Methyl benzoate and cinnamate analogs as modulators of DNA methylation in hepatocellular carcinoma

Abstract

Phenolic acids represent a large collection of phytochemical molecules present in the plant kingdom; they have an important role as epigenetic regulators, particularly as inhibitors of DNA methylation. In the present study, 14 methyl benzoate and cinnamate analogs were synthesized (11–24). Their cytotoxic activity on hepatocellular carcinoma cells (Hep3B) and immortalized human hepatocyte cells was then evaluated. In addition, its effect on the inhibition of global DNA methylation in Hep3B was also determined. Our results showed that the cinnamic derivatives 11–14 and 20–22 were more potent than the free caffeic acid (IC50 109.7–364.2 µM), being methyl 3,4‐dihydroxycinammate (12) the most active with an IC50 = 109.7 ± 0.8 µM. Furthermore, 11–14, 20–23 compounds decreased overall DNA methylation levels by 63% to 97%. The analogs methyl 4‐hydroxycinnamate (11), methyl 3,4,5‐trimethoxycinnamate (14), methyl 4‐methoxycinnamate (21), and methyl 3,4‐dimethoxycinnamate (22) showed relevant activities of both cytotoxicity and global DNA methylation inhibition. The molecular docking of 21 and 14 suggested that they partly bind to the SAH‐binding pocket of DNA methyltransferase 1. These results emphasize the importance of natural products and their analogs as potential sources of DNA methylation modulating agents.

Screening of in Vitro Inhibition of Lactoperoxidase Enzyme by Methyl Benzoate Derivatives with Molecular Docking Studies

“…They found methyl 4-amino-2-bromobenzoate displayed the best inhibitor property (K i = 25.10 � 4.73 μM). In another study, Castro-Vazquez et al [30] synthesized fourteen methyl cinnamate and benzoate compounds and studied the inhibition of global DNA methylation in Hep3B. They determined that the cinnamic derivatives showed the most active properties.…”