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.

中文翻译：

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苯甲酸甲酯和肉桂酸类似物作为肝细胞癌 DNA 甲基化调节剂

酚酸代表了植物界中存在的大量植物化学分子。它们作为表观遗传调节剂具有重要作用，特别是作为 DNA 甲基化的抑制剂。在本研究中，合成了 14 种苯甲酸甲酯和肉桂酸类似物 ( 11 – 24 )。然后评估它们对肝细胞癌细胞 (Hep3B) 和永生化人肝细胞的细胞毒活性。此外，还确定了它对抑制 Hep3B 中全局 DNA 甲基化的影响。我们的结果表明，肉桂衍生物11 – 14和20 – 22比游离咖啡酸 (IC ₅₀109.7–364.2 µM)，是 3,4-二羟基肉桂酸甲酯 ( 12 )，活性最高，IC ₅₀  = 109.7 ± 0.8 µM。此外，11 – 14、20 – 23种化合物将整体 DNA 甲基化水平降低了 63% 至 97%。类似物 4-羟基肉桂酸甲酯 ( 11 )、3,4,5-三甲氧基肉桂酸甲酯 ( 14 )、4-甲氧基肉桂酸甲酯 ( 21 ) 和 3,4-二甲氧基肉桂酸甲酯 ( 22 ) 显示出细胞毒性和整体 DNA 甲基化的相关活性抑制。21和14的分子对接表明它们部分与 DNA 甲基转移酶 1 的 SAH 结合口袋结合。这些结果强调了天然产物及其类似物作为 DNA 甲基化调节剂的潜在来源的重要性。