HDACs are responsible for repressing the expression of genes associated with cell growth arrest, differentiation, and apoptosis. Many cancers express high levels of HDACs and appear to have an increased sensitivity to HDAC inhibitors relative to normal cells. It has also been suggested that HDAC inhibitors with strong potency and isoform selectivity may broaden their clinical utility and minimize side effects. Therefore, it is essential to identify novel, more selective compounds that overcome current limitations. Here we report our study on chiral HDAC inhibitors utilizing amino acids or simple chiral natural products as building blocks. These compounds were tested against HDAC 1 through 11 and it was found that compound AO-A115 exhibited selectivity and good inhibition against HDAC8. The crucial interaction between AO-A115 and HDAC8 was rationalized by computer modeling. These results may serve as a starting point for the discovery of potent and isoform selective HDAC inhibitors.

Chiral histone deacetylase inhibitors: Synthesis and biological evaluation

251st National Meeting (2016)

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