Myxobacteria versus sponge-derived alkaloids: the bengamide family identified as potent immune modulating agents by scrutiny of LC-MS/ELSD libraries.
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 90 nM, 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.
Department of Nutritional Sciences & Toxicology, University of California, Berkeley, CA 94720, USA.
Tyler A
TA
Johnson
Johann
J
Sohn
Yvette M
YM
Vaske
Kimberly N
KN
White
Tanya L
TL
Cohen
Helene C
HC
Vervoort
Karen
K
Tenney
Frederick A
FA
Valeriote
Leonard F
LF
Bjeldanes
Phillip
P
Crews
D000470:Alkaloids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D045325:HCT116 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007155:Immunologic Factors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D009231:Myxococcales / Q000737:chemistry*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011161:Porifera / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000470:Alkaloids; D001381:Azepines; D018932:Chemokine CCL2; D007155:Immunologic Factors; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C427481:bengamide E; D052247:Nitric Oxide Synthase Type II; D051550:I-kappa B Kinase