Amsilarotene

A method for the deprotonative silylation of aromatic C-H bonds has been developed using trifluoromethyltrimethylsilane (CF₃SiMe₃, Ruppert-Prakash reagent) and a catalytic amount of fluoride. In this reaction, CF₃SiMe₃ is considered to act as a base and a silicon electrophile. This process is highly tolerant to various functional groups on heteroarenes and benzenes. Furthermore, this method can be applied to the synthesis of trimethylsilyl group-containing analogs of TAC-101, which is a bioactive synthetic retinoid with selective affinity for retinoic acid receptor α (RAR-α) binding. We also report further transformations of the silylated products into useful derivatives.

Hepatitis C virus (HCV) is a positive‐sense single‐stranded RNA virus with an estimated infection in ∼180 million people worldwide, and its chronic infection leads to development of cirrhosis and hepatocellular carcinoma. Although recent development of direct acting antiviral (DAA) compounds improved anti‐HCV regimens, alternative therapeutic compounds are still demanded due to an expected emergence of escape mutants for those DAAs. In order to identify novel anti‐HCV agents, we conducted chemical library screening for 2086 compounds using HCV Rep‐Feo reporter replicon in Huh7 hepatoma cells. Our screening identified retinoid derivative Tp80, which inhibits replication of HCV Rep‐Feo (genotype 1b) and JFH1 HCV (genotype 2a) with 0.62 μM and 1.0 μM, respectively, of 50% effective concentration (EC50), at which cytotoxicity is not evident for host hepatocytes. Subsequent transcriptome profiling revealed Tp80 exhibits anti‐HCV activity through restoration of gastrointestinal glutathione peroxidase (GI‐GPx), suppression of which is responsible for HCV‐induced oxidative stress to facilitate HCV replication. Furthermore, comparison of Tp80 with other retinoid derivatives revealed Tp80 shows best potency in both GI‐GPx restoration and anti‐HCV activity among compounds we examined. In conclusion, our current study provides Tp80 as a promising candidate of anti‐HCV compound, suppressing host cellular oxidative stress through a restoration of GI‐GPx.