Bicyclic tetrapeptide histone deacetylase inhibitors with methoxymethyl ketone and boronic acid zinc-binding groups

• Bicyclic tetrapeptide methoxymethyl ketone (MMK) and boronic acid were synthesized.
• Boronic acid bearing bicyclic tetrapeptide showed poor HDAC inhibitory activity.
• MMK bearing bicyclic tetrapeptide displayed impressive HDAC inhibitory activity.
• MMK-based bicyclic tetrapeptide might be promising anticancer drug candidate.

Histone deacetylase (HDAC) inhibitors are a class of potential therapeutics for the treatment of cancer. Bicyclic tetrapeptides equipped with methoxymethyl ketone and boronic acid as zinc-binding group were designed and synthesized. The inhibitory activities of these compounds were evaluated against HDAC enzymes. The cell-free and cell-based assay data showed that both potency and selectivity changed with the change in zinc-binding group. Boronic acid-based compound showed poor activity whereas methoxymethyl ketone-based compound displayed impressive activity in both cell-free and cell-based conditions.

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