Exploring putative histone deacetylase inhibitors with antiproliferative activity of chrysin derivatives

Abstract

Thirty-three derivatives of chrysin were designed and synthesized to evaluate biological activities. All compounds were characterized using spectroscopy techniques (IR, ¹H NMR and ¹³C NMR). Moreover, twelve new derivatives were fully characterized via the HRMS technique. The derivatives and the lead compound, chrysin (1) were screened against HDAC inhibition at 100 µM. Three derivatives (C22, C23 and C24) demonstrated the most effective inhibition against HDACs with the IC₅₀ values as 27.13 ± 2.74 µM to 47.47 ± 1.13 µM. Furthermore, the HDAC8 inhibitory activity of compounds C22 and C23 (IC₅₀ = 75.37 ± 3.42 µM and 79.74 ± 0.41 µM, respectively) were more potent than that of chrysin (1) (IC₅₀ > 100 µM). A molecular docking study found that the most active compound C22 was more selective with HDAC8 (ΔG = −8.54 kcal/mol) than other isoforms (HDAC1, 2 and 3). The carboxyl moiety of the strongest derivatives plays an essential role in chelation with the Zn²⁺ cofactor based on metal chelation assay. The Western blot assay confirmed that compounds C23 and C24 were the best HDACis. The most selective HDAC8 inhibitor, compound C22, showed the IC₅₀ value as 13.04 ± 1.08 µM against colon cancer cell lines (HCT-116), whereas compound C24 exhibited the lowest IC₅₀ value as 11.96 ± 0.18 µM against the same cancer cell lines. The ClogP values of all derivatives were acceptable for oral administration (ClogP = 3.57 to 4.26). Therefore, the chrysin derivatives C22, C23 and C24 showed potential for further development as anti-cancer candidates.