Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 59, Issue 50, Pages 22494-22499Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202006725
Keywords
DNA damage; histone deacetylase; multi-target drugs; PROTAC; solid-phase synthesis
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Funding
- Deutsche Forschungsgemeinschaft (DFG) [INST 208/6901 FUGG, RO5526/1-1]
- Alexander von Humboldt Foundation
- Forschungskommission [2018-04]
- DSO-Netzwerkverbundes, HHU Dsseldorf
- Projekt DEAL
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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 usinghydroxamic 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 (gamma-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.
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