Barleria alluaudii and Diospyros maritima 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 (1) and 2,3-epoxy-2,3-dihydro-8-hydroxylapachol (2), both not previously isolated from natural sources, and the known 2-methyl anthraquinone (3) were identified from B. alluaudii. Time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra were utilized to establish the absolute configuration of 1 and 2. Additionally, five known naphthoquinone derivatives, maritinone (4), elliptinone (5), plumbagin (6), (+)-cis-isoshinanolone (7), and ethylidene-6,6′-biplumbagin (8) were isolated from D. maritima. Compounds 1, 2, and 4-6 showed varying levels of synergy with TRAIL. Maritinone (4) and elliptinone (5) showed the highest synergistic effect, with more than a three-fold increase in activity observed with TRAIL than with compound alone.Tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the tumor necrosis factor (TNF) family of apoptosis triggering proteins. 1 TRAIL promotes recruitment of the adaptor protein FADD (Fas associated death domain) upon binding to death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). FADD is responsible for recruiting procaspase-8 and procaspase-10, which results in the formation of a trimerized receptor-ligand complex called DISC (death-inducing signaling complex). The activated initiator caspase-8 then activates effector caspase-3, caspase-6, and caspase-7, which triggers the caspase cascade and subsequently results in apoptosis. 2,3 In type I cancer cells, caspase-8 can directly activate downstream effector caspases to promote apoptosis. However, in type II cancer cells, apoptosis proceeds through cross-talk between # Dedicated to Dr. Gordon M. Cragg, formerly of the National Cancer Institute, Frederick, Maryland, for his pioneering work on the development of natural product anticancer agents. * Corresponding Author: Tel: (301) 846-1943. Fax: (301) 846-6851. mckeeta@mail.nih.gov. ASSOCIATED CONTENT:Supporting Information: 1 H and 13 C NMR spectra for 1-2, chiral HPLC analysis of 1, Gaussian keywords, calculated excitation energies, oscillator strengths, and rotational strengths for 1-2, important dihedral angles of conformers 1a-1f and 2a-2f, conformational analysis of 1, calculated ORD values for 1-2, and coordinates of conformers 1a-1f and 2a-2f. This material is available free of charge via the Internet at http://pubs.acs.org. the extrinsic and intrinsic pathways and involves the participation of the mitochondria. 4 TRAIL is particularly important because it selectively induces apoptosis in cancer cells, while showing little to no effect in normal cells. 1,5 However, TRAIL resistance has been widely documented, 5-9 and there is evidence to suggest that combination chemotherapy regimens may b...