A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.

Edited by F. Anne StephensonPrion diseases are devastating neurodegenerative disorders with no known cure. One strategy for developing therapies for these diseases is to identify compounds that block conversion of the cellular form of the prion protein (PrP C ) into the infectious isoform (PrP Sc ). Most previous efforts to discover such molecules by high-throughput screening methods have utilized, as a read-out, a single kind of cellular assay system: neuroblastoma cells that are persistently infected with scrapie prions. Here, we describe the use of an alternative cellular assay based on suppressing the spontaneous cytotoxicity of a mutant form of PrP (⌬105-125). Using this assay, we screened 75,000 compounds, and identified a group of phenethyl piperidines (exemplified by LD7), which reduces the accumulation of PrP Sc in infected neuroblastoma cells by >90% at low micromolar doses, and inhibits PrP Sc -induced synaptotoxicity in hippocampal neurons. By analyzing the structure-activity relationships of 35 chemical derivatives, we defined the pharmacophore of LD7, and identified a more potent derivative. Active compounds do not alter total or cell-surface levels of PrP C , and do not bind to recombinant PrP in surface plasmon resonance experiments, although at high concentrations they inhibit PrP Sc -seeded conversion of recombinant PrP to a misfolded state in an in vitro reaction (RTQuIC). This class of small molecules may provide valuable therapeutic leads, as well as chemical biological tools to identify cellular pathways underlying PrP Sc metabolism and PrP C function.Prion diseases are fatal neurodegenerative disorders that are due to the conversion of a normal, neuronal glycoprotein (PrP C ) 3 into an infectious isoform (PrP Sc ) that propagates itself by an autocatalytic templating process (1, 2). In addition to their intrinsic interest to biologists, prion diseases are of enormous medical and public health concern. A global epidemic of bovine spongiform encephalopathy, a prion disease of cattle, emerged in the 1980s and 1990s, resulting in contamination of food supplies and transmission of the disease to a small number of human beings (3, 4). Prion contamination has also increased the risk of blood transfusions, and organ transplants (5). Most recently, a prion-like process has been found to play a role in the CNS dissemination of misfolded proteins in more common neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and tauopathies, and there is even evidence that these diseases can be spread between individuals by iatrogenic means (6, 7). There are currently no cures for prion diseases. A great deal of effort has been invested over the past 25 years in identifying compounds that block the conversion of PrP C into PrP Sc as a therapeutic strategy. Most of these efforts have used as a readout a single kind of cellular assay system: N2a neuroblastoma cells that are chronically infected with scrapie prions (designated ScN2a cells). N2a cells are one of the few cell lines capable...

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OpenBU http://open.bu.edu Chemistry BU Open Access Articles 2019-08-14 Intercepted retro-Nazarov reaction: syntheses of amidino-rocaglate derivatives and their biologi...

Herein, we report the development of continuous flow photoreactors for large scale ESIPT-mediated [3+2]-photocycloaddition of 2-(p-methoxyphenyl)-3-hydroxyflavone and cinnamate- derived dipolarophiles. These reactors can be efficiently numbered up to increase throughput two orders of magnitude greater than the corresponding batch reactions.