Abstract
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 IC50 value of 7.4 μM, a level three times greater than the positive control, L-NG-monomethyl arginine citrate, followed by 6 (sigmosceptrellin A, IC50 = 9.9 μM), whereas other compounds exhibited only modest activity (Table 1). These compounds did not show appreciable cytotoxicity at their IC50 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-3β 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.
Highlights
Sesterterpenes isolated from marine organisms are often modified by the loss or addition of one or more carbon units
Further fractionation led to the isolation of seven norsesterterpene cyclic peroxides including epimuqubilin A (1) [14], muqubilone B (2) [24], unnamed cyclic peroxide ester (3) [25], epimuqubilin
The results indicated epimuqubilin A (1) possessed potent NO inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide release with an IC50 value of 7.4 μM, followed by 6, whereas other compounds exhibited activity with the IC50 values in the range of 23.8−65.7 μM
Summary
Sesterterpenes isolated from marine organisms are often modified by the loss or addition of one or more carbon units. Marine sponges of the Latrunculiidae family, which include the genera Sigmosceptrella [1,2], Latrunculia [3,4] and Diacarnus [5,6], have proven to be a rich source of norterpene cyclic peroxides, a novel class of bioactive marine metabolites. Australian Latrunculia species have been shown to be a rich source of novel norterpene acids and peroxides [3,4,13]. In our continuing efforts to identify new protein kinase inhibitors for potential use as anticancer agents, a yeast glycogen synthase kinase-3β assay was adopted, to rapidly screen and identify candidate compounds that target serine/threonine and/or tyrosine kinases activities. Further fractionation led to the isolation of seven norsesterterpene cyclic peroxides including. Compounds 1–7 were evaluated for their inhibitory activity in the yeast GSK-3β assay
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