Matthews, CJ; (2016) Histone deacetylase inhibitors containing chiral heterocyclic capping groups. Doctoral thesis , UCL (University College London).

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Abstract

Histone deacetylase (HDAC) enzymes are one of the best characterised epigenetic targets; aberrant activity of one or more of the 11 zinc-dependent HDAC isoforms has been associated with many different cancers, as well as several other diseases. Some HDAC inhibitors have been proven to be efficacious in treating cancer; three are FDA approved for treating cutaneous T-cell lymphoma or multiple myeloma. Animal models of other diseases have shown that HDAC inhibitors have potential as therapeutic agents. However the clinical use of HDAC inhibitors is currently limited by toxicity and side effects, amongst other problems, possibly arising because the inhibitors are not isoform selective. This thesis focuses on attempts to synthesise novel HDAC inhibitors with increased isoform selectivity. A series of mocetinostat analogues substituted at the 4-poisition of the terminal 2-aminophenyl ring, was synthesised and tested for inhibition of HDAC isoforms, but no improvement over mocetinostat was found. Subsequently multiple series of compounds containing a chiral heterocycle, in place of the pyrimidine ring in mocetinostat, were prepared and evaluated against a selection of HDAC isoforms. The development of highly convergent methodology enabled the rapid synthesis of these chiral mocetinostat analogues. Several compounds were discovered that are more potent and selective inhibitors than mocetinostat against HDAC3. Those compounds containing a 2-amino-linked dihydrooxazole ring were the most potent, and in all cases the amino-linked heterocycle outperformed its thioetherlinked analogue. Mocetinostat and a novel chiral analogue were shown to be slow, tightbinding inhibitors of HDAC2 and HDAC3. Attempts were made to discover a novel zinc-binding group; a selection of potential bi-dentate zinc-chelating fragments was assayed and 8-hydroxyquinoline emerged as a promising candidate for HDAC8 inhibition. Accordingly some substituted 8-hydroxyquinolines were prepared in order to conduct a brief SAR study of the novel zinc-binding group, however no improvement on the unsubstituted 8-hydroxyquinoline was found.

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