Design, synthesis and investigating the in vitro and in silico HDAC8 inhibitory activities of derivatives of [6]-shogaol and [6]-gingerol isolated from ginger (Zingiber officinale).

The main components, [6]-shogaol (6) and [6]-gingerol (7), were obtained from the rhizome of Zingiber officinale. Both natural phenolic compounds were modified at C_4′ position to get new sixteen derivatives. All derivatives were screened for their HDAC inhibitory activity at 50 µM using HeLa nuclear extract. Among the synthesized compounds, derivatives 6b, 6e, 6f and 6g were the most effective against HDACs with the IC₅₀ values as 44.60 ± 1.40 µM, 49.23 ± 1.13 µM, 50.55 ± 4.25 µM and 48.52 ± 1.52 µM, respectively. In addition, the selected derivatives were investigated against HDAC8 inhibitory activity. The results demonstrated that among them, 6b was selective with HDAC8 (IC₅₀ = 23.19 ± 1.57 µM). The molecular docking study via MOE docking program also revealed that compound 6b bound into the active pocket of HDAC8 with ΔG value as −6.92 kcal/mol. Moreover, the in vitro antiproliferative activity of four most potent compounds were evaluated against nine cancer cell lines with MTT assay. The results showed that all selected derivatives were most effective against lung (A549), colon (HCT116 and HT29) and human cervical (HeLa) cancer cell lines. Especially, compound 6g was the most potent against A549 cancer cell line with the IC₅₀ value as 8.41 ± 0.04 µM. Therefore, compound 6b and 6g are considered as promising HDACs-inhibitor-anticancer agents. [ABSTRACT FROM AUTHOR]