Borinostats: solid-phase synthesis of carborane-capped histone deacetylase inhibitors with a tailor-made selectivity profile

• Published in: Chemical science (Cambridge) Vol. 12; no. 35; pp. 11873 - 11881
• Main Authors: Selg, Christoph, Schöler, Andrea, Schliehe-Diecks, Julian, Hanl, Maria, Sinatra, Laura, Borkhardt, Arndt, Sárosi, Menyhárt B, Bhatia, Sanil, Hey-Hawkins, Evamarie, Hansen, Finn K
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 15.09.2021; The Royal Society of Chemistry
• Subjects: Carborane; Chemistry; Histones; Inhibitors; Selectivity; Solid phase synthesis; Toxicity
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/d1sc02268g

The elevated expression of histone deacetylases (HDACs) in various tumor types renders their inhibition an attractive strategy for epigenetic therapeutics. One key issue in the development of improved HDAC inhibitors (HDACis) is the selectivity for single HDAC isoforms over unspecific pan inhibition to minimize off-target toxicity. Utilizing the carborane moiety as a fine-tuning pharmacophore, we herein present a robust solid phase synthetic approach towards tailor-made HDACis meeting both ends of the selectivity spectrum, namely pan inhibition and highly selective HDAC6 inhibition. This work describes a versatile solid phase synthesis of carborane-capped histone deacetylase inhibitors with a tunable selectivity profile and synergistic anticancer activity with bortezomib.