| Summary: | Ancient physicians frequently used the resin of <i>Ferula</i> species to treat cancer. Today, some folkloric recipes used for cancer treatment also contain the resin of <i>Ferula</i> species. The dichloromethane extract of the roots of <i>Ferula huber-morathii</i> exhibited cytotoxic activities against COLO 205 (colon), K-562 (lymphoblast), and MCF-7 (breast) cancer cell lines (IC<sub>50</sub> = 52 µg/mL, 72 µg/mL, and 20 µg/mL, respectively). Fifteen sesquiterpene coumarin ethers with cytotoxic activity were isolated from the dichloromethane extract of the roots of <i>F. huber-morathii</i> using bioactivity-directed isolation studies. Extensive spectroscopic analyses and chemical transformations have elucidated the structures of these sesquiterpene coumarin ethers as conferone (<b>1</b>), conferol (<b>2</b>), feselol (<b>3</b>), badrakemone (<b>4</b>), mogoltadone (<b>5</b>), farnesiferol A (<b>6</b>), farnesiferol A acetate (<b>7</b>), gummosin (<b>8</b>), ferukrin (<b>9</b>), ferukrin acetate (<b>10</b>), deacetylkellerin (<b>11</b>), kellerin (<b>12</b>), samarcandone (<b>13</b>), samarcandin (<b>14</b>), and samarcandin acetate (<b>15</b>). The absolute configuration of samarcandin (<b>14</b>) was unequivocally determined by the X-ray crystallographic analysis of the semi-synthetic (<i>R</i>)-MTPA ester of samarcandin (<b>24</b>). Conferol (<b>2</b>) and mogoltadone (<b>5</b>) were found to be the most potent cytotoxic compounds against all three cancer cell lines; furthermore, these compounds exhibit low cytotoxic activity against the non-cancerous human umbilical vein epithelial cells (HUVEC) cell line. Investigation of the biological activity mechanisms of mogoltadone (<b>5</b>) revealed that while suppressing the levels of Bcl-XL and procaspase-3 in the COLO 205 cancer cell line, it did not have a significant effect on the Bcl-XL, caspase-3, and β-catenin protein levels of the HUVEC cell line, which may explain the cytotoxic selectivity of mogoltadone (<b>5</b>) on cancer cell lines.
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