Dokument: Synthesis and biological evaluation of HDAC class I/IIb and HDAC6 selective inhibitors
| Titel: | Synthesis and biological evaluation of HDAC class I/IIb and HDAC6 selective inhibitors | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=54283 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20211006-091039-0 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Pflieger, Marc [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: | Over the last decades, epigenetic dysregulations, such as overexpression and mutations of HDACs, were identified as an indicator of cancer, which facilitates a cell to undergo uncontrolled proliferation and the manifestation of resistances against commonly applied anti-cancer drugs such as cisplatin. The combination of HDACi with anti-cancer drugs is a promising approach to overcome chemoresistance and to improve the treatment of cancer. However, the required HDAC isozyme profile of an effective chemosensitising HDACi remains to be established. This work is about the development of HDAC class l/HDAC6 dual inhibitors as well as HDAC6 selective inhibitors, which could exhibit chemosensitising properties towards cancer cells in combination with commonly applied anti-cancer drugs. Panobinostat, a potent pan-HDACi, served as a lead structure and was modified with a hydroxylamine based connecting unit (CU}. MPK409, exhibiting an alkoxyamide CU, was identified as the most potent HDACi in this series and demonstrated a HDAC class 1 and HDAC6 selectivity. In combination with cisplatin, MPK409 caused a chemosensitisation of Cal27CisR towards cisplatin with a shift factor of 6.86. The second project dealt with the establishment of a synthetic procedure for the carba-analogue (MPK544) of the alkoxyurea based HDACi KSK64. Isozyme profiling of MPK544 and KSK64 further emphasised the significance of the CU and indicated that a derivatisation of HDACi with an alkoxyurea CU can result in a refined HDAC isozyme profile with HDAC6 preference. HDAC6, as drug target, is of interest for the pharmacological intervention of cancer as well as immunological and neurological diseases. Selective HDAC6 inhibitors usually show sterically demanding or branched CAP groups, an aromatic linker and a hydroxamic acid as zinc binding group. Since HDACi with hydroxylamine-based CU demonstrated HDAC6 preference, this CU was further explored for the design of HDAC6 selective inhibitors. Novel t-butyl-(alkoxycarbamate) based hydroxamic acids were discovered that showed an up to 4.4 higher HDAC6 selectivity (MPK169) than the HDAC6 selective inhibitor nexturastat A. Another approach to obtain HDAC6 selectivity was pursued by the employment of chromenones as bulky CAP groups. MPK805 was the most selective compound in this series with an approximately 1.6-fold higher HDAC6 selectivity than the HDAC6 selective inhibitor tubastatin A. | |||||||
| 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: | 25.06.2020 | |||||||
| Datum der Promotion: | 14.08.2020 |
