Fijiolides A and B, Inhibitors of TNF-α-Induced NFκB Activation, from a Marine-Derived Sediment Bacterium of the Genus Nocardiopsis

Abstract

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...

Isolation and Characterization of New p-Terphenyls with Antifungal, Antibacterial, and Antioxidant Activities from Halophilic Actinomycete Nocardiopsis gilva YIM 90087

“…39 Many of them display interesting bioactivities such as FKBP12 binding activity, 26 apoptosis, 29 cytotoxicity, 31,33,37 macrophage activating properties, 34 and an inhibitory effect on TNF-α-induced NFκB activation. 39 However, little is known about the secondary metabolites of halophilic actinomycetes.…”

“…39 Many of them display interesting bioactivities such as FKBP12 binding activity, 26 apoptosis, 29 cytotoxicity, 31,33,37 macrophage activating properties, 34 and an inhibitory effect on TNF-α-induced NFκB activation. 39 However, little is known about the secondary metabolites of halophilic actinomycetes. 6,7 The chemical investigations of the secondary metabolites of N. gilva YIM 90087 led to the isolation of a new p-terphenyl 1, a new p-terphenyl derivative 3 bearing a benzothiazole moiety, and 13 known compounds, including pterphenyl 2, novobiocin 4, nine cyclodipeptides (5−13), and two aromatic acids (14 and 15).…”

Nuclear Magnetic Resonance Spectroscopy for Structural Characterization of Bioactive Compounds

“…Advanced Mosher's method was also quite useful in elucidating the absolute configuration of the fijiolides A 37 and B 38, inhibitors of TNF-␣-NF-kB activation obtained from a marine-derived bacterium of the genus Nocardiopsis, that possess in their structures an aminosugar, an NH group, and an OH group [51].…”

“…Calculation of ∆␦ SR values of the MPTA esters of fijiolide A 37 indicates an (R)-configuration at C-13. The absolute configuration of the remaining C-8 and C-9 were established by the correlations presented in the NOESY spectra [51].…”

Development of a vector and host system and characterization of replication of plasmid pSQ10 in moderately halophilic <italic>Nocardiopsis</italic>

“…Four 3-methyl-4-ethylideneproline-containing peptides, lucentamycins A-D, showed significant in vitro cytotoxicity against human colon carcinoma [12]. Fijiolides A and B displayed activities on inhibition of TNF-a-induced NF-kB [13]. The marine Nocardiopsis lucentensis MSA04 produces a glycolipid biosurfactant, potential for bioremediation processes [14].…”