Synergistic TRAIL Sensitizers from <i>Barleria alluaudii</i> and <i>Diospyros maritima</i>

Abstract

<i>Barleria alluaudii</i> and <i>Diospyros maritima</i> were both investigated as part of an ongoing search for synergistic TRAIL (tumor necrosis factor-α-related apoptosis-inducing ligand) sensitizers. As a result of this study, two naphthoquinone epoxides, 2,3-epoxy-2,3-dihydrolapachol (<b>1</b>) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (<b>2</b>), both not previously isolated from natural sources, and the known 2-methylanthraquinone (<b>3</b>) were identified from <i>B. alluaudii.</i> Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of <b>1</b> and <b>2</b>. Additionally, five known naphthoquinone derivatives, maritinone (<b>4</b>), elliptinone (<b>5</b>), plumbagin (<b>6</b>), (+)-<i>cis</i>-isoshinanolone (<b>7</b>), and ethylidene-6,6′-biplumbagin (<b>8</b>), were isolated from <i>D. maritima</i>. Compounds <b>1</b>, <b>2</b>, and <b>4</b>–<b>6</b> showed varying levels of synergy with TRAIL. Maritinone (<b>4</b>) and elliptinone (<b>5</b>) showed the highest synergistic effect, with more than a 3-fold increase in activity observed with TRAIL than with compound alone