Potent Cytotoxic Arylnaphthalene Lignan Lactones from <i>Phyllanthus poilanei</i>

Abstract

Two new (<b>1</b> and <b>2</b>) and four known arylnaphthalene lignan lactones (<b>3</b>–<b>6</b>) were isolated from different plant parts of <i>Phyllanthus poilanei</i> collected in Vietnam, with two further known analogues (<b>7</b> and <b>8</b>) being prepared from phyllanthusmin C (<b>4</b>). The structures of the new compounds were determined by interpretation of their spectroscopic data and by chemical methods, and the structure of phyllanthusmin D (<b>1</b>) was confirmed by single-crystal X-ray diffraction analysis. Several of these arylnaphthalene lignan lactones were cytotoxic toward HT-29 human colon cancer cells, with compounds <b>1</b> and 7-<i>O</i>-[(2,3,4-tri-<i>O</i>-acetyl)-α-l-arabinopyranosyl)]­diphyllin (<b>7</b>) found to be the most potent, exhibiting IC₅₀ values of 170 and 110 nM, respectively. Compound <b>1</b> showed activity when tested in an in vivo hollow fiber assay using HT-29 cells implanted in immunodeficient NCr <i>nu</i>/<i>nu</i> mice. Mechanistic studies showed that this compound mediated its cytotoxic effects by inducing tumor cell apoptosis through activation of caspase-3, but it did not inhibit DNA topoisomerase IIα activity