Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans

Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Towards the Use of Natural Compounds for Crop Protection and Food Safety

The six research articles/communications and one review that comprise this Special Issue, which concerns studies towards natural compound use for crop protection and food safety purposes, highlight the most recent research and investigations into this exciting area [...

Lignans: A Chemometric Analysis

The physicochemical properties of classical lignans, neolignans, flavonolignans and carbohydrate-lignan conjugates (CLCs) were analysed to assess their ADMET profiles and establish if these compounds are lead-like/drug-like and thus have potential to be or act as leads in the development of future therapeutics. It was found that while no studied compounds were lead-like, a very large proportion (>75%) fulfilled all the requirements to be deemed as present in drug-like space and almost all compounds studied were in the known drug space. Principal component analysis was an effective technique that enabled the investigation of the relationship between the studied molecular descriptors and was able to separate the lignans from their sugar derivatives and flavonolignans, primarily according to the parameters that are considered when defining chemical space (i.e., number of hydrogen bond donors, acceptors, rotatable bonds, polar surface area and molecular weight). These results indicate that while CLCs and flavonolignans are less drug-like, lignans show a particularly high level of drug-likeness, an observation that coupled with their potent biological activities, demands future pursuit into their potential for use as therapeutics

Lifestyle, Lineage, and Geographical Origin Influence Temperature-Dependent Phenotypic Variation across Yeast Strains during Wine Fermentation

Saccharomyces cerevisiae yeasts are a diverse group of single-celled eukaryotes with tremendous phenotypic variation in fermentation efficiency, particularly at different temperatures. Yeast can be categorized into subsets based on lifestyle (Clinical, Fermentation, Laboratory, and Wild), genetic lineage (Malaysian, Mosaic, North American, Sake, West African, and Wine), and geographical origin (Africa, Americas, Asia, Europe, and Oceania) to start to understand their ecology; however, little is known regarding the extent to which these groupings drive S. cerevisiae fermentative ability in grape juice at different fermentation temperatures. To investigate the response of yeast within the different subsets, we quantified fermentation performance in grape juice by measuring the lag time, maximal fermentation rate (Vmax), and fermentation finishing efficiency of 34 genetically diverse S. cerevisiae strains in grape juice at five environmentally and industrially relevant temperatures (10, 15, 20, 25, and 30 °C). Extensive multivariate analysis was applied to determine the effects of lifestyle, lineage, geographical origin, strain, and temperature on yeast fermentation phenotypes. We show that fermentation capability is inherent to S. cerevisiae and that all factors are important in shaping strain fermentative ability, with temperature having the greatest impact, and geographical origin playing a lesser role than lifestyle or genetic lineage

Asymmetric Synthesis and CD Investigation of the 1,4-Benzodioxane Lignans Eusiderins A, B, C, G, L, and M

The enantioselective synthesis of (−)-eusiderins A (<b>1</b>), B (<b>2</b>), G (<b>25</b>), L (<b>23</b>), M (<b>5</b>) and (+)-eusiderin C (<b>20</b>) and a range of analogues was undertaken using an efficient, divergent synthesis all from a single chiral aldehyde <b>15</b>, which was derived from (<i>S</i>)-ethyl lactate <b>9</b>. A comprehensive set of NMR data along with ECD spectra and optical rotation measurements of the synthesized natural products and analogues were then obtained. This data confirmed the absolute stereochemistry of eusiderins A (<b>1</b>) and C (<b>20</b>) and for the first time gives the ECD and optical rotation for eusiderins B (<b>2</b>), G (<b>25</b>), L (<b>23</b>), and M (<b>5</b>) and a range of other substituted 1,4-benzodioxanes. This data will now allow for the determination of absolute stereochemistry of other members in this class of compound

New Precursors to 3-Sulfanylhexan-1-ol? Investigating the Keto–Enol Tautomerism of 3-S-Glutathionylhexanal

The volatile thiol compound 3-sulfanylhexan-1-ol (3SH) is a key impact odorant of white wines such as Sauvignon Blanc. 3SH is produced during fermentation by metabolism of non-volatile precursors such as 3-S-gluthathionylhexanal (glut-3SH-al). The biogenesis of 3SH is not fully understood, and the role of glut-3SH-al in this pathway is yet to be elucidated. The aldehyde functional group of glut-3SH-al is known to make this compound more reactive than other precursors to 3SH, and we are reporting for the first time that glut-3SH-al can exist in both keto and enol forms in aqueous solutions. At wine typical pH (~3.5), glut-3SH-al exists predominantly as the enol form. The dominance of the enol form over the keto form has implications in terms of potential consumption/conversion of glut-3SH-al by previously unidentified pathways. Therefore, this work will aid in the further elucidation of the role of glut-3SH-al towards 3SH formation in wine, with significant implications for the study and analysis of analogous compounds

Attempts to Create Products with Increased Health-Promoting Potential Starting with Pinot Noir Pomace: Investigations on the Process and Its Methods

A process for using grape (Pinot noir) pomace to produce products with improved health-promoting effects was investigated. This process integrated a solid&ndash;liquid extraction (SLE) method and a method to acylate the polyphenolics in the extract. This report describes and discusses the methods used, including the rationale and considerations behind them, and the results obtained. The study begins with the work to optimize the SLE method for extracting higher quantities of (+)-catechin, (&minus;)-epicatechin and quercetin by trialing 28 different solvent systems on small-scale samples of Pinot noir pomace. One of these systems was then selected and used for the extraction of the same flavonoids on a large-scale mass of pomace. It was found that significantly fewer quantities of flavonoids were observed. The resultant extract was then subject to a method of derivatization using three different fatty acylating agents. The antiproliferative activities of these products were measured; however, the resulting products did not display activity against the chosen cancer cells. Limitations and improvements to the methods in this process are also discussed

Tethered Aryl Groups Increase the Activity of Anti-Proliferative Thieno[2,3-<i>b</i>]Pyridines by Targeting a Lipophilic Region in the Active Site of PI-PLC

The compounds 2-amino-3-carboxamido-thieno[2,3-b]pyridines have demonstrated excellent anti-proliferative activity against human cancer cell lines, including the triple-negative breast cancer cell line MDA-MB-231. In this study, 81 novel thieno[2,3-b]pyridines were synthesised in four series to further improve their anti-proliferative activity, in particular by targeting an adjacent lipophilic pocket in the putative target enzyme phosphoinositide phospholipase C (PI-PLC). Overall, it was found that appending a propyl-aryl group at C-5 on 2-amino-3-carboxamido-thieno[2,3-b]pyridine resulted in compounds with potent biological activity, exhibiting IC50 values in the nanomolar range. The propyl linker could be an α,β-unsaturated ketone or a saturated propyl ketone, but the highest activity was obtained when allylic alcohols were the tether between thieno[2,3-b]pyridine and the appended aryl group, with compound 21r having IC50 values lower than 50 nM. Compounds with one extra carbon in the tether (i.e., a four-atom chain) were found to be considerably less active. Molecular modelling revealed this propyl tether places the newly introduced aryl ring in an untargeted lipophilic pocket within the active site of the phosphoinositide phospholipase C (PI-PLC) enzyme

Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation

Dibenzylbutyrolactone lignans (DBLs) are a class of natural products with a wide variety of biological activities. Due to their potential for the development of human therapeutic agents, DBLs have been subjected to various SAR studies in order to optimise activity. Previous reports have mainly considered changes on the aromatic rings and at the benzylic carbons of the compounds, whilst the effects of substituents in the lactone, at the C-9′ position, have been relatively unexplored. This position has an unexploited potential for the development of novel dibenzyl butyrolactone derivatives, with previous preliminary findings revealing C-9′-hydroxymethyl analogues inducing programmed cell cycle death. Using the core structure of the bioactive natural product arctigenin, C-9′ derivatives were synthesised using various synthetic pathways and with prepared derivatives providing more potent anti-proliferative activity than the C-9′-hydroxymethyl lead compound