Effects of 2,3-Dehydrosilybin and Its Galloyl Ester and Methyl Ether Derivatives on Human Umbilical Vein Endothelial Cells

The effects in vitro of 2,3-dehydrosilybin and several galloyl esters and methyl ethers on the viability, proliferation, and migration of human umbilical vein endothelial cells (HUVECs) were evaluated. The monogalloyl esters were synthesized by a chemoselective esterification method or by Steglich esterification of suitably protected 2,3-dehydrosilybin (<b>1</b>) with protected gallic acid. 2,3-Dehydrosilybin (<b>1</b>) displayed more potent cytotoxic, antiproliferative, and antimigratory activities (IC₅₀ 12.0, 5.4, and 12.2 μM, respectively) than silybin. The methylated derivatives were less active, with the least potent being 3,7-di-<i>O</i>-methyl-2,3-dehydrosilybin (<b>6</b>). On the other hand, galloylation at C-7 OH and C-23 OH markedly increased the cytotoxicity and the effects on the proliferation and migration of HUVECs. The most active derivative was 7-<i>O</i>-galloyl-2,3-dehydrosilybin (<b>13</b>; IC₅₀ value of 3.4, 1.6, and 4.7 μM in the cytotoxicity, inhibition of proliferation, and antimigratory assays, respectively). Overall, this preliminary structure–activity relationship study demonstrated the importance of a 2,3-double bond, a C-7 OH group, and a galloyl moiety in enhancing the activity of flavonolignans toward HUVECs