Dokument: Design, Synthesis and Biological Evaluation of Anti-Cancer and Anti-Parasitic Histone Deacetylase Inhibitors

Titel:	Design, Synthesis and Biological Evaluation of Anti-Cancer and Anti-Parasitic Histone Deacetylase Inhibitors
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=44130
URN (NBN):	urn:nbn:de:hbz:061-20171114-094521-1
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Stenzel, Katharina [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 28,71 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 14.11.2017 / geändert 14.11.2017
Beitragende:	Prof. Dr. Kurz, Thomas [Gutachter] Prof. Dr. Kassack, Matthias U. [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 540 Chemie
Beschreibung:	The objective of this work was the synthesis and biological evaluation of anti-cancer and anti-parasitic histone deacetylase inhibitors (HDACi). Three HDACi-sets were synthesized and analyzed. Project 1: Alkoxyurea-based HDACi increase cisplatin potency in chemoresistant cancer cell lines In the first project we present the synthesis and biological evaluation of novel and potent alkoxyurea-based HDACi with quinoline- or naphthyl cap group, an alkoxyurea connecting unit linker region and a hydroxamic acid Zn2+-binding group. Compound 4d displays slightly higher HDAC inhibition in the cellular HDAC assay compared to vorinostat and significantly enhanced cytotoxic effects against the tumor cell line Cal27 and A2780 as well as their cisplatin resistant sublines. The HDAC isoform profiling was in line with the results of the docking study and revealed that compounds 4b d are inhibitors with HDAC6 preference and nanomolar activity (Figure 9). Compound 4d demonstrates strong inhibition of HDAC6 (IC50 2.8 nM), moderate preference over HDAC1 (SI: 15.4) and selectivity over HDAC8 (SI: 550) and HDAC4 (SI >3500). The combination of cisplatin and compounds 4b-d enhanced the sensitivity of the cisplatin-resistant cell line Cal27 CisR. Notably, 4d was able to revert the cisplatin resistance in the Cal27 CisR cell line with a shift factor of 11.2. The high acetylated H3 histone levels and acetylated α tubulin levels found, revealed that the inhibition of HDAC1 and HDAC6 may both contribute to the enhancement of cisplatin chemosensitivity. Project 2: Design and synthesis of terephthalic acid-based histone deacetylase inhibitors with dual stage anti-Plasmodium activity Zn2+-dependent HDACs are currently pharmaceutically highly investigated targets for epigenetic therapy. Chemical control of epigenetic pathways could represent a suitable possibility to attack eukaryotic parasites. Some of the terephthalic acid-based derivatives in this study are not cytotoxic at the highest concentration tested in HepG2 cells (IC50 > 50 µM). Compound 9f was the most active compound in this series and was >450-fold more cytotoxic towards asexual blood stage parasites of P. falciparum 3D7 strain (IC50 0.090 µM) versus mammalian cell line HepG2. While most work to date has focused on asexual stage parasites we could show that 9f has potent activity (IC50 0.180 µM) against exo-erythrocytic stage P. berghei parasites. It was possible to develop HDACi that selectively target two malaria parasite life cycle stages and 9f may be a valuable starting point for the development of novel anti-malarial drug leads with low host cell toxicity. Project 3: Isophthalic acid-based HDAC inhibitors as potent inhibitors of HDAC8 from Schistosoma mansoni In the third project a series of alkoxyamide-based and hydrazide-based HDACi including an isophthalic linker were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. Three preselected compounds show IC50 values in the range of 0.33-0.75 µM against SmHDAC8 and 13d and 15a show a preference for SmHDAC8 over its human orthologue. All three compounds demonstrate high selectivity for SmHDAC8 and human HDAC8 over the major human HDAC isoforms HDAC1 and 6. Selectivity over human HDAC8 still requires optimization, but there are strong indications that the high selectivity over human HDAC1 and 6, that we have already obtained, is of higher importance for a potential therapeutic setting. Docking studies provided insights into the putative binding modes and allowed rationalization of the observed selectivity profile. However, the most potent derivatives 13d and 15a only show moderate or no influence on the viability of S. mansoni schistosomula.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische und Medizinische Chemie
Dokument erstellt am:	14.11.2017
Dateien geändert am:	14.11.2017
Promotionsantrag am:	22.03.2017
Datum der Promotion:	03.07.2017