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Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, we highlight the importance of site-selective C-H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

Site-selective functionalization of the heterobenzylic C(sp 3 )-H bonds of pyridines and related heteroaromatic compounds presents challenges associated with the basic nitrogen atom and the variable reactivity among different positions on the heteroaromatic ring. Methods for functionalization of 2- and 4-alkylpyridines are increasingly available through polar pathways that leverage resonance stabilization of charge build-up at these positions. In contrast, functionalization of 3-alkylpyridines is largely inaccessible. Here, we report a photochemically promoted method for chlorination of non-resonant heterobenzylic C(sp 3 )-H sites in 3-alkylpyridines and related alkylheteroaromatics. Density functional theory calculations show that the optimal reactivity reflects a balance between the energetics of the two radical-chain propagation steps, with the preferred reagent consisting of an N -chlorosulfonamide. The operationally simple chlorination protocol enables access to heterobenzylic chlorides which serve as versatile intermediates in C-H cross-coupling reactions between heteroaromatic building blocks and diverse oxidatively sensitive nucleophiles using high-throughput experimentation., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing interests.

Per- and polyfluoroalkyl substances (PFAS) represent a large group of contaminants of concern based on their widespread use, environmental persistence, and potential toxicity. Many traditional models for estimating toxicity, bioaccumulation, and other toxicological properties are not well suited for PFAS. Consequently, there is a need to generate hazard information for PFAS in an efficient and cost-effective manner. In the present study, Daphnia magna were exposed to multiple concentrations of 22 different PFAS for 24 h in a 96-well plate format. Following exposure, whole-body RNA was extracted and extracts, each representing five exposed individuals, were subjected to RNA sequencing. Following analytical measurements to verify PFAS exposure concentrations and quality control on processed cDNA libraries for sequencing, concentration-response modeling was applied to the data sets for 18 of the tested compounds, and the concentration at which a concerted molecular response occurred (transcriptomic point of departure; tPOD) was calculated. The tPODs, based on measured concentrations of PFAS, generally ranged from 0.03 to 0.58 µM (9.9-350 µg/L; interquartile range). In most cases, these concentrations were two orders of magnitude lower than similarly calculated tPODs for human cell lines exposed to PFAS. They were also lower than apical effect concentrations reported for seven PFAS for which some crustacean or invertebrate toxicity data were available, although there were a few exceptions. Despite being lower than most other available hazard benchmarks, D. magna tPODs were, on average, four orders of magnitude greater than the maximum aqueous concentrations of PFAS measured in Great Lakes tributaries. Overall, this high-throughput transcriptomics assay with D. magna holds promise as a component of a tiered hazard evaluation strategy employing new approach methodologies. Environ Toxicol Chem 2024;00:1-16. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Traditional toxicity testing has been unable to keep pace with the introduction of new chemicals into commerce. Consequently, there are limited or no toxicity data for many chemicals to which fish and wildlife may be exposed. Per- and polyfluoroalkyl substances (PFAS) are emblematic of this issue in that ecological hazards of most PFAS remain uncharacterized. The present study employed a high-throughput assay to identify the concentration at which 20 PFAS, with diverse properties, elicited a concerted gene expression response (termed a transcriptomics-based point of departure [tPOD]) in larval fathead minnows (Pimephales promelas; 5-6 days postfertilization) exposed for 24 h. Based on a reduced transcriptome approach that measured whole-body expression of 1832 genes, the median tPOD for the 20 PFAS tested was 10 µM. Longer-chain carboxylic acids (12-13 C-F); an eight-C-F dialcohol, N-alkyl sulfonamide; and telomer sulfonic acid were among the most potent PFAS, eliciting gene expression responses at concentrations <1 µM. With a few exceptions, larval fathead minnow tPODs were concordant with those based on whole-transcriptome response in human cell lines. However, larval fathead minnow tPODs were often greater than those for Daphnia magna exposed to the same PFAS. The tPODs overlapped concentrations at which other sublethal effects have been reported in fish (available for 10 PFAS). Nonetheless, fathead minnow tPODs were orders of magnitude higher than aqueous PFAS concentrations detected in tributaries of the North American Great Lakes, suggesting a substantial margin of safety. Overall, results broadly support the use of a fathead minnow larval transcriptomics assay to derive screening-level potency estimates for use in ecological risk-based prioritization. Environ Toxicol Chem 2024;00:1-16. © 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA., (© 2024 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

We describe the first total synthesis of complex aspidosperma alkaloids (-)-voacinol and (-)-voacandimine C via a late-stage C7-methylenation strategy inspired by a biogenetic hypothesis. We envisioned rapid access to these natural alkaloids from a common, symmetrical precursor assembled by methylenation of a D-ring-oxidized variant of the structurally related natural product (-)-deoxoapodine. Chemoselective N9-oxidation of a pentacyclic deoxoapodine precursor enabled the synthesis of the corresponding hexacyclic C8-aminonitrile. Stereocontrolled methylenation of a C8-enamine derivative of deoxoapodine, accessed by ionization of the C8-aminonitrile, afforded a symmetrical dodecacyclic bisaminonitrile as a versatile precursor to these bisindole alkaloids. The final-stage, biosynthesis-inspired, controlled reductive opening of the oxolane substructures of this dodecacyclic intermediate provided a unified approach to (-)-voacinol and (-)-voacandimine C, while direct reduction of the same intermediate afforded the structurally related (-)-methylenebisdeoxoapodine.

We describe a palladium-catalyzed C7-acetoxylation of indolines with a range of amide directing groups. While a variety of substituents are tolerated on the indoline-core and the N1-acyl group, the acetoxylation is most sensitive to the C2- and C6-indoline substituents. The practicality of this indoline C7-acetoxylation is demonstrated using a cinnamamide substrate on a mmol scale. Several N1-acyl groups, including those present in natural alkaloids, guide C7-acetoxylation of indoline substrates over a competitive C5-oxidation. The application of this chemistry allowed for the first synthesis of N -benzoylcylindrocarine by late-stage C17-acetoxylation of N -benzoylfendleridine.

In many ecosystems, especially aquatic ecosystems, size plays a critical role in the factors that determine an individual's ability to survive and reproduce. In aquatic ecotoxicology, size informs both realized and potential acute and chronic effects of chemical exposure. This paper demonstrates how chemical and nonchemical effects on growth, survival, and reproduction can be linked to population-level dynamics using size-structured integral projection models (IPM). The modeling approach was developed with the goals and constraints of ecological risk assessors in mind, who are tasked with estimating the effects of chemical exposures to wildlife populations in a data-limited environment. The included case study is a collection of daily time-step IPMs parameterized for the life history and annual cycle of fathead minnows ( Pimephales promelas ), which motivated the development of modeling techniques for seasonal, iteroparous reproduction, density dependent growth effects, and size-dependent over-winter survival. The effects of a time-variable annual chemical exposure were interpreted using a toxicokinetic-toxicodynamic model for acute survival and sub-lethal growth effects model for chronic effects and incorporated into the IPMs. This paper presents a first application of integral projection models to ecotoxicology. Our research demonstrates that size-structured IPMs provide a promising, flexible, framework for synthesizing ecotoxicologically relevant data and theory to explore the effects of chemical and nonchemical stressors and the resulting impacts on exposed populations., Competing Interests: Declaration of conflicting interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

How biodiversity arises and can be maintained in asexual microbial populations growing on a single resource remains unclear. Many models presume that beneficial genotypes will outgrow others and purge variation via selective sweeps. Environmental structure like that found in biofilms, which are associated with persistence during infection and other stressful conditions, may oppose this process and preserve variation. We tested this hypothesis by evolving Pseudomonas aeruginosa populations in biofilm-promoting arginine media for 3 months, using both a bead model of the biofilm life cycle and planktonic serial transfer. Surprisingly, adaptation and diversification were mostly uninterrupted by fixation events that eliminate diversity, with hundreds of mutations maintained at intermediate frequencies. The exceptions included genotypes with mutator alleles that also accelerated genetic diversification. Despite the rarity of hard sweeps, a remarkable 40 genes acquired parallel mutations in both treatments and often among competing genotypes within a population. These incomplete soft sweeps include several transporters (including pitA, pntB, nosD, and pchF) suggesting adaptation to the growth media that becomes highly alkaline during growth. Further, genes involved in signal transduction (including gacS, aer2, bdlA, and PA14&#95;71750) reflect likely adaptations to biofilm-inducing conditions. Contrary to evolution experiments that select mutations in a few genes, these results suggest that some environments may expose a larger fraction of the genome and select for many adaptations at once. Thus, even growth on a sole carbon source can lead to persistent genetic and phenotypic variation despite strong selection that would normally purge diversity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Aim: The neonatal intensive care unit can be a stressful environment for parents. The Beads of Courage program is an arts-in-medicine, psychosocial intervention, designed to strengthen and support children and families who are coping with serious or life-threatening illness. We hypothesised that the program would improve the parent experience in the neonatal unit., Methods: Infants less than 32 weeks' gestation were eligible for enrolment on the program. The study was conducted from 2016 to 2018. A 13 point questionnaire was sent to participating parents post discharge from the unit including a combination of Likert scale and open-ended questions., Results: During the study period 123 infants were enrolled. Mean gestational age was 27.7(±2.2) weeks and median length of stay was 49 days (lower quartile 34; upper quartile 76). All respondents rated the program as "helpful and enjoyable" with 72.5% rating it "extremely helpful and enjoyable", 85% felt the program made their stay in the neonatal unit easier., Conclusion: The Beads of Courage program was found to be an extremely popular initiative for parents in a neonatal unit setting and was found to be a useful adjunct to communication and inclusion of parents in the care of their infants., Summary: The Beads of Courage program in a NICU setting was found to be very helpful for parents in improving awareness of procedures and understanding overall care of their infants. Parents felt their journey was made easier with the additional engagement and communication with being in the program., (Copyright © 2021 Elsevier B.V. All rights reserved.)