Pharmaceuticals that target histone deacetylase (HDAC) enzymes have gained much attention in recent decades. The overexpression of HDACs correlates with numerous prevalent diseases, such as Alzheimer's disease and cancer. WF-3161 was first isolated from a strain of fungus, Petriella guttulata, by Umehara et al., who amassed a large body of structural and biological data on its activity, including anti-cancer activity against blood cancer cells in mice and antifungal activity against Trichophyton asteroides. In 2008, Proksch et al. obtained similar results with lymphoma cells from mice.

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  • P. Proksch, R. Ebel, R. Edrada, F. Riebe, H. Liu, A. Diesel, M. Bayer, X. Li, W. H. Lin, V. Grebenyuk, W. E. G. Müller, S. Draeger, A. Zuccaro, B. Schulz, Bot. Mar. 2008, 51, 209–218.

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.

  • M. Kohr, N. Papenkordt,M. Jung, U. Kazmaier, "Total synthesis and biological evaluation of histone deacetylase inhibitor WF-3161", Org. Biomol. Chem. 2023, 21, 4382−4387. DOI: 10.1039/D3OB00641G