Cardenolides in <i>Asclepias syriaca</i> Seeds: Exploring\nthe Legacy of Tadeus Reichstein

The\ncommon milkweed <i>Asclepias syriaca</i> is widespread\nin North America and produces cardenolide toxins that deter herbivores\nby targeting the transmembrane enzyme Na<sup>+</sup>/K<sup>+</sup>-ATPase. In 1979, Nobel Laureate Tadeus Reichstein elucidated the\nstructure of novel cardenolides isolated from <i>A. syriaca</i> roots and proposed structures for several other cardenolides that\ncould not be confirmed. In this study, we investigate the cardenolide\ncomposition of <i>A. syriaca</i> seeds, focusing on their\nabundance and <i>in vitro</i> inhibitory potency on the\nsensitive porcine Na<sup>+</sup>/K<sup>+</sup>-ATPase and that of\nthe highly resistant large milkweed bug, <i>Oncopeltus fasciatus</i>. We identify five previously unreported cardenolides (<b>1</b>–<b>5</b>), three of which are predominantly found in\nseeds, in addition to the known syrioside (<b>6</b>), aspecioside\n(<b>7</b>), and the 2-thiazoline ring-containing cardenolide\nlabriformin (<b>8</b>). Glucopyranosyl-allomethylosyl-12-deoxy\naspecioside (<b>5</b>) is distinguished by lack of oxidation\nat C-12, and compounds <b>2</b>, <b>3</b>, <b>6</b>, and <b>8</b> contain a rare 1,4-dioxane motif. Inhibitory\nefficacy of the isolated cardenolides for sensitive and resistant\nenzymes appears to be correlated. Finally, we confirmed the structure\nof compound <b>2</b>, originally proposed by Tadeus Reichstein,\nand are pleased to share his original 1979 handwritten manuscript.