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Title: The search for small molecule inhibitors of histone acetylation
Author: Carey, Krystle Lea
ISNI:       0000 0004 2695 3985
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2010
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Histone acetylation is a key mechanism of transcriptional regulation, which is mediated by two sets of enzymes; HATs and HDACs. Under normal physiological circumstances there is an orchestrated balance between the actions of HATs and HDACs. Disruption of this balance can lead to a number of cellular events which can cause the onset of various diseases for example cancer and HIV. The search for small molecule inhibitors of histone acetylation focuses on anacardic acid and the azumamides. Anacardic acid is a natural compound found in cashew nut shell liquid. Its structure consists of salicylic acid and a long hydrophobic alkyl tail, which suggests that the compound would be rather insoluble and unable to permeate cells. However, it has been discovered that anacardic acid has micro molar HAT inhibitory activity towards the HATs PCAF and p300 and is able to suppress cancer cell growth. In contrast, the azumamides are a series of cyclic tetrapeptides that were discovered in Mycale izuensis, a Japanese marine invertebrate. Azumamides A-E exhibit nano molar HDAC inhibitory activity and cytotoxic effects. This report details the synthesis of anacardic acid by Suzuki coupling and the application of the Mitsunobu synthesis to generate a series of anacardic acid analogues. In vitro biological assays were used to assess the potency of anacardic acid and forty four analogues towards cancer cell growth inhibition, HAT, xanthine oxidase, luciferase and p21 reporter activity. Analogue KC_19 was identified to inhibit HAT and xanthine oxidase activity with equivalent potency to anacardic acid. KC_39 (IC50 = 18.2 ± 2.6 μM) was the most potent analogue in the MCF7 cell growth inhibition but it showed no evidence of HAT inhibition. Analogue KC_14 was determined in terms of ease of synthesis, MCF7 growth inhibition (IC50 = 52.4 ± 4.5) and PCAF inhibition (IC50 = 31.7 ± 5.0 μM) to be the best anacardic acid analogue overall. The report ends with a small investigation in the inhibition of HDACs by the azumamides A, E and three novel azumamides. The azumamide hydroxamic acid was discovered to be potent inhibitor of HeLa HDAC activity (IC50 = 7.0 ± 2.5 nM).
Supervisor: Ganesan, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry