The nuclear factor-kappaB (NF-kappaB) signaling pathway is constitutively active in many types of cancers and is a potential therapeutic target. Using a cell-based assay for stability of inhibitor of kappa B (IkappaB), a critical regulator of NF-kappaB activity, we found that an organic solvent extract of the plant Cryptocarya rugulosa inhibited constitutive NF-kappaB activity in human lymphoma cell lines. The active components were identified as rugulactone, a new alpha-pyrone (1), and the known cryptocaryone (2). Rugulactone was the more active compound, exhibiting up to 5-fold induction of IkappaB at 25 microg/mL; maximal activity was observed with 10 h exposure of test cells to 1 or 2.

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CAN triggers PKR/eIF2alpha/caspase 12-dependent apoptosis and inhibits protein synthesis in cancer cells but only inhibits protein synthesis in normal cells.

Fractionation of cytotoxic extracts of specimens of a newly described sponge genus, Candidaspongia, has yielded the candidaspongiolides (3), a complex mixture of acyl esters of a macrolide related to tedanolide. The general structure of the candidaspongiolides was determined by analyses of various 2D NMR and MS data sets. The acyl ester components were identified by GC-MS analysis of the derived fatty acid methyl esters. The mixture could be selectively converted to the deacylated macrolide core (4) by enzymolysis with immobilized porcine lipase, with the structure of the candidaspongiolide core then secured by NMR and MS analysis. The candidaspongiolide mixture was potently cytotoxic, exhibiting a mean panel 50% growth inhibition (GI 50 ) of 14 ng/mL in the National Cancer Institute's 60-cell-line in itro antitumor screen.Among the first natural products extract leads selected for study on the basis of data from the U.S. National Cancer Institute's human disease-oriented, 60-cell-line primary antitumor screen1-3 were the aqueous and organic extracts of a then undescribed new sponge genus (collection Q66C0330). Both extracts exhibited significant cytotoxicity in the primary antitumor screen, as well as selective or differential activity toward melanoma and central nervous system tumor cell lines, with mean panel LC 50 values of less than 1 μg/mL. This relatively uncommon sponge was already the object of scrutiny at the Australian Institute of Marine Science (AIMS), as part of a chemotaxonomic study of folliose Dictyoceratid sponges of the Great Barrier Reef4 and for significant cytotoxicity in a P388 murine tumor cell line assay. Paucity of the sponge material and concomitant conservation considerations, * To whom correspondence should be addressed. Tel: 301-846-1493. Fax: 301-846-6919. E-mail: mckee@ncifcrf.gov. † Screening Technologies Branch, National Cancer Institute. ‡ Australian Institute of Marine Science. § Molecular Targets Development Program, National Cancer Institute. ⊥ Natural Products Branch, National Cancer Institute. || Zoologisch Museum, University of Amsterdam. ▽ Mitchell Cancer Institute, University of South Alabama.Supporting Information Available: 1D and 2D NMR spectra of the candidaspongiolide mixture (3) and the core macrocycle (4) and table of 1 H NMR assignments in CDCl 3 for candidspongiolide mixture (3) and tedanolide (1, isolated5 and synthetic7). This material is available free of charge via the Internet at http://pubs.acs.org. together with a common focus on the antitumor potential of its secondary metabolites, prompted a collaborative effort to isolate and characterize the cytotoxic constituents. Ultimately, the acquisition of two collections of the same genus from Papua New Guinea, containing the same mixture of compounds, permitted completion of the isolation, characterization, and biological testing of the candidaspongiolides, a complex series of novel analogues of tedanolide (1).5 NIH Public Access Results and DiscussionAt AIMS, the dichloromethane extract of lyophilize...

A new isoflavan, (3R)-6,2'-dihydroxy-7-methoxy-4',5'-methylenedioxyisoflavan, hildegardiol (1), and two known flavonoids, 2-hydroxymaackiain (2) and farrerol (3), were isolated from the antifungal root extract of Hildegardia barteri. The pterocarpan 2 was largely responsible for the observed antifungal activity.

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