Five resveratrol sulfate metabolites were synthesized and assessed for activities known to be mediated by resveratrol: inhibition of tumor necrosis factor (TNF)-α-induced NFκB activity, cylcooxygenases (COX-1 and COX-2), aromatase, nitric oxide production in endotoxin-stimulated macrophages, and proliferation of KB or MCF7 cells, induction of quinone reductase 1 (QR1), accumulation in the sub-G 1 phase of the cell cycle, and quenching of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical. Two metabolites showed activity in these assays; the 3-sulfate exhibited QR1 induction, DPPH free radical scavenging, and COX-1 and COX-2 inhibitory activities, and the 4′-sulfate inhibited NFκB induction, as well as COX-1 and COX-2 activities. Resveratrol, as well as its 3′-sulfate and 4-sulfate, inhibit NO production by NO scavenging and down-regulation of iNOS expression in RAW 264.7 cells. Resveratrol sulfates displayed low antiproliferative activity and negligible uptake in MCF7 cells.

Our data suggests that AEE is primarily an IL-5 selective TH2 response, with a possible TH1 component, and a differential role of eosinophilic chemoattractants. The role of mast cells in the pathogenesis of AEE needs additional study.

An extensive study of the secondary metabolites produced by several strains of the marine actinomycete Salinispora arenicola has led to the isolation of two unusual bicyclic polyketides, saliniketals A and B (1, 2). The structures, which contain a new 1,4-dimethyl-2,8-dioxabicyclo[3.2.1]octan-3-yl ring, were assigned mainly by 2D NMR spectroscopic methods. Unexpectedly, chemical derivatization of saliniketal A with Mosher's acid chloride resulted in a functional group interconversion of an unsaturated primary amide to the corresponding nitrile in a quantitative yield under unusually mild conditions. Saliniketals A and B were found to inhibit ornithine decarboxylase induction, an important target for the chemoprevention of cancer, with IC50 values of 1.95 +/- 0.37 and 7.83 +/- 1.2 microg/mL, respectively.

Two new (1 and 2) and one known phenazine derivative (lavanducyanin, 3) were isolated and identified from the fermentation broth of a marine-derived Streptomyces sp. (strain CNS284). In mammalian cell culture studies, compounds 1, 2 and 3 inhibited TNF-α-induced NFκB activity (IC50 values of 4.1, 24.2, and 16.3 μM, respectively) and LPS-induced nitric oxide production (IC50 values of >48.6, 15.1, and 8.0 μM, respectively). PGE2 production was blocked with greater efficacy (IC50 values of 7.5, 0.89, and 0.63 μM, respectively), possibly due to inhibition of cyclooxygenases in addition to the expression of COX-2. Treatment of cultured HL-60 cells led to dose-dependent accumulation in the subG1 compartment of the cell cycle, as a result of apoptosis. These data provide greater insight on the biological potential of phenazine derivatives, and some guidance on how various substituents may alter potential anti-inflammatory and anti-cancer effects.

Fijiolide A, a potent inhibitor of TNF-α induced NFκB activation, along with fijiolide B, were isolated from a marine-derived bacterium of the genus Nocardiopsis. The planar structures of fijiolides A (1) and B (2) were elucidated by interpretation of 2D NMR spectroscopic data, while the absolute configurations of these compounds were defined by interpretation of circular dichroism (CD) and 2D NMR data combined with application of the advanced Mosher's method. Fijiolides A and B are related to several recently isolated chloroaromatic compounds, which appear to be the Bergman cyclization products of enediyne precursors. Fijiolide A reduced TNF-α induced NFκB activation by 70.3%, with an IC 50 value of 0.57 µM. Fijiolide B demonstrated less inhibition, only 46.5%, without dose-dependence. The same pattern was also observed with quinone reductase (QR) activity: fijiolide A was found to induce quinone reductase-1 (QR1), with an induction ratio (IR) of 3.5 at a concentration of 20 µg/mL (28.4 µM). The concentration required to double activity (CD) was 1.8 µM. Fijiolide B did not affect QR1 activity, indicating the importance of the nitrogen substitution pattern for biological activity. Based on these data, fijiolide A is viewed as a promising lead for more advanced anticancer testing.Nature is an important resource for the discovery of anticancer drugs. The relevance of the marine environment as a source of novel anticancer compounds has been validated by discovery ca. 2,500 new metabolites with antiproliferative activity.1 Bacteria belonging to the order Actinomycetales, commonly known as actinomycetes, have provided nearly 50% of the bioactive microbial natural products discovered as of 2002.2 Although most microbial small molecule discovery efforts have focused on actinomycetes from terrestrial environments, marine-derived actinomycetes are proving to be an important resource that has led to the discovery of biologically active molecules with unique chemical structures.3 Excellent examples are the salinosporamides4a and marinomycins.4b Salinosporamide A, isolated from Salinispora tropica, is a potent 20S proteasome inhibitor that recently completed phase I clinical trials for treatment of solid tumors, lymphomas, and multiple myeloma. The marinomycins isolated from a "Marinispora" sp. showed significant antimicrobial activity against drug-resistant bacterial pathogens and selective cancer cell cytotoxicity against melanoma cell lines.4bCorresponding Author: Tel: 1-858-534-2133; Fax: 1-858-534-1318; wfenical@ucsd.edu. Supporting Information Available: The 1 H, 13 C, and 2D NMR spectra of fijiolide A (1) and 1 H spectrum of fijiolide B (2), and 1 H NMR spectrum of MTPA esters 3a, 3b, 4a, 4b, 6a, 6b, and 1 H NMR spectrum of acetonide 5 are available free of charge via the Internet at http://pubs.acs.org. As part of a program to explore marine bacterial metabolites as inhibitors of tumor initiation and promotion, we have targeted nuclear factor kappa B (NFκB), a transcription factor that regulates the expressi...

The isolation of 2-bromo-1-hydroxyphenazine from a marine Streptomyces sp., strain CNS284, and its activity against NFκB, suggested that a short and flexible route for the synthesis of this metabolite and a variety of phenazine analogues be developed. Numerous phenazines were subsequently prepared and evaluated as inducers of quinone reductase 1 (QR1) and inhibitors of quinone reductase 2 (QR2), NF-κB, and inducible nitric oxide synthase (iNOS). Several of the active phenazine derivatives displayed IC 50 values vs. QR1 induction and QR2 inhibition in the nanomolar range, suggesting they may find utility as cancer chemopreventive agents.

Three new cyclohexadepsipeptides, arenamides A–C (1–3), were isolated from the fermentation broth of a marine bacterial strain identified as Salinispora arenicola. The planar structures of these compounds were assigned by detailed interpretation of NMR and MS/MS spectroscopic data. The absolute configurations of the amino acids, and those of the chiral centers on the side chain, were established by application of the Marfey’s and modified Mosher methods. The effect of arenamides A and B on NFκB activity was studied with stably transfected 293/NFκB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNF). Arenamides A (1) and B (2) blocked TNF-induced activation in a dose- and time-dependent manner with IC50 values of 3.7 and 1.7 μM, respectively. In addition, the compounds inhibited nitric oxide (NO) and prostaglandin E2 (PGE2) production with lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. Moderate cytotoxicity was observed with the human colon carcinoma cell line HCT-116, but no cytotoxic effect was noted with cultured RAW cells. Taken together, these data suggest that the chemoprevention and anti-inflammatory characteristics of arenamides A and B warrant further investigation.

Moringa oleifera Lamarack is commonly consumed for nutritional or medicinal properties. We recently reported the isolation and structure elucidation of novel bioactive phenolic glycosides, including 4-[(2′-O-acetyl-α-l-rhamnosyloxy)benzyl]isothiocyanate (RBITC), which was found to suppress inducible nitric oxide synthase (iNOS) expression and nitric oxide production in lipopolysaccharide-stimulated RAW 264.7 mouse macrophage cells. Inhibitors of proteins such as cyclooxygenase-2 (COX-2) and iNOS are potential anti-inflammatory and cancer chemopreventive agents. The inhibitory activity of RBITC on NO production (IC50 = 0.96 ± 0.23 µM) was greater than that mediated by other well-known isothiocyanates such as sulforaphane (IC50 = 2.86 ± 0.39 µM) and benzyl isothiocyanate (IC50 = 2.08 ± 0.28 µM). RBITC inhibited expression of COX-2 and iNOS at both the protein and mRNA levels. Major upstream signaling pathways involved mitogen-activated protein kinases and nuclear factor-κB (NF-κB). RBITC inhibited phosphorylation of extracellular signal regulated kinase and stress-activated protein kinase, as well as ubiquitin-dependent degradation of inhibitor κBα (IκBα). In accordance with IκBα degradation, nuclear accumulation of NF-κB, and subsequent binding to NF-κB cis-acting element, was attenuated by treatment with RBITC. These data suggest RBITC should be included in the dietary armamentarium of isothiocyanates potentially capable of mediating anti-inflammatory or cancer chemopreventive activity.