The search for small molecule inhibitors of histone acetylation

Abstract

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 ?M)
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 ?M) 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).

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