Oxa Analogues of Nexturastat A Demonstrate Improved HDAC6 Selectivity and Superior Antileukaemia Activity
| Autor: | Andrea Schöler, Thomas Kurz, Sanil Bhatia, Jing Yang, Nadine Horstick-Muche, Finn K. Hansen, Alexandra Hamacher, Melf Sönnichsen, Arndt Borkhardt, Marc Pflieger, Matthias U. Kassack, Julian Schliehe-Diecks |
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| Rok vydání: | 2021 |
| Předmět: |
Cell Survival
Leukaemia cell Antineoplastic Agents Pharmacology Histone Deacetylase 6 Hydroxamic Acids 01 natural sciences Biochemistry Pathogenesis Structure-Activity Relationship Cell Line Tumor inhibitors Drug Discovery medicine Humans General Pharmacology Toxicology and Pharmaceutics Patient compliance Cell Proliferation Dose-Response Relationship Drug Molecular Structure Full Paper 010405 organic chemistry Chemistry Phenylurea Compounds Organic Chemistry Cancer Biological activity Full Papers HDAC6 HDAC isozyme profile medicine.disease 0104 chemical sciences Histone Deacetylase Inhibitors Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Leukemia leukaemia Molecular Medicine Drug Screening Assays Antitumor Selectivity histone deacetylases |
| Zdroj: | Chemmedchem |
| ISSN: | 1860-7187 1860-7179 |
| DOI: | 10.1002/cmdc.202001011 |
| Popis: | The acetylome is important for maintaining the homeostasis of cells. Abnormal changes can result in the pathogenesis of immunological or neurological diseases, and degeneration can promote the manifestation of cancer. In particular, pharmacological intervention in the acetylome with pan‐histone deacetylase (HDAC) inhibitors is clinically validated. However, these drugs exhibit an undesirable risk‐benefit profile due to severe side effects. Selective HDAC inhibitors might promote patient compliance and represent a valuable opportunity in personalised medicine. Therefore, we envisioned the development of HDAC6‐selective inhibitors. During our lead structure identification, we demonstrated that an alkoxyurea‐based connecting unit proves to be beneficial for HDAC6 selectivity and established the synthesis of alkoxyurea‐based hydroxamic acids. Herein, we report highly potent N‐alkoxyurea‐based hydroxamic acids with improved HDAC6 preference compared to nexturastat A. We further validated the biological activity of these oxa analogues of nexturastat A in a broad subset of leukaemia cell lines and demonstrated their superior anti‐proliferative properties compared to nexturastat A. A hydroxylamine connecting unit facilitates HDAC6 preference: The derivatization of nexturastat A with alkoxyurea connecting units is reported. This modification resulted in an increased preference for HDA6 and increased antiproliferative properties in haematological cancer cell lines. |
| Databáze: | OpenAIRE |
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