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Sie sind hier: Startseite AK Hansen Publikationen Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)

Laura Sinatra, Jan J Bandolik, Martin Roatsch, Melf Sönnichsen, Clara T Schoeder, Alexandra Hamacher, Andrea Schöler, Arndt Borkhardt, Jens Meiler, Sanil Bhatia, Matthias U Kassack, and Finn K Hansen (2020)

Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)

Angewandte Chemie International Edition, 59(50):22494–22499.

Inhibition of more than one cancer-related pathway by multi-target agents is an emerging approach in modern anticancer drug discovery. Here, based on the well-established synergy between histone deacetylase inhibitors (HDACi) and alkylating agents, we present the discovery of a series of alkylating HDACi using a pharmacophore-linking strategy. For the parallel synthesis of the target compounds, we developed an efficient solid-phase-supported protocol using hydroxamic acids immobilized on resins (HAIRs) as stable and versatile building blocks for the preparation of functionalized HDACi. The most promising compound, 3 n, was significantly more active in apoptosis induction, activation of caspase 3/7, and formation of DNA damage (γ-H2AX) than the sum of the activities of either active principle alone. Furthermore, to demonstrate the utility of our preloaded resins, the HAIR approach was successfully extended to the synthesis of a proof-of-concept proteolysis-targeting chimera (PROTAC), which efficiently degrades histone deacetylases.

DNA damage, PROTAC, histone deacetylase, multi-target drugs, solid-phase synthesis