No abstract

The use of a liquid electrolyte is nearly ubiquitous in electrosynthetic systems and can have a significant impact on the selectivity and efficiency of electrochemical reactions. Solvent selection is thus a key step during optimization, yet this selection process usually involves trial-and-error. As a step toward more rational solvent selection, this work examines how the electrolyte solvent impacts the selectivity of electrocarboxylation of organic halides. For the carboxylation of a model alkyl bromide, hydrogenolysis is the primary side reaction. Isotope-labeling studies indicate the hydrogen atom in the hydrogenolysis product comes solely from the aprotic electrolyte solvent. Further mechanistic studies reveal that under synthetically relevant electrocarboxylation conditions, the hydrogenolysis product is formed via deprotonation of the solvent. Guided by these mechanistic findings, a simple computational descriptor based on the free energy to deprotonate a solvent molecule was shown to correlate strongly with carboxylation selectivity, overcoming limitations of traditional solvent descriptors such as pK a . Through careful mechanistic analysis surrounding the role of the solvent, this work furthers the development of selective electrocarboxylation systems and more broadly highlights the benefits of such analysis to electrosynthetic reactions.

The dearomatization of 2‐naphthols represents a simple method for the construction of complex 3D structures from simple planar starting materials. We describe a cyclopropanation of 2‐naphthols that proceeds via cyclopropene ring‐opening using rhodium and acid catalysis under mild conditions. The vinyl cyclopropane molecules were formed with high chemoselectivity and scalability, which could be further functionalized at different sites. Both computational and experimental evidence were used to elucidate the reaction mechanism.

Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol enhances the ability of the anthelmintic Ivermectin to paralyze C. elegans and the ruminant nematode parasite Haemonchus contortus. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through a validated anthelmintic target.

Histone deacetylase 6 (HDAC6) inhibition is an attractive strategy for treating numerous cancers, and HDAC6 catalytic inhibitors are currently in clinical trials. The HDAC6 zincfinger ubiquitin-binding domain (UBD) binds free C-terminal diglycine motifs of unanchored ubiquitin polymer chains and protein aggregates, playing an important role in autophagy and aggresome assembly. However, targeting this domain with small molecule antagonists remains an underdeveloped avenue of HDAC6-focused drug discovery. We report SGC-UBD253 (25), a chemical probe potently targeting HDAC6-UBD in vitro with selectivity over nine other UBDs, except for weak USP16 binding. In cells, 25 is an effective antagonist of HDAC6-UBD at 1 μM, with marked proteome-wide selectivity. We identified SGC-UBD253N (32), a methylated derivative of 25 that is 300-fold less active, serving as a negative control. Together, 25 and 32 could enable further exploration of the biological function of the HDAC6-UBD and investigation of the therapeutic potential of targeting this domain.