Synthesis of Peptoid-Based Class I-Selective Histone Deacetylase Inhibitors with Chemosensitizing Properties
| Autor: | Thomas Kurz, Finn K. Hansen, Fangyuan Cao, Alexandra Hamacher, Katharina Stenzel, Viktoria Krieger, Holger Gohlke, Linda Schäker-Hübner, Christoph G. W. Gertzen, Matthias U. Kassack, Frank J. Dekker |
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| Přispěvatelé: | Chemical and Pharmaceutical Biology, Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Medicinal Chemistry and Bioanalysis (MCB) |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Protein Conformation Caspase 3 Antineoplastic Agents Apoptosis CISPLATIN RESISTANCE 01 natural sciences Histone Deacetylases 03 medical and health sciences Peptoids DESIGN Drug Discovery Tumor Cells Cultured Humans ASSAY DOCKING COMBINATION 030304 developmental biology Cell Proliferation Ovarian Neoplasms 0303 health sciences Aniline Compounds Histone deacetylase 2 Chemistry PROLIFERATION HDAC INHIBITOR HDAC3 CANCER HDAC1 0104 chemical sciences Squamous carcinoma Histone Deacetylase Inhibitors 010404 medicinal & biomolecular chemistry KEY FACTOR Cell culture Drug Resistance Neoplasm Cancer cell ACID Benzamides Cancer research Carcinoma Squamous Cell Molecular Medicine Female Histone deacetylase Cisplatin |
| Zdroj: | Journal of Medicinal Chemistry, 62(24), 11260-11279. AMER CHEMICAL SOC |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | There is increasing evidence that histone deacetylase (HDAC) inhibitors can (re)sensitize cancer cells for chemotherapeutics via "epigenetic priming". In this work, we describe the synthesis of a series of class I-selective HDAC inhibitors with 2-aminoanilides as zinc-binding groups. Several of the synthesized compounds revealed potent inhibition of the class I HDAC isoforms HDAC1, HDAC2, and/or HDAC3 and promising antiproliferative effects in the human ovarian cancer cell line A2780 and the human squamous carcinoma cell line Cal27. Selected compounds were investigated in a cellular model of platinum resistance. In particular, compound 2a revealed potent chemosensitizing properties and full reversal of cisplatin resistance in Cal27CisR cells. This effect is related to a synergistic increase in caspase 3/7 activation and induction of apoptosis. Thus, this work demonstrates that pan-HDAC inhibition or dual class I/class IIb inhibition is not required for full reversal of cisplatin resistance. |
| Databáze: | OpenAIRE |
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