Planta Med 2012; 78 - PJ135
DOI: 10.1055/s-0032-1321295

Synergistic trail sensitizers from Barleria alluaudii and Diospyros maritima

EL Whitson 1, H Sun 2, CL Thomas 1, CJ Henrich 1, 3, TJ Sayers 3, 4, KR Gustafson 1, JB McMahon 1, C Griesinger 2, TC McKee 1
  • 1Molecular Targets Laboratory, Molecular Discovery Program, Center for Cancer Research, Frederick National Lab for Cancer Research, Frederick, MD 21702, USA
  • 2Department of NMR Based Structural Biology, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany
  • 3SAIC-Frederick, Inc., Frederick, MD 21702, USA
  • 4Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, FNLCR, Frederick, MD 21702, USA

A high-throughput screen was developed to identify compounds that could sensitize tumor cells to the killing effects of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL). Extracts from Barleria alluaudii and Diospyros maritima showed promising activity in the initial screen and were further investigated. 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.