Late-Stage Chemical Editing as a Route to Naturally Occurring Cyclic Tetrapeptides as Selective Inhibitors of Histone Deacetylase 1.

Abstract

A green approach for the late-stage diversification of the pendant tail of a cyclic tetrapeptide scaffold has been developed. This involves a classical Horner-Wadsworth-Emmons olefination as the means of diversification, avoiding soluble heavy-metal usage leading to the total synthesis of two natural products and two analogues containing a purpose-built oxygenation pattern in the tail region of the molecules. A comparative study of their histone deacetylase inhibition (HDACi) properties revealed that all of them act as selective histone deacetylase 1 (HDAC1) inhibitors, but the degree of selectivity and efficacy is different. Thus, the targeted compounds selectively inhibited HDAC1 over HDAC4 and HDAC6. The natural products 7 and 8a displayed comparable potency. Compound 8a lacking additional oxygenation showed higher selectivity, whereas 22 having additional oxygenation showed lower potency and selectivity in favor of HDAC1. Conformational studies and docking studies revealed that binding to HDAC1 in compounds 7, 8a, and 22 is more pronounced in a particular T4 conformation, compared to the biologically more relevant CT3 conformation. However, an additional oxygen atom along the C9-C10 region may not have a significant role in binding to the HDAC1 isoform in either conformation. This may have implications in drug discovery studies for certain cancer types.

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