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The structures and absolute stereochemistry of four isomeric, cembranoid diterpenes derived from alcyoniid soft corals are reported. Two of these compounds, sarcophytoxide [1] and isosacrophytoxide [6], are known, but their diastereomeric counterparts [3] and [7] are here reported for the first time. High field nmr data are reported for all four compounds. The results of a single crystal X-ray structure determination of one of the isosarcophytoxides [71 permits unambiguous assignment of all four structures. A new cembranoid diterpene 15-hydroxycembra-1,3,7,11-tetraene [5] is reported.

Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are wellestablished, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and ontarget activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G 2 -M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo. This combination warrants further study.

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...

Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells.

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The steroids from two soft corals of the genus Capnella have been determined. Capnella sp. nov . afforded the novel pregnane derivatives 3-methoxy-19-norpregna-1,3,5(10),20-tetraen-4-ol (8) and 19-norpregna- 1,3,5(10),20-tetraen-3-ol (10) while Capnella erecta yielded the previously described pregna-1,20-dien-3-one (13).

Chemical analysis of the eggs spawned by fiveSinularia soft corals (Octocorallia, Alcyoniidae) collected in the central region of the Great Barrier Reef, Australia, revealed the presence of the known cembranoid diterpenes epoxypukalide and/or pukalide in all cases. Examination of the colonies from which the eggs were released one month before spawning and also some time after spawning failed to detect either diterpene in the coral tissue. The three dimensional structures of pukalide and epoxypukalide, as determined by the single-crystal X-ray technique, are reported for the first time. The wide distribution of pukalide and epoxypukalide and of related compounds within the octocorallia is discussed.