Hydroxamic Acids Immobilized on Resins (HAIRs): Synthesis of Dual‐Targeting HDAC Inhibitors and HDAC Degraders (PROTACs)
| Autor: | Finn K. Hansen, Alexandra Hamacher, Jens Meiler, Jan J. Bandolik, Martin Roatsch, Clara T. Schoeder, Andrea Schöler, Laura Sinatra, Sanil Bhatia, Matthias U. Kassack, Melf Sönnichsen, Arndt Borkhardt |
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| Rok vydání: | 2020 |
| Předmět: |
MULTITARGET DRUGS
solid-phase synthesis Dual targeting DNA damage Antineoplastic Agents Apoptosis Caspase 3 Hydroxamic Acids 010402 general chemistry 01 natural sciences Histone Deacetylases Catalysis PROTAC Chimera (genetics) Solid-phase synthesis Cell Line Tumor Humans POLYPHARMACOLOGY Multi‐Target Drugs | Hot Paper Molecular Structure biology 010405 organic chemistry Chemistry Communication TEMOZOLOMIDE General Chemistry Anticancer drug Communications multi-target drugs 0104 chemical sciences Cell biology Histone Deacetylase Inhibitors Resins Synthetic Histone histone deacetylase biology.protein Histone deacetylase |
| Zdroj: | Sinatra, L, Bandolik, J J, Roatsch, M, Soennichsen, M, Schoeder, C T, Hamacher, A, Schoeler, A, Borkhardt, A, Meiler, J, Bhatia, S, Kassack, M U & Hansen, F K 2020, ' Hydroxamic Acids Immobilized on Resins (HAIRs) : Synthesis of Dual-Targeting HDAC Inhibitors and HDAC Degraders (PROTACs) ', Angewandte Chemie International Edition, vol. 59, no. 50, pp. 22494-22499 . https://doi.org/10.1002/anie.202006725 Angewandte Chemie (International Ed. in English) |
| ISSN: | 1521-3773 1433-7851 |
| DOI: | 10.1002/anie.202006725 |
| Popis: | 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. Hydroxamic acids immobilized on resins (HAIRs) were developed and utilized for the library synthesis of DNA‐alkylating HDAC inhibitors and a proof‐of‐concept HDAC degrader (PROTAC). A hybrid compound based on the pharmacophores of chlorambucil and panobinostat was identified as the most promising chimeric HDAC inhibitor and demonstrated improved anticancer properties compared to the sum of the activities of either pharmacophore alone. |
| Databáze: | OpenAIRE |
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