Fijiolides A and B, inhibitors of TNF-alpha-induced NFkappaB activation, from a marine-derived sediment bacterium of the genus Nocardiopsis.
Fijiolide A, a potent inhibitor of TNF-alpha-induced NFkappaB 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 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-alpha-induced NFkappaB activation by 70.3%, with an IC(50) value of 0.57 micro-M. 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 of 3.5 at a concentration of 20 microg/mL (28.4 microM). The concentration required to double the activity was 1.8 microM. Fijiolide B did not affect QR1 activity, indicating the importance of the nitrogen substitution pattern for biological activity. On the basis of these data, fijiolide A is viewed as a promising lead for more advanced anticancer testing.
Nam
Sang-Jip
SJ
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California-San Diego, La Jolla, CA 92093-0204, USA.
Gaudêncio
Susana P
SP
Kauffman
Christopher A
CA
Jensen
Paul R
PR
Kondratyuk
Tamara P
TP
Marler
Laura E
LE
Pezzuto
John M
JM
Fenical
William
W
D000192:Actinomycetales / Q000737:chemistry*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D006801:Humans; D008386:Marine Biology; D051379:Mice; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006027:Glycosides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C550822:fijiolide A; C550823:fijiolide B; D016660:NAD(P)H Dehydrogenase (Quinone)