The search for small molecule inhibitors of histone acetylation

Histone acetylation is a key mechanism of transcriptional regulation, which is mediated by two sets<br/>of enzymes; HATs and HDACs. Under normal physiological circumstances there is an orchestrated<br/>balance between the actions of HATs and HDACs. Disruption of this balance can lead to a number<br/>of cellular events which can cause the onset of various diseases for example cancer and HIV. The<br/>search for small molecule inhibitors of histone acetylation focuses on anacardic acid and the<br/>azumamides. Anacardic acid is a natural compound found in cashew nut shell liquid. Its structure<br/>consists of salicylic acid and a long hydrophobic alkyl tail, which suggests that the compound<br/>would be rather insoluble and unable to permeate cells. However, it has been discovered that<br/>anacardic acid has micro molar HAT inhibitory activity towards the HATs PCAF and p300 and is<br/>able to suppress cancer cell growth. In contrast, the azumamides are a series of cyclic tetrapeptides<br/>that were discovered in Mycale izuensis, a Japanese marine invertebrate. Azumamides A-E exhibit<br/>nano molar HDAC inhibitory activity and cytotoxic effects. This report details the synthesis of<br/>anacardic acid by Suzuki coupling and the application of the Mitsunobu synthesis to generate a<br/>series of anacardic acid analogues. In vitro biological assays were used to assess the potency of<br/>anacardic acid and forty four analogues towards cancer cell growth inhibition, HAT, xanthine<br/>oxidase, luciferase and p21 reporter activity. Analogue KC_19 was identified to inhibit HAT and<br/>xanthine oxidase activity with equivalent potency to anacardic acid. KC_39 (IC50 = 18.2 ± 2.6 ?M)<br/>was the most potent analogue in the MCF7 cell growth inhibition but it showed no evidence of<br/>HAT inhibition. Analogue KC_14 was determined in terms of ease of synthesis, MCF7 growth<br/>inhibition (IC50 = 52.4 ± 4.5) and PCAF inhibition (IC50 = 31.7 ± 5.0 ?M) to be the best anacardic<br/>acid analogue overall. The report ends with a small investigation in the inhibition of HDACs by<br/>the azumamides A, E and three novel azumamides. The azumamide hydroxamic acid was<br/>discovered to be potent inhibitor of HeLa HDAC activity (IC50 = 7.0 ± 2.5 nM).

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2010

Author dc:creator

• Carey, K.L.

Advisor dc:contributor.advisor

• Ganesan, A.