Synergistic trail sensitizers from Barleria alluaudii and Diospyros maritima

Abstract

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...

Identification of Natural Products That Inhibit the Catalytic Function of Human Tyrosyl-DNA Phosphodiesterase (TDP1)

“…Compound identifications for all natural products were determined by comparison of nuclear magnetic resonance spectroscopy and mass spectrometry data for the isolated molecules and results published previously for the halenaquinone series 23 and 2,3-epoxy-8-hydroxy-lapachol. 24…”

“…34 We also identified 2,3-epoxy-8-hydroxy-lapachol (EHL) as an inhibitor of TDP1. EHL is a compound isolated from the organic extract of the stems of Barleria alluaudii, a plant from the Acanthaceae family native to Madagascar 24 (Fig. 4A).…”