Inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells by the norsesterterpene peroxide, epimuqubilin A.
Seven norsesterterpene peroxides: epimuqubilin A (1), muqubilone B (2), unnamed cyclic peroxide ester (3), epimuqubilin B (4), sigmosceptrellin A methyl ester (5), sigmosceptrellin A (6), and sigmosceptrellin B methyl ester (7), isolated from the marine sponge Latrunculia sp., were examined with regard to their effects on nitric oxide (NO) production in lipopolysaccharide (LPS)-activated murine macrophage RAW 264.7 cells. The results indicated epimuqubilin A (1) possessed potent NO inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide release with an IC(50) value of 7.4 microM, a level three times greater than the positive control, L-N(G)-monomethyl arginine citrate, followed by 6 (sigmosceptrellin A, IC(50) = 9.9 microM), whereas other compounds exhibited only modest activity (Table 1). These compounds did not show appreciable cytotoxicity at their IC(50) values for NO-inhibitory activity. The structure-activity upon NO inhibition could be summarized as follows: (1) a monocyclic carbon skeleton framework was essential for activity, (2) free acids gave higher activity, (3) the orientation of H3-22 with an equatorial position increased activity, and (4) a bicyclic structure reduced activity. This is the first report of a norsesterterpene peroxide with NO-inhibitory activity. In addition, compounds 1-7 were also evaluated for their inhibitory activities in the yeast glycogen synthase kinase-3beta assay. In summary, several norsesterterpene peroxides showed novel biological activities of inhibition in NO production, suggesting that these might provide leads for anti-inflammatory or cancer chemopreventive agents.
Cheenpracha
Sarot
S
Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawaii Hilo, 34 Rainbow Drive, Hilo, HI 96720, USA. cheenpracha@gmail.com
Park
Eun-Jung
EJ
Rostama
Bahman
B
Pezzuto
John M
JM
Chang
Leng Chee
LC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D020128:Inhibitory Concentration 50; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis*; D010545:Peroxides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry*; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D015003:Yeasts / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D010545:Peroxides; D012717:Sesquiterpenes; C553039:epimuqubilin A; D009569:Nitric Oxide
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