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...

Renal or kidney cancer accounts for about 3% of all cancer cases reported each year in the US. Molecular signatures that define the cancer, such as the loss of functional VHL, are found in both sporadic and familial cases of cancer. In clear cell renal cancer, the transcription factor HIF-2α has been shown to have a distinct role in tumorigenesis. Our laboratories developed a cell-based screen to identify modulators of HIF-2α. Screening of the NCI's Natural Product Extract Repository resulted in the identification of 10 sponge extracts from which 12 compounds were isolated. The biological evaluation of these compounds will be discussed including evaluation of HIF-1α vs. HIF-2αselectively and the isolated compounds' effects on mRNA from several pathways regulated by HIF.Approximately 58,000 individuals were diagnosed with renal cell carcinoma (RCC, kidney cancer) in 2011, 1 accounting for 3% of the cancers in the USA. 2 RCC is not a single disease, but can be separated into several distinct diseases based on clinical, morphological and molecular features. Many of these molecular features have been identified based on the study of families that are affected by inherited renal cancer syndromes. 2 Certain molecular features of patients with Von Hippel Lindau (VHL) disease are also present in individuals who develop sporadic clear cell RCC, the most prevalent RCC subtype. 3 Specifically, loss of VHL gene function as occurs in Von Hippel Lindau patients is seen in > 90% of sporadic RCC tumors. VHL protein (pVHL) is part of an E3 ubiquitin ligase system that recognizes and marks substrates for degradation. 4 The primary substrate of the pVHL complex is hypoxia inducible factor-alpha subunit (HIF-α). There are three known isoforms of HIF-α: * Corresponding Author: Tel: (301) 846-1943. Fax: (301) Under normal levels of oxygen, specific proline residues in HIF-1α and HIF-2α are hydroxylated. This reaction allows VHL to bind and ubiquitylate the α-subunit leading to its degradation. Under hypoxic conditions, this hydroxylation does not take place, HIF-α subunits accumulate within the cell, dimerize with ARNT, and translocate to the nucleus where they bind to hypoxia response elements (HREs), turning on transcription of a large number of genes. HIF regulated genes function in a variety of pathways including angiogenesis (e.g., vascular endothelial growth factor, VEGF), cell survival (e.g., erythropoietin, EPO) and glucose metabolism (e.g., glucose transporter-1, GLUT1) that together allow the cell to cope with and survive under the hypoxic conditions. 5 It is therefore not surprising that HIF has been shown to be upregulated in many tumors due to intratumoral hypoxia or by genetic mutation. Indeed upregulation of HIF is often associated with aggressive growth, treatment resistance, metastasis, and poor prognosis. 6 In renal cancer, HIF-2α plays a primary role in tumorigenesis. [7][8][9] To better understand the importance of HIF-2α to RCC, our laboratories generated a cellbased screen to identify inhibitors of HIF...

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