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Synthesis of inhibitors of histone deacetylase.

Dines, J.; (2008) Synthesis of inhibitors of histone deacetylase. Doctoral thesis , University of London. Green open access

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Abstract

It has been known for some years now that histone deacetylase (HDAC) inhibition exerts a variety of effects on cellular proliferation and apoptosis. The potential for use of inhibitors of HDAC in the field of cancer therapy has now been realised the first drug of this class recently being approved for use. Structurally, a great variety of molecules have been shown to be capable of producing an inhibitory effect, through mechanisms elucidated by crystallographic studies of the inhibitor-bound enzyme. Despite the diversity of these compounds, several structural features common to most of the known inhibitors can be identified, including a moiety capable of binding a zinc ion present at the enzymes active site. A great number of the known inhibitors bear a hydroxamic acid group for this reason, despite the reportedly unfavourable characteristics of this functionality in vivo. This thesis focuses on the synthesis of novel inhibitors of HDAC, attempts to develop non-hydroxamate inhibitors and biological evaluation of the HDAC inhibitory capability of compounds synthesised within this group. A series of compounds bearing aryloxyalkanoic acid hydroxyamide motifs were synthesised following the identification of this class of compounds as potent HDAC inhibitors. Systematic variation of these molecules allowed optimisation of their activity in isolated enzyme inhibition assays and in human cancer cell line cytotoxicity assays. Attempts to identify novel zinc-binding groups capable of replacing the hydroxamic acid motif were possible through use of the structure of a known potent inhibitor and substitution of the motif with a variety of structures proposed to provide the same role. A further group of novel hydroxamate inhibitors were synthesised based on the simple structure of a known inhibitor. Diversification of the structure and substitution of bio-isosteres led to enhancement of inhibitory activity. Finally, a selection of novel compounds synthesised within this group were evaluated for their effect on cell cycle, cell protein expression and isolated HDAC inhibition.

Type: Thesis (Doctoral)
Title: Synthesis of inhibitors of histone deacetylase.
Identifier: PQ ETD:592546
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest.
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/1445228
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