Ever since the discovery that reversal of aberrant epigenetic regulation can be exploited in drug development for cancer and other diseases, efforts have been focused on developing compounds with such capability. Inhibition of Histone deactylases (HDAC), an epigenetic regulator, has since been validated as a viable therapeutic route, with the Food and Drugs Administration (FDA) approving two HDAC inhibitors (HDACi) (Suberoylanilide hydroxamic acid (SAHA) and Romidepsin or FK228) for treatment of Cutaneous T-Cell Lymphoma. Despite their success, SAHA and FK228 suffer from lack of efficacy against solid tumors and off-target toxicity. Towards obtaining tissue selective HDACi, we have designed a series of clarithromycin-capped hydroxamic acid-based HDACi following similar pharmacophoric model with SAHA. We designed and synthesized two series of these compounds having HDACi moiety attached to the desosamine and the cladinose sugars of clarithromycin. Linker lengths in each series were varied to determine the optimum length. Furthermore, we evaluated the HDAC isoform selectivity of these compounds as well as their antiproliferative activity in breast cancer cell line (MCF-7).

Nonpeptide macrocyclic histone deacetylase inhibitors derived from clarithromycin

246th National Meeting (2013)

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