Dokument: Development of class IIa histone deacetylase inhibitors
| Titel: | Development of class IIa histone deacetylase inhibitors | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=54268 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20211006-090131-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Asfaha, Yodita [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Kurz, Thomas [Gutachter] Prof. Dr. Kassack, Matthias U. [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 540 Chemie | |||||||
| Beschreibung: | Studies over the past decades have demonstrated that histone deacetylases (HDACs) participate in the regulation of expressions and the activity of numerous proteins involved in cancer development and progression. As crucial epigenetic regulators, HDACs are clinically validated cancer targets. Besides the natural product romidepsin, four trichostatin A derived HDAC inhibitors (HDACi) (vorinostat, belinostat, panobinostat, chidamide) are approved for the treatment of lymphoma and myeloma. The first project focused on structural optimization of alkoxyamide-based HDACi by modifying the cap group to increase the synergistic anticancer activity with cisplatin. Among the synthesized compounds, YAK61 displayed a similar inhibition of HDAC2 and HDAC6 compared to the lead compound (SF = 8.36), but YAK61 (SF = 12.8) was slightly more effective in reversing the cisplatin resistance of Cal27CisR. So far, the most common used HDACi in preclinical and clinical evaluations are nonselective HDACi (pan-inhibitor). The design and development of isozyme selective HDACi provide a promising approach to widen the therapeutic window and to reduce the side effects that have been observed for pan HDACi. In contrast to the established role of class I HDACs in cancer, the significance of class IIa HDACs for cancer treatment is controversially discussed.
The second research project focused on the design and development of class IIa-selective HDAC inhibitors. The first strategy focused on the generation of class IIa-selective HDAC inhibitors by addressing the lower selectivity pocket which is only present in class IIa HDACs. Our approaches to target the lower pocket with various α phenyl substituted scaffolds e.g. thiazolyl based hydroxamates and thioether based hydroxamates did not lead to potent and selective class IIa HDACs inhibitors but HDAC8 selective inhibitors The second strategy to design HDAC class IIa selective inhibitors was the employment of the TFMO moiety as a selectivity directing ZBG. The two para-substituted TFMO-based compounds FFK29 (IC50(HDAC4) = 24.5 nM) and FFK24 (IC50(HDAC4) = 12 nM) were identified as nanomolar and selective HDAC class IIa inhibitors. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie | |||||||
| Dokument erstellt am: | 06.10.2021 | |||||||
| Dateien geändert am: | 06.10.2021 | |||||||
| Promotionsantrag am: | 01.02.2017 | |||||||
| Datum der Promotion: | 14.08.2020 |
