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

Small Molecule Macrocyclic Kinase Inhibitors

With over 500 family members, kinases are key mediators of many important disease relevant signaling pathways involved in cancer and immune-inflammatory diseases. Since the US FDA approval of imatinib in 2001, inhibitors of kinases are now one of the most important classes of drug molecules, covering diverse chemical scaffolds with a broad range of activity and family selectivity. Recent advances discussed in this chapter highlight the notable more recent application of macrocycles as small molecule kinase inhibitors. The potential benefits of macrocyclization are discussed in detail with highlighted case studies presented from literature studies. The key features of macrocyclic kinase inhibitors that enable them to bind specifically in ATP sites are discussed along with the different modes of inhibition. The chemical synthesis of macrocyclic kinase inhibitors is also summarized covering a surprisingly wide range of different chemistry approaches and strategies. Macrocyclic kinase inhibitors have now progressed into clinical testing where they have the potential to give additional benefit to patients. An update on clinical status is provided showing the most advanced agents may soon be approved as drug molecules

Bortezomib Warhead-Switch Confers Dual Activity against Mycobacterial Caseinolytic Protease and Proteasome and Selectivity against Human Proteasome

Mycobacteria harbor two main degradative proteolytic machineries, the caseinolytic protease ClpP1P2 and a proteasome. We recently showed that Bortezomib inhibits ClpP1P2 and exhibits whole cell activity against Mycobacterium tuberculosis. Bortezomib, a dipeptide with a boronic acid warhead, is a human proteasome inhibitor approved for cancer therapy. The boronic acid warhead of the compound has been shown to drive potency against both the human proteasome and ClpP1P2 protease. Selectivity for the bacterial ClpP1P2 protease over the human proteasome is lacking but needs to be achieved to move this new anti-tuberculosis lead forward. In this study we explored whether an alternative warhead could influence Bortezomib's selectivity. We synthesized an analog containing a chloromethyl ketone instead of the boronic acid warhead and determined potencies against the bacterial and human enzymes. Surprisingly, the analog retained activity against mycobacterial ClpP1P2 and was active against the mycobacterial proteasome, but was devoid of activity against the human proteasome. Interrogation of a set of chloromethyl ketone peptides identified three additional compounds similarly inhibiting both ClpP1P2 and the proteasome in the bacteria while leaving the human proteasome untouched. Finally, we showed that these compounds display bactericidal activity against M. tuberculosis with cytotoxicity ranging from acceptable to undetectable. These results suggest that selectivity over the human proteasome is achievable. Selectivity, together with dual-targeting of mycobacterial ClpP1P2 and proteasome makes this new scaffold an attractive starting point for optimization

Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6)

Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1. A preferred compound, 13b, had unprecedented sub-nanomolar JAK2 potency with an IC50 of 41 pM and a sub-nanomolar IC50 against HDAC6 of 200 pM. Binding models show a good fit into both JAK2 and HDAC6

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