Amyloid binding and beyond: a new approach for Alzheimer's disease drug discovery targeting Aβo–PrPC binding and downstream pathways

Amyloid β oligomers (Aβo) are the main toxic species in Alzheimer''s disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aβo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aβo binding by a combined ¹⁹F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aβo binding to its receptor PrP^C in HEK293 cells. They reduced the pFyn levels triggered by Aβo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer''s disease pathology, i.e. prion, Aβ and Tau, affecting three different pathways through specific binding to Aβo and are, indeed, promising candidates for further development.

A new approach combining virtual screening, ¹⁹F and STD NMR, and biochemical assays using hiPSC and targetting multiple pathways involving Aβ, PrP^C and Tau provides a more effective strategy for Alzheimer''s disease drug discovery than Aβ only approach.     

Machine learning and semi-empirical calculations: a synergistic approach to rapid,accurate, and mechanism-based reaction barrier prediction

Modern QM modelling methods, such as DFT, have provided detailed mechanistic insights into countless reactions. However, their computational cost inhibits their ability to rapidly screen large numbers of substrates and catalysts in reaction discovery. For a C–C bond forming nitro-Michael addition, we introduce a synergistic semi-empirical quantum mechanical (SQM) and machine learning (ML) approach that allows the prediction of DFT-quality reaction barriers in minutes, even on a standard laptop using widely available modelling software. Mean absolute errors (MAEs) are obtained that are below the accepted chemical accuracy threshold of 1 kcal mol⁻¹ and substantially better than SQM methods without ML correction (5.71 kcal mol⁻¹). Predictive power is shown to hold when the ML models are applied to an unseen set of compounds from the toxicology literature. Mechanistic insight is also achieved via the generation of full SQM transition state (TS) structures which are found to be very good approximations for the DFT-level geometries, revealing important steric interactions in some TSs. This combination of speed, accuracy, and mechanistic insight is unprecedented; current ML barrier models compromise on at least one of these important criteria.

A synergistic approach that combines machine learning with semi-empirical methods enables the fast and accurate prediction of DFT-quality reaction barriers, with mechanistic insights available from semi-empirical transition state geometries.     

Molecular Weight Control via Cross Metathesis in Photo-Redox Mediated Ring-Opening Metathesis Polymerization

Photo-redox mediated ring-opening metathesis polymerization (photo-ROMP) is an emerging ROMP technique that uses an organic redox mediator and a vinyl ether initiator, in contrast to metal-based initiators traditionally used in ROMP. The reversibility of the redox-mediated initiation and propagation steps enable spatiotemporal control over the polymerization. Herein, we explore a simple, inexpensive means of controlling molecular weight, using alpha olefins as chain transfer agents. This method enables access to low molecular weight oligomers, and molecular weights between 1 and 30 kDa can be targeted simply by altering the stoichiometry of the reaction. This method of molecular weight control was then used to synthesize a functionalized norbornene copolymer in a range of molecular weights for specific materials applications.     

6FDA-containing polyimide-ionene + ionic liquid gas separation membranes

Polyimides (PI) synthesized from 4,4′-(hexafluoroisopropylidene)diphthalic anhydride (6FDA) with various diamines have been frequently studied as gas separation membranes. The use of 6FDA in polyimides creates a bent structure than can increase fractional free volume (FFV) and gas permeability. Here, we demonstrate that 6FDA is also a useful building block for PI-ionene materials, which contain cations directly within the polymer backbone. These new 6FDA-containing PI-ionenes were combined with several different imidazolium ionic liquids (ILs) to form thin membranes. The thermal properties of all the derivatives were investigated to determine the relationship between regiochemistry and degradation as well as the intermolecular forces that are present within these structures. The gas separation properties of these 6FDA-containing PI-ionene + IL materials were investigated, showing modest CO₂ permeabilities similar to other polyimide-ionenes and CO₂/CH₄ and CO₂/N₂ permselectivities that were relatively higher than other polyimide-ionenes.     

Intramolecular acylative ring-switching reactions of 3-(tetrahydro-2'-furyl)propanoic acid derivatives to give butanolides: mechanism and scope

The mechanism by which dihydro-5-(3'-trifluoroacetoxypropyl)-2(3H)-furanone is formed when 3-(tetrahydro-2'-furyl)propanoic-trifluoroacetic mixed anhydride is treated with an acidic catalyst is defined, and routes to some potentially useful butanolide synthons are described.     

Stereoselective total syntheses of (±)-chanoclavine I and (±)-isochanoclavine I by an intramolecular nitrone-olefin/cycloaddition. Preliminary communication

The racemic alkaloids chanoclavine I ( 1 ) and isochanoclavine I ( 2 ) have been synthesized stereoselectively from indole-4-carbaldehyde ( 3 ) by a sequence of 11 operations in overall yields of 14% and 2.4%, respectively. The key step 6 → 8 (Scheme 2) involves a transient nitrone 7 which undergoes a regio- and stereoselective intramolecular cycloaddition to a 1,2-disubstituted olefinic bond.     

Decarboxylation syntheses of transition metal organometallics. III polyfluorophenylplatinum(II) complexes with nitrogen donor ligands

Summary The platinum(II) carboxylates,trans-Pt(O₂CR)₂(py)₂ and Pt(O₂CR)₂bpy (R=C₆F₅,p-HC₆F₄,m-HC₆F₄, oro-HC₆F₄; bpy=2,2-bipyridyl), have been prepared by reactions oftrans-Pt(OH)₂(py)₂ or Pt(OH)₂bpy with the appropriate polyfluorobenzoic acids, whilst [Pt(py)₄](O₂CC₆F₅)₂ has been obtained from reaction oftrans-PtCl₂(py)₂ with thallous pentafluorobenzoate in pyridine at room temperature. In boiling pyridine, the platinum(II) polyfluorobenzoates undergo either decarboxylation givingtrans-PtR₂(py)₂ and PtR₂bpy (R= C₆F₅,p-HC₆F₄, orm-HC₆F₄) complexes or substitution, giving [Pt(py)₄](O₂CC₆F₄H-o)₂ and [Ptbpy(py)₂](O₂CC₆F₄H-o)₂. Reactions oftrans-PtX₂(py)₂ and PtX₂bpy (X=Cl or Br) with appropriate thallous polyfluorobenzoates in boiling pyridine have yielded the complexestrans-PtR₂(py)₂, PtR₂bpy, PtCl(R)bpy (R=C₆F₅,p-HC₆F₄, orm-HC₆F₄ in each case),trans-PtCl(R)(py)₂ (R = C₆F₅ orm-HC₆F₄),trans-PtBr(C₆F₅)(py)₂, and PtBr(C₆F₅)bpy. The complexestrans-PtR₂(py)₂ (R=C₆F₅ orp-HC₆F₄) have also been prepared from potassium tetrachloroplatinate(II) and the appropriate thallous polyfluorobenzoate in boiling py, andtrans-Pt(C₆F₅)₂(py)₂ has been similarly obtained fromcis-PtCl₂(py)₂ and C₆F₅CO₂Tl. Significant decarboxylation was not observed on reaction oftrans-PtCl₂(py)₂ or PtCl₂bpy with thallous 2,3,4,5-tetrafluorobenzoate.Part II, ref. 4;Preliminary communication, ref. 3;