Adam G. Meyer

Naturally occurring polyphenolic inhibitors of amyloid beta aggregation.

Alzheimers disease is the most common neurodegenerative disease and is one of the main causes of death in developed countries. Consumption of foods rich in polyphenolics is strongly correlated with reduced incidence of Alzheimers disease. Our study has investigated the biological activity of previously untested polyphenolic compounds in preventing amyloid β aggregation. The anti-aggregatory potential of these compounds was assessed using the Thioflavin-T assay, transmission electron microscopy, dynamic light scattering and size exclusion chromatography. Two structurally related compounds, luteolin and transilitin were identified as potent inhibitors of Aβ fibril formation. Computational docking studies with an X-ray derived oligomeric structure offer a rationale for the inhibitory activity observed and may facilitate development of improved inhibitors of Aβ aggregation and toxicity.

1,3-Dipolar Cycloaddition−Decarboxylation Reactions of an Azomethine Ylide with Isatoic Anhydrides: Formation of Novel Benzodiazepinones

A nonstabilized azomethine ylide reacts with a wide range of substituted isatoic anhydrides to afford novel 1,3-benzodiazepin-5-one derivatives, which are generally isolated in high yield. The transformations involve 1,3-dipolar cycloaddition reactions of the ylide with the anhydrides to give transient, and in a representative case spectroscopically observable, oxazolidine intermediates that undergo ring-opening-decarboxylation-ring-closing reaction cascades to yield the 1,3-benzodiazepin-5-one products.

Carboxymethylated-κ-casein: a convenient tool for the identification of polyphenolic inhibitors of amyloid fibril formation

Reduced and carboxymethylated-kappa-casein (RCM-kappa-CN) is a milk-derived amyloidogenic protein that readily undergoes nucleation-dependent aggregation and amyloid fibril formation via a similar pathway to disease-specific amyloidogenic peptides like amyloid beta (Abeta), which is associated with Alzheimers disease. In this study, a series of flavonoids, many known to be inhibitors of Abeta fibril formation, were screened for their ability to inhibit RCM-kappa-CN fibrilisation, and the results were compared with literature data on Abeta inhibition. Flavonoids that had a high degree of hydroxylation and molecular planarity gave good inhibition of RCM-kappa-CN fibril formation. IC(50) values were between 10- and 200-fold higher with RCM-kappa-CN than literature results for Abeta fibril inhibition, however, with few exceptions, they showed a similar trend in potency. The convenience and reproducibility of the RCM-kappa-CN assay make it an economic alternative first screen for Abeta inhibitory activity, especially for use with large compound libraries.

Antiviral activity of gliotoxin, gentian violet and brilliant green against Nipah and Hendra virus in vitro.

BackgroundUsing a recently described monolayer assay amenable to high throughput screening format for the identification of potential Nipah virus and Hendra virus antivirals, we have partially screened a low molecular weight compound library (>8,000 compounds) directly against live virus infection and identified twenty eight promising lead molecules. Initial single blind screens were conducted with 10 μM compound in triplicate with a minimum efficacy of 90% required for lead selection. Lead compounds were then further characterised to determine the median efficacy (IC50), cytotoxicity (CC50) and the in vitro therapeutic index in live virus and pseudotype assay formats.ResultsWhile a number of leads were identified, the current work describes three commercially available compounds: brilliant green, gentian violet and gliotoxin, identified as having potent antiviral activity against Nipah and Hendra virus. Similar efficacy was observed against pseudotyped Nipah and Hendra virus, vesicular stomatitis virus and human parainfluenza virus type 3 while only gliotoxin inhibited an influenza A virus suggesting a non-specific, broad spectrum activity for this compound.ConclusionAll three of these compounds have been used previously for various aspects of anti-bacterial and anti-fungal therapy and the current results suggest that while unsuitable for internal administration, they may be amenable to topical antiviral applications, or as disinfectants and provide excellent positive controls for future studies.

Characteristics of Nipah virus and Hendra virus replication in different cell lines and their suitability for antiviral screening

We have recently described the development and validation of a high throughput screening assay suitable for henipavirus antiviral identification. While we are confident this assay is robust and effective, we wished to investigate assay performance in a range of alternative cell lines to determine if assay sensitivity and specificity could be improved. We evaluated ten different cell lines for their susceptibility to Hendra and Nipah virus infection and their sensitivity of detection of the effects of the broad spectrum antiviral, ribavirin and nine novel antivirals identified using our initial screening approach. Cell lines were grouped into three categories with respect to viral replication. Virus replicated best in Vero and BSR cells, followed by Hep-2, HeLa, BHK-21 and M17 cells. The lowest levels of RNA replication and viral protein expression were observed in BAEC, MMEC, A549 and ECV304 cells. Eight cell lines appeared to be similarly effective at discriminating the antiviral effects of ribavirin (<2.7-fold difference). The two cells lines most sensitive to the effect of ribavirin (ECV304 and BAEC) also displayed the lowest levels of viral replication while Vero cells were the least sensitive suggesting excess viral replication may limit drug efficacy and cell lines which limit viral replication may result in enhanced antiviral efficacy. However, there was no consistent trend observed with the other nine antivirals tested. While improvements in antiviral sensitivity in other cell lines may indicate an important role in future HTS assays, the slightly lower sensitivity to antiviral detection in Vero cells has inherent advantages in reducing the number of partially effective lead molecules identified during initial screens. Comparison of a panel of 54 novel antiviral compounds identified during routine screening of an in-house compound library in Vero, BHK-21 and BSR cells suggests no clear advantage of screening in either cell type.

1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides with Carbonyl Dipolarophiles Yielding Oxazolidine Derivatives

We provide a comprehensive account of the 1,3-dipolar cycloaddition reactions of azomethine ylides with carbonyl dipolarophiles. Many different azomethine ylides have been studied, including stabilized and non-stabilized ylides. Of the carbonyl dipolarophiles, aldehydes including formaldehyde are the most studied, although there are now examples of cycloadditions with ketones, ketenes and carboxyl systems, in particular isatoic anhydrides and phthalic anhydrides. Intramolecular cycloadditions with esters can also occur under certain circumstances. The oxazolidine cycloadducts undergo a range of reactions triggered by the ring-opening of the oxazolidine ring system.

Discovery of ectoparasiticidal hydrazonotrifluoromethanesulfonanilides.

A series of hydrazonotrifluorosulfonanilide derivatives were synthesized and evaluated for in vitro activity against the ectoparasites Ctenocephalides felis and Rhipicephalus sanguineus. Some compounds with excellent activity against tick were identified.

Synthesis and conformational analysis of an α-cyclodextrin [2]-rotaxane

An α-cyclodextrin [2]-rotaxane has been prepared in 10% yield, by threading α-cyclodextrin (α-CD) with (E)-4,4′-diaminostilbene in aqueous solution and capping the included guest through reaction with 2,4,6-trinitrobenzene-1-sulfonate. 1D 1H NMR spectroscopy and DQCOSY and ROESY experiments show that the α-CD rotates freely around the axle of the rotaxane, but is localised over the olefinic moiety of the stilbene. The pKa values of the α-CD [2]-rotaxane were found to be 9.3 and 9.6, which are attributable to deprotonations of the (E)-4,4′-bis(2,4,6-trinitrophenylamino)stilbene moiety. NMR experiments show that these deprotonations do not perturb the conformation of the rotaxane.

Seven-membered rings

New synthetic methods continue to be developed to construct seven-membered heterocyclic compounds containing one, two, or three of the heteroatoms N, O, or S. The focus of much of the literature has been on aromatic systems containing at least 1 N atom and has often been driven by a desire to prepare these heterocycles in a stereocontrolled fashion, the search for new bioactives, and the synthesis of natural products. Prominent synthetic methods include transition metal-catalyzed, cycloaddition/annulation, cascade-type, and CeH functionalization processes. Review articles on the synthesis of seven-membered nitrogen heterocycles through the Ugi multicomponent reaction (17CHE382), synthetic approaches, and biological activities of benzodiazepines (17MOC453), the isolation, structure determination, medicinal properties, and total synthesis of marine natural products containing an oxepanyl ring (17MAD361), the synthesis and medicinal importance of benzoxepines (17LDD1086), methods for the synthesis of 1,2,3-, 1,2,4-, 1,2,5-, and 1,3,5-triazepines (17JCCS1023), and the isolation, biosynthesis, and biological activity of natural products that contain a sevenmembered ring with three or more heteroatoms (17JNP3060), as well as indole-fused azepines and analogs as anticancer lead molecules (17EJM244) have been published.

An iterative in silico and modular synthetic approach to aqueous soluble tercyclic α-helix mimetics

Tercyclic scaffolds, designed to have improved synthetic accessibility and aqueous solubility, were evaluated as structural α-helix mimetics by using an iterative in silico approach. The synthesis of these tercyclic scaffolds was accomplished using a modular synthetic approach by employing functionalised methoxyphenyl units which were readily manipulated to allow the introduction of various nitrogen-based heterocycles. The ability of these scaffolds to mimic the key i, i + 3 and i + 7 residues of a polyalanine α-helix was ratified by in silico studies, X-ray crystallographic and NOESY analysis, and their aqueous solubility was measured by a kinetic turbidimetric method.