Highly Oxidized Germacranolides from <i>Elephantopus tomentosus</i> and the Configurational Revision of Some Previously Reported Analogues

Abstract

Highly oxidized germacranolides are mainly found in the genus <i>Elephantopus</i>, contain a characteristic ten-membered molecular core that is highly flexible, and exhibit potential cytotoxic properties. However, their configurations were assigned ambiguously in previous reports due to spectroscopic observation of macrocyclic systems. Herein, 17 highly oxidized germacranolides, including 12 new germacranolides (<b>1</b>-<b>12</b>), were isolated from <i>Elephantopus tomentosus</i>. Their structures were characterized by spectroscopic data analysis combined with X-ray crystallography and ECD calculations, and it was possible to propose configurational revisions of five previously reported analogues (<b>13</b>-<b>17</b>). Cytotoxic activities for <b>1</b>-<b>17</b> against two hepatocellular carcinoma cell lines (HepG2 and Hep3B) were tested, and compounds <b>1</b>-<b>10</b> and <b>13</b>-<b>16</b> generated IC₅₀ values of 2.2-9.8 μM. Furthermore, the observed cytotoxic activity of <b>1</b> was determined as being mediated by inducing the apoptosis of HepG2 and Hep3B cells via mitochondrial dysfunction.