A Novel Asymmetric [2+2] Cycloaddition and Its Application to the Total Synthesis of 1233A

The first enantioselective [2+2] cycloaddition of aldehydes with (trimethylsilyl)ketene is discovered and developed using chirally modified Lewis acids. In order to demonstrate the utility of the new methodology, the total synthesis of the cholesterol biosynthesis inhibitor 1233A was undertaken. Background biochemistry on cholesterol biosynthesis and coronary heart disease is discussed followed by previous syntheses of the target molecule. The stereoselective synthesis of 1233A was completed using four key steps: (i) a cobalt semicorrin catalysed enantioselective reduction of an alpha,beta-unsaturated ester; (ii) a copper-mediated coupling of a vinyl iodide with a vinyl stannane; (iii) a novel [2+2] cycloaddition of an aldehyde with (trimethylsilyl)ketene and (iv) a beta-lactone aldol-type reaction quenching with carbon dioxide to install the final carbon of 1233A

The International Companion to Scottish Poetry

A range of leading international scholars provide the reader with a comprehensive and innovative investigation of the extraordinary richness and diversity of Scotland\u2019s poetry. Addressing Languages and Chronologies, Poetic Forms, and Topics and Themes, this International Companion covers the entire subject from from the early Middle Ages to the modern day, and explores the connections, influences and interrelations between English, Gaelic, Latin, Old Norse and Scots verse. CONTENTS Series Editors\u2019 Preface Introduction (Carla Sassi) Part 1: Languages and Chronologies Early Celtic Poetry (to 1500) (Thomas Owen Clancy) Scots poetry in the Fourteenth and Fifteenth Centuries (R. D. S. Jack) Poetry in Latin (Roger Green) Poetry in the Languages and Dialects of Northern Scotland (Roberta Frank, Brian Smith) The Sixteenth and Seventeenth Centuries (S\uecm Innes, Alessandra Petrina) The Eighteenth Century (Ronald Black, Gerard Carruthers) The Nineteenth Century (Ian Duncan, Sheila Kidd) The Poetry of Modernity (1870\u20131950) (Emma Dymock, Scott Lyall) Contemporary Poetry (1950\u2013) (Attila D\uf3sa, Michelle Macleod) Part 2: Poetic Forms The Form of Scottish Gaelic poetry (William Gillies) Scots Poetic Forms (Derrick McClure) The Ballad in Scots and English (Suzanne Gilbert) Part 3: Topics and Themes Nature, Landscape and Rural Life (Louisa Gairn) Nation and Home (Carla Sassi, Silke Stroh) Protest and Politics (Wilson McLeod, Alan Riach) Love and Erotic Poetry (Peter Mackay) Faith and Religion (Meg Bateman, James McGonigal) Scottish Poetry as World Poetry (Paul Barnaby) The Literary Environment (Robyn Marsack) Endnotes Further Reading Notes on Contributors Index

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Hydrogen sulfide promotes adipogenesis in 3T3L1 cells.

The effect of hydrogen sulfide (H2S) on differentiation of 3T3L1-derived adipocytes was examined. Endogenous H2S was increased after 3T3L1 differentiation. The expression of the H2S-synthesising enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST), was increased in a time-dependent manner during 3T3L1 differentiation. Expression of genes associated with adipogenesis related genes including fatty acid binding protein 4 (FABP4/aP2), a key regulator of this process, was increased by GYY4137 (a slow-releasing H2S donor compound) and sodium hydrosulfide (NaHS, a classical H2S donor) but not by ZYJ1122 or time-expired NaHS. Furthermore expression of these genes were reduced by aminooxyacetic acid (AOAA, CBS inhibitor), DL-propargylglycine (PAG, CSE inhibitor) as well as by CSE small interference RNA (siCSE) and siCBS. The size and number of lipid droplets in mature adipocytes was significantly increased by both GYY4137 and NaHS, which also impaired the ability of CL316,243 (β3-agonist) to promote lipolysis in these cells. In contrast, AOAA and PAG had the opposite effect. Taken together, we show that the H2S-synthesising enzymes CBS, CSE and 3-MST are endogenously expressed during adipogenesis and that both endogenous and exogenous H2S modulate adipogenesis and adipocyte maturation

Intranasal administration of a stapled relaxin-3 mimetic has anxiolytic- and antidepressant-like activity in rats

10.1111/bph.14774BRITISH JOURNAL OF PHARMACOLOGY176203899-392

Effect of CBS and CSE knockdown on FABP4/aP2 protein expression in differentiated 3T3L1 cells.

<p>3T3L1 cells were incubated with empty lipofectamine (siControl), siCBS (5 μg) or siCSE (5 μg) for 3 days during differentiation. Expression of FABP4/aP2, CBS and CSE protein expression was determined by Western Blotting. Data shows a representative blot (A) as well as protein expression compared to the control group and normalized to β-actin as 1 (B-D). Statistical significance was determined by ANOVA followed by Fisher's LSD posthoc analysis. Data shown are mean±SEM of 4 independent experiments. *P < 0.05 vs. negative control group; ^&P < 0.05 vs. 3 days positive control group.</p

FABP4/aP2 protein expression is inhibited by AOAA and PAG treated 3T3L1 cells.

<p>3T3L1 cells were incubated with either AOAA (1 mM) or PAG (10mM) for 5 days during differentiation, FABP4/aP2 expression was determined by Western Blotting. Data shows protein expression compared to the control group (normalized to β-actin) set as 1. Statistical significance was determined by ANOVA followed by Fisher's LSD posthoc analysis. Data shown are mean±SEM of 4 independent experiments. *P < 0.05 vs. negative control group; ^&P < 0.05 vs. 5 days positive control group.</p

Upregulation of CBS, CSE and 3-MST during differentiation of 3T3L1 cells.

<p>H₂S-synthesising enzyme (CBS, CSE and 3-MST) expression during adipocyte differentiation was determined by Western Blotting. Data shows protein expression compared to the negative control group (normalized to β-actin) set as 1. Statistical significance was determined by ANOVA followed by Fisher's LSD posthoc analysis. Data shown are mean±SEM from 4 independent experiments. *P < 0.05 vs. negative control group.</p

H₂S promotes lipid accumulated in mature 3T3L1 adipocytes.

<p>3T3L1 cells were incubated with either GYY4137 (50 μM), NaHS (50 μM), AOAA (1 mM) or PAG (10 mM) for 7 days of differentiation, lipid accumulation was determined by Oil-red O staining and well scanning (under 540 nm). Statistical significance was determined by ANOVA followed by Fisher's LSD posthoc analysis. Data shown are mean±SEM OF 6 independent experiments. *P < 0.05 vs. negative control group (non-DF); ^&P < 0.05 vs. positive control group (DF).</p

Fragment-based whole cell screen delivers hits against M. tuberculosis and non-tuberculous mycobacteria

Reactive multi-target ‘fragment drugs’ represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small ‘dirty’ drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumonia, Acinetobacter baumanii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and non-tuberculous mycobacterial pathogens. These hits will now be evaluated in animal models of mycobacterial infection to determine whether any of them can be moved forward as a new antimycobacterial fragment drug candidate