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

Silychristin: Skeletal Alterations and Biological Activities

Silychristin is the second most abundant flavonolignan (after silybin) present in the fruits of <i>Silybum marianum</i>. A group of compounds containing silychristin (<b>3</b>) and its derivatives such as 2,3-dehydrosilychristin (<b>4</b>), 2,3-dehydroanhydrosilychristin (<b>5</b>), anhydrosilychristin (<b>6</b>), silyhermin (<b>7</b>), and isosilychristin (<b>8</b>) were studied. Physicochemical data of these compounds acquired at high resolution were compared. The absolute configuration of silyhermin (<b>7</b>) was proposed to be identical to silychristin A (<b>3a</b>) in ring D (10<i>R</i>,11<i>S</i>). The preparation of 2,3-dehydrosilychristin (<b>4</b>) was optimized. The Folin–Ciocalteau reduction and DPPH and ABTS radical scavenging assays revealed silychristin and its analogues to be powerful antioxidants, which were found to be more potent than silybin and 2,3-dehydrosilybin. Compounds <b>4</b>–<b>6</b> exhibited inhibition of microsomal lipoperoxidation (IC₅₀ 4–6 μM). Moreover, compounds <b>4</b>–<b>8</b> were found to be almost noncytotoxic for 10 human cell lines of different histogenetic origins. On the basis of these results, compounds <b>3</b>–<b>6</b> are likely responsible for most of the antioxidant properties of silymarin attributed traditionally to silybin (silibinin)