Miliusanes, A Class of Cytotoxic Agents from <i>Miliusa sinensis</i>

Bioassay-directed fractionation of the leaves, twigs, and flowers of <i>Miliusa sinensis </i>Finet and Gagnep. (Annonaceae) led to the isolation of a new class of potential anticancer lead molecules. They are a cluster of compounds composed of a C<sub>18</sub> carbon skeleton, a known but heretofore unnamed type, which we have designated as miliusane. Two known (<b>1</b> and <b>2</b>) as well as 20 new miliusanes (<b>3</b>−<b>22</b>) have been isolated and identified. They belong to two substructural classes of miliusanes. One subclass (<b>1</b>−<b>19</b>) was determined to be composed of a γ-lactone spiro-ring system, the opening of which led to the second group of compounds (<b>21</b> and <b>22</b>) containing a tetrahydrofuran ring system. Compounds <b>1</b>−<b>3</b>, <b>5</b>, <b>8</b>, <b>9</b>, <b>18</b>, <b>20</b>, and <b>21</b> demonstrated significant cytotoxic activity in our cancer cell line panel comprising KB, Col-2, LNCaP, Lu-1, MCF-7, and HUVEC. The structures were determined by spectroscopic and chemical methods. The structure of miliusate was further confirmed by X-ray crystallographic analysis. The absolute stereochemistry of miliusanes was established by the Mosher ester method. Forty-two modified miliusane derivatives were also prepared and evaluated for their cytotoxic activities.