Miliusanes, A Class of Cytotoxic Agents from Miliusa sinensis

Bioassay-directed fractionation of the leaves, twigs, and flowers of Miliusa sinensis 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 C18 carbon skeleton, a known but heretofore unnamed type, which we have designated as miliusane. Two known (1 and 2) as well as 20 new miliusanes (322) have been isolated and identified. They belong to two substructural classes of miliusanes. One subclass (119) was determined to be composed of a γ-lactone spiro-ring system, the opening of which led to the second group of compounds (21 and 22) containing a tetrahydrofuran ring system. Compounds 13, 5, 8, 9, 18, 20, and 21 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.