describes realistic simulations with trained, standardized patients that present ethical problems to graduate-level nurse-midwifery students. Student interactions with the standardized patients were monitored by faculty and peers, and group debriefing was used to help explore students' emotions and reactions. Student feedback postsimulation was exceedingly positive. This simulation could be easily adapted for use by health care education programs to assist students in developing competency with ethics., (© 2014 by the American College of Nurse-Midwives.)

A simple method to convert readily available carboxylic acids into sulfinate salts by employing an interrupted Barton decarboxylation reaction is reported. A medicinally oriented panel of ten new sulfinate reagents was created using this method, including a key trifluoromethylcyclopropanation reagent, TFCS-Na. The reactivity of six of these salts towards C-H functionalization was field-tested using several different classes of heterocycles., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

A practical C-H functionalization method for the methylation of heteroarenes is presented. Inspiration from Nature's methylating agent, S-adenosylmethionine (SAM), allowed for the design and development of zinc bis(phenylsulfonylmethanesulfinate), or PSMS. The action of PSMS on a heteroarene generates a (phenylsulfonyl)methylated intermediate that can be easily separated from unreacted starting material. This intermediate can then be desulfonylated to the methylated product or elaborated to a deuteriomethylated product, and can divergently access medicinally important motifs. This mild, operationally simple protocol that can be conducted in open air at room temperature is compatible with sensitive functional groups for the late-stage functionalization of pharmacologically relevant substrates.

The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) as a source of CF2H radical for a rapid and inexpensive chemical "litmus test" for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO.

Crizotinib (1), an anaplastic lymphoma kinase (ALK) receptor tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration in 2011, is efficacious in ALK and ROS positive patients. Under pressure of crizotinib treatment, point mutations arise in the kinase domain of ALK, resulting in resistance and progressive disease. The successful application of both structure-based and lipophilic-efficiency-focused drug design resulted in aminopyridine 8e, which was potent across a broad panel of engineered ALK mutant cell lines and showed suitable preclinical pharmacokinetics and robust tumor growth inhibition in a crizotinib-resistant cell line (H3122-L1196M).

Background: We systematically reviewed evidence addressing the effectiveness of nitrous oxide for the management of labor pain, the influence of nitrous oxide on women's satisfaction with their birth experience and labor pain management, and adverse effects associated with nitrous oxide for labor pain management., Methods: We searched the MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases for articles published in English. The study population included pregnant women in labor intending a vaginal birth, birth attendees or health care providers who may be exposed to nitrous oxide during labor, and the fetus/neonate., Results: We identified a total of 58 publications, representing 59 distinct study populations: 2 studies were of good quality, 11 fair, and 46 poor. Inhalation of nitrous oxide provided less effective pain relief than epidural analgesia, but the quality of studies was predominately poor. The heterogeneous outcomes used to assess women's satisfaction with their birth experience and labor pain management made synthesis of studies difficult. Most maternal adverse effects reported in the literature were unpleasant side effects that affect tolerability, such as nausea, vomiting, dizziness, and drowsiness. Apgar scores in newborns whose mothers used nitrous oxide were not significantly different from those of newborns whose mothers used other labor pain management methods or no analgesia. Evidence about occupational harms and exposure was limited., Conclusions: The literature addressing nitrous oxide for the management of labor pain includes few studies of good or fair quality. Further research is needed across all of the areas examined: effectiveness, satisfaction, and adverse effects.

The present protocol details the synthesis of zinc bis(alkanesulfinate)s that can be used as general reagents for the formation of radical species. The zinc sulfinates described herein are generated from the corresponding sulfonyl chlorides by treatment with zinc dust. The products may be used crude, or a simple purification procedure may be performed to minimize incorporation of water and zinc chloride. Although the synthesis of the zinc sulfinate salts can generally be completed within 3 h, workup can take up to 24 h and purification can take up to 3 h. Following the steps in this protocol would enable the user to generate a small toolkit of zinc sulfinate reagents over the course of 1 week.

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-mediated cross-coupling have simplified the synthesis of such molecules; however, C-H functionalization of medicinally important heterocycles that does not rely on pre-functionalized starting materials is an underdeveloped area. Unfortunately, the innate properties of heterocycles that make them so desirable for biological applications--such as aqueous solubility and their ability to act as ligands--render them challenging substrates for direct chemical functionalization. Here we report that zinc sulphinate salts can be used to transfer alkyl radicals to heterocycles, allowing for the mild (moderate temperature, 50 °C or less), direct and operationally simple formation of medicinally relevant C-C bonds while reacting in a complementary fashion to other innate C-H functionalization methods (Minisci, borono-Minisci, electrophilic aromatic substitution, transition-metal-mediated C-H insertion and C-H deprotonation). We prepared a toolkit of these reagents and studied their reactivity across a wide range of heterocycles (natural products, drugs and building blocks) without recourse to protecting-group chemistry. The reagents can even be used in tandem fashion in a single pot in the presence of water and air.