Ben Neuenswander

Optimization of Potent Hepatitis C Virus NS3 Helicase Inhibitors Isolated from the Yellow Dyes Thioflavine S and Primuline

A screen for hepatitis C virus (HCV) NS3 helicase inhibitors revealed that the commercial dye thioflavine S was the most potent inhibitor of NS3-catalyzed DNA and RNA unwinding in the 827-compound National Cancer Institute Mechanistic Set. Thioflavine S and the related dye primuline were separated here into their pure components, all of which were oligomers of substituted benzothiazoles. The most potent compound (P4), a benzothiazole tetramer, inhibited unwinding >50% at 2 ± 1 μM, inhibited the subgenomic HCV replicon at 10 μM, and was not toxic at 100 μM. Because P4 also interacted with DNA, more specific analogues were synthesized from the abundant dimeric component of primuline. Some of the 32 analogues prepared retained ability to inhibit HCV helicase but did not appear to interact with DNA. The most potent of these specific helicase inhibitors (compound 17) was active against the replicon and inhibited the helicase more than 50% at 2.6 ± 1 μM.

Application of 6,7-indole aryne cycloaddition and Pd(0)-catalyzed Suzuki-Miyaura and Buchwald-Hartwig cross-coupling reactions for the preparation of annulated indole libraries.

The construction of an unprecedented class of an indole-based library, namely, a 6,7-annulated-4-substituted 93-member indole library, using a strategic combination of 6,7-indolyne cycloaddition and cross-coupling reactions under both Suzuki-Miyaura and Buchwald-Hartwig conditions is described. This work represents the first example of library development that employs the indole aryne methodology. Annulated indoles, with the exception of only a few biologically active natural products (i.e., the trikentrins, herbindoles, teleocidins, and nodulisporic acids), have no representation in the PubChem or MLSMR databases. These structural entities are therefore predicted to have unique chemical property space characteristics and a high probability of exhibiting interesting biological activity.

Synthesis and receptor profiling of Stemona alkaloid analogues reveal a potent class of sigma ligands

Reported biological activities of Stemona natural products, such as antitussive activity, inspired the development of synthetic methods to access several alkaloids within this family and in so doing develop a general route to the core skeleta shared by the class of natural products. The chemistry was subsequently adapted to afford a series of analogue sets bearing simplified, diverse Stemona-inspired skeleta. Over 100 of these analogues were subjected to general G protein-coupled receptor profiling along with the known antitussive compound, neostenine; this led to the identification of hit compounds targeting several receptor types. The particularly rich hit subset for sigma receptors was expanded with two focused library sets, which resulted in the discovery of a fully synthetic, potent chemotype of sigma ligands. This collaborative effort combined the development of synthetic methods with extensive, flexible screening resources and exemplifies the role of natural products in bioactivity mining.

Three-Component Synthesis of 1,4-Diazepin-5-ones and the Construction of γ-Turn-like Peptidomimetic Libraries

The parallel synthesis of gamma-turn-inspired peptidomimetic libraries has been demonstrated through two approaches toward the preparation of 1,4-diazepin-5-ones. In the first approach, 1,4-diazepin-5-ones scaffolds were prepared on gram scale and subsequently diversified to produce libraries. In a second approach, libraries of 1,4-diazepin-5-ones were produced directly through a three-component strategy that maximizes the diversity obtained in a single step.

Nitrate deposition following an astrophysical ionizing radiation event

Abstract It is known that a gamma ray burst (GRB) originating near the Earth could be devastating to life. The mechanism of ozone depletion and subsequent increased UVB exposure is the primary risk, but models also show increased nitrification culminating in nitric acid rainout. These effects are also expected after nearby supernovae and extreme solar proton events. In this work we considered specifically whether the increased nitric acid rainout from such events is a threat to modern terrestrial ecosystems. We also considered its potential benefit to early terrestrial Paleozoic ecosystems. We used established critical loads for nitrogen deposition in ecoregions of Europe and the US and compared them with previously predicted values of nitric acid rainout from a typical GRB within our galaxy. The predicted rainout was found to be too low to harm modern ecosystems, however, it is large compared with probable nitrate flux onto land prior to the invasion of plants. We suggest that this flux may have contributed nutrients to this invasion if, as hypothesized, the end-Ordovician extinction event were initiated by a GRB or other ionizing radiation event.