Myxobacteria versus sponge-derived alkaloids: The bengamide family identified as potent immune modulating agents by scrutiny of LC–MS/ELSD libraries

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 14; pp. 4348 - 4355
• Main Authors: Johnson, Tyler A., Sohn, Johann, Vaske, Yvette M., White, Kimberly N., Cohen, Tanya L., Vervoort, Helene C., Tenney, Karen, Valeriote, Frederick A., Bjeldanes, Leonard F., Crews, Phillip
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.07.2012; Elsevier
• Subjects: alkaloids; Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Analytical chemistry; Animals; Anti-tumor; anticarcinogenic activity; Azepines - chemistry; Azepines - isolation & purification; Azepines - pharmacology; bacteria; Bengamides; Biological and medical sciences; Chemistry; Chemokine CCL2 - metabolism; chemokines; Chromatographic methods and physical methods associated with chromatography; Chromatography, High Pressure Liquid; cytotoxicity; diastereomers; Exact sciences and technology; HCT116 Cells; Humans; I-kappa B Kinase - metabolism; IL-6; Immunologic Factors - chemistry; Immunologic Factors - isolation & purification; Immunologic Factors - pharmacology; immunomodulators; inducible nitric oxide synthase; Inflammation; interleukin-6; Interleukin-6 - metabolism; Lipopolysaccharides - toxicity; luciferase; macrophages; Macrophages - drug effects; Macrophages - metabolism; Mass Spectrometry; MCP-1; Medical sciences; Mice; Myxobacteria; Myxococcales - chemistry; Myxococcus virescens; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; nitric oxide; Nitric Oxide Synthase Type II - metabolism; nuclear magnetic resonance spectroscopy; Other chromatographic methods; Pharmacology. Drug treatments; phosphorylation; Phosphorylation - drug effects; Porifera - chemistry; quantitative polymerase chain reaction; Sponge; structure-activity relationships; TNFα; transcription factor NF-kappa B; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - metabolism; Western blotting; NF-κB; TNFα; MCP-1; Anti-tumor; Bengamides; Myxobacteria; Sponge; Inflammation; IL-6; Antineoplastic agent; Lactam; HPLC chromatography; Interleukin 6; Marine environment; Alkaloid; Chemical compound library; Bacteria; Transcription factor NFκB; Tumor necrosis factor α; Coupled method; Cytokine; Animal origin; Myxobacterales; Chemokine; Microbial origin; Porifera; Evaporative light scattering detector; Invertebrata; Mass spectrometry; Monocyte chemoattractant protein 1
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.05.043

A nuclear factor-κB (NF-κB) luciferase assay has been employed to identify the bengamides, previously known for their anti-tumor activity, as a new class of immune modulators. A unique element of this study was that the bengamide analogs were isolated from two disparate sources, Myxococcus virescens (bacterium) and Jaspis coriacea (sponge). Comparative LC–MS/ELSD and NMR analysis facilitated the isolation of M. viriscens derived samples of bengamide E (8) and two congeners, bengamide E′ (13) and F′ (14) each isolated as an insperable mixture of diastereomers. Additional compounds drawn from the UC, Santa Cruz repository allowed expansion of the structure activity relationship (SAR) studies. The activity patterns observed for bengamide A (6), B (7), E (8), F (9), LAF 389 (12) and 13–14 gave rise to the following observations and conclusions. Compounds 6 and 7 display potent inhibition of NF-κB (at 80 and 90nM, respectively) without cytotoxicity to RAW264.7 macrophage immune cells. Western blot and qPCR analysis indicated that 6 and 7 reduce the phosphorylation of IκBα and the LPS-induced expression of the pro-inflammatory cytokines/chemokines TNFα, IL-6 and MCP-1 but do not effect NO production or the expression of iNOS. These results suggest that the bengamides may serve as therapeutic leads for the treatment of diseases involving inflammation, that their anti-tumor activity can in part be attributed to their ability to serve as immune modulating agents, and that their therapeutic potential against cancer merits further consideration.