The intriguing role of USP30 inhibitors as deubiquitinating enzymes from the patent literature since 2013.

INTRODUCTION: Ubiquitin specific peptidase 30 (USP30) is a mitochondrial deubiquitinase that antagonizes ubiquitination-mediated mitophagy of damaged or impaired mitochondria driven by the activity of PARK2/Parkin ubiquitin ligase and PINK1 protein kinase. Researchers have related low levels of USP30 to enhanced mitophagy and therefore have been pursuing mitophagy activation utilizing USP30 inhibitors as an alternative approach to target neurodegenerative disorders and other human diseases associated with defective mitophagy. AREAS COVERED: This review covers the research and patent literature on the discovery and development of USP30 inhibitors since 2013. EXPERT OPINION: Strategies toward mitophagy activation utilizing small-molecule inhibitors of USP30 have emerged as alternative pathways for the potential treatment of many human diseases. Research efforts have led to identifying potent and selective small-molecule USP30 inhibitors. Most small-molecule USP30 inhibitors share a common N-cyano motif that binds covalently to the target. Non-covalently binding inhibitors have recently been disclosed as well. Lead compounds exhibit satisfactory inhibitory activities and are currently in preclinical development. Regrettably, complete pharmacological characterization and in vivo evaluation to validate and prove the therapeutic potential is lacking. Target validation could pave the way for discovering and developing USP30 inhibitors that could ultimately lead to marketed drugs.

Total Synthesis of Repraesentin F and Configuration Reassignment by a Gold(I)-Catalyzed Cyclization Cascade.

The first total synthesis of repraesentin F has been accomplished by a highly diastereoselective gold(I)-catalyzed cyclization cascade as the key step. This cycloisomerization/Prins-type tandem transformation enabled direct access to the atypical tricyclic carbon skeleton of the natural product with the required syn/ anti/ syn ring fusion. This synthetic effort also allowed reassignment of the relative configuration of repraesentin F and determination of its absolute configuration.

Role of σ,π-Digold(I) Alkyne Complexes in Reactions of Enynes.

Gold(I) acetylide and σ,π-digold(I) alkyne complexes derived from one prototypical 1,6-enyne and from 7-ethynyl-1,3,5-cycloheptatriene have been prepared and structurally characterized. Their possible role in gold(I)-catalyzed cycloisomerizations has been studied by experiment and by DFT calculations. Gold(I) acetylides are totally unproductive complexes in the absence of Brønsted acids. Similarly, no cyclizations were observed by heating σ,π-digold(I) alkyne digold(I) at least up to 130 °C. Theoretical studies provide a rationale for the much lower reactivity of digold species in reactions of enynes.

Synthesis of Barbaralones and Bullvalenes Made Easy by Gold Catalysis.

The gold(I)-catalyzed oxidative cyclization of 7-ethynyl-1,3,5-cycloheptatrienes gives 1-substituted barbaralones in a general manner, which simplifies the access to other fluxional molecules. As an example, we report the shortest syntheses of bullvalene, phenylbullvalene, and disubstituted bullvalenes, and a readily accessible route to complex cage-type structures by further gold(I)-catalyzed reactions.