Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161

A novel synthesis of the naturally occurring HDAC inhibitor WF-3161 is described. Key steps include the Matteson homologation to generate the stereogenic centres in the side chain, and Pd-catalysed C-H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, whereas no activity was observed towards HDAC6. High activity was also found against the cancer cell line HL-60.

Automated summary

This study describes a novel synthesis strategy for the naturally occurring HDAC inhibitor WF-3161. The key steps involve Matteson homologation to generate stereogenic centers in the side chain, and Pd-catalysed C-H functionalisation to connect the side chain to the peptide backbone. WF-3161 was found to be highly selective for HDAC1, with no activity observed towards HDAC6. It also exhibited high activity against the cancer cell line HL-60.