Histone Deacetylase Inhibitory and Cytotoxic Activities of the Constituents from the Roots of Sophora Pachycarpa

Abstract

Four prenylated flavonoids, including isosophoranone, sophoraflavanone G, alopecurone J, alopecurone P, and a resveratrol derivative HPD (2-(4-hydroxyphenyl)-2,3-dihydrobenzo[b] furan-3,4,6-triol), were isolated from the roots of Sophora pachycarpa. The cytotoxic activity of obtained compounds was evaluated against A2780, A549, HeLa, and HCT116 human cancer cell lines. We also evaluated their histone deacetylase (HDAC) inhibitory activities. Of all compounds tested, alopecurone J was the most active with IC₅₀ values in the range of 9.97-30.91 μM against four cancer cell lines with potent pan-HDAC inhibitory activity (IC₅₀ = 0.08-3.85 μM). Molecular docking experiments of these compounds with HDAC8 displayed potential selective HDAC inhibitory. Molecular docking data showed consistent results in the in-vitro experiments with high selectivity towards HDAC8. The Resveratrol group plays an essential role in HDAC inhibition.

Keywords: Cytotoxicity; Histone deacetylase inhibitors; Molecular docking; Sophora pachycarpa; prenylated flavonoids.

Figure 1

Structures of isosophoranone (1), sophoraflavanone G (2), 2-(4-hydroxyphenyl)-2,3-dihydrobenzo[b]furan-3,4,6-triol (3), alopecurone J (4) and alopecurone P (5).

Figure 2

Docking model structure of compound 4 into the active site of HDAC8 protein binding pocket

Figure 3

Binding model of compound 4 into active pocket of HDAC8