[Show abstract][Hide abstract] ABSTRACT: Three advances necessary to bring dolastatin 16 (1) into full-scale preclinical development as an anticancer drug have been accomplished. The X-ray crystal structure of dolastatin 16 has been solved, which allowed stereoselective syntheses of its two new amino acid units, dolamethylleuine (Dml) and dolaphenvaline (Dpv), to be completed. The X-ray crystal structures of synthetic Z-Dml and TFA-Dpv have also been completed.
Journal of Natural Products 05/2011; 74(5):1003-8. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We describe here the development of a chemifluorescent competitive enzyme-linked immunosorbent assay (ELISA) that quantifies marinobufagenin (MBG) levels in biological fluids. Based on a polyclonal antibody raised against a novel MBG-bovine serum albumin conjugate, this assay achieved an MBG detection limit of less than 9 pg/mL. MBG levels in various rat urine and serum samples were effectively determined using this methodology. Interassay variability averaged 9.8%, while intra-assay variability averaged 1.9 and 2.5% in representative serum and urine samples, respectively. Recovery of exogenously added MBG averaged 106%, and parallelism data further established the accuracy of the assay. Employment of this assay to detect MBG abnormalities represents a powerful tool for the possible diagnosis, prevention and management of human hypertensive states, particularly preeclampsia.
Journal of Immunoassay and Immunochemistry 01/2011; 32(1):31-46. · 0.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
[Show abstract][Hide abstract] ABSTRACT: Bioassay-guided fractionation of extracts of various plants, marine organisms, and microorganisms has led to the discovery of new natural sources of a number of known compounds that have significant biological activity. The isolation of interesting and valuable cancer cell growth inhibitors including majusculamide C ( 1), axinastatin 5 ( 5), bengazoles A ( 6), B ( 7), and E ( 8), manzamine A ( 10), jaspamide ( 11), and neoechinulin A ( 19) has been summarized.
Journal of Natural Products 04/2008; 71(3):438-44. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Gulf of California shell-less mollusc Dolabella auricularia has been found to contain a new 14-membered macrocyclic lactone linked to a 2,4-di-O-methyl-l-alpha-rhamnopyranoside, designated dolastatin 19 (1). The new cancer cell growth inhibitor (1, 8.33 x 10(-8)% yield) was obtained by bioassay (P388 lymphocytic leukemia and human cancer cell lines) directed isolation, accompanied by debromoaplysiatoxin (9.17 x 10(-7)% yield) and anhydrodebromoaplysiatoxin (2.0 x 10(-7)% yield). The structures were determined on the basis of analyses of high-resolution mass spectra and high-field NMR data. All the relative stereochemistry for the chiral centers was designated by utilizing NMR techniques.
Journal of Natural Products 09/2004; 67(8):1252-5. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Indo-Pacific marine sponge Ircinia ramosa has been found to contain two powerful (GI50 from 0.001 to <0.0001 microg/mL) murine and human cancer cell growth inhibitors. Both were isolated (10(-3)-10(-4)% yields) by cancer cell line bioassay-guided techniques and named irciniastatins A (1) and B (2). Structural elucidation by a combination of spectral analyses, primarily high resolution mass and 2D-NMR (principally APT, HMQC, HMBC, and ROESY) spectroscopy, revealed the unusual structures 1 and 2.
Journal of Medicinal Chemistry 02/2004; 47(5):1149-52. · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cephalostatin 1 is a bis-steroidal marine natural product with a unique cytotoxicity profile in the in vitro screen system of the National Cancer Institute, suggesting that it may affect novel molecular target(s). Here we show that cephalostatin 1 induces a novel pathway of receptor-independent apoptosis that selectively uses Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point) as a mitochondrial signaling molecule. At nanomolar concentrations, cephalostatin 1 triggers dose- and time-dependent DNA fragmentation in leukemia Jurkat T cells. Apoptosis was found to be dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone blocks cephalostatin 1-mediated DNA fragmentation. The CD95 death receptor as well as other caspase-8-requiring death receptors were not involved because Jurkat T cells lacking the CD95 receptor or caspase-8 and control cells responded equally to cephalostatin 1. Although cephalostatin 1 affects mitochondria by dissipating the mitochondrial membrane potential, neither cytochrome c nor apoptosis-inducing factor is released, as shown by Western blot analysis. Interestingly, cephalostatin 1 selectively triggers the mitochondrial release of the inhibitor of apoptosis antagonist Smac/DIABLO. Overexpression of the antiapoptotic protein Bcl-x(L) delayed both Smac/DIABLO release and onset of apoptosis, suggesting that Smac/DIABLO is required for cephalostatin 1-induced apoptosis. This new mitochondrial pathway is accompanied by marked structural changes of mitochondria as shown by transmission electron microscopy.
Cancer Research 01/2004; 63(24):8869-76. · 8.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A human cancer cell line bioassay-directed investigation of the Western Pacific marine sponge Agelas sp. led to isolation of a trace (7.42 × 10–6% yield) cancer cell growth inhibitor (lung NCI-H460 GI50 0.77 µg m–1 to ovary OVCAR-3 GI50 2.8 µg ml–1) designated agelagalastatin 6; it is the first example of a natural product containing a digalactofuranosyl unit.
Chemical Communications 01/1999; · 6.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bioassay-guided separation of cancer cell growth inhibitory fractions derived from the sea hare Dolabella auricularia obtained in Papua New Guinea led to isolation (1.51 × 10−7% yield) of the new thiazole-containing peptide, dolastatin 18 (4). Structural determination was completed by employmentment of results from high-field (500 MHz) 2-D NMR experiments and tandem MS/MS mass spectral sequence analyses. Dolastatin 18 (4) was found to inhibit a selection of cancer cell lines among which GI50 0.39 μg/mL was found for the nonsmall cell lung cancer NCI-H460.
[Show abstract][Hide abstract] ABSTRACT: The Southeast African marine worm has been found to contain two new and exceedingly potent human cancer cell growth inhibitors Cephalostatins 16 (3) and 17 (4).
[Show abstract][Hide abstract] ABSTRACT: Phakellistatins 7–9 respresent the first cancer cell growth inhibitory (P388 ED50 3.0, 2.9 and 4.1 μg/mL respectively) cyclic decapeptides. Each was isolated from the Federated States of Micronesia (Chuuk) marine sponge Phakellia costata.The Federated States of Micronesia (Chuuk) marine sponge Phakellia costata has been found to contain (10−5 and 10−6% yields) three cancer cell line active (P388 ED50 3.0, 2.9 and 4.1 μg/mL respectively) cyclic decapeptides named phakellistatins 7 (1), 8 (2) and 9 (3). Phakellistatins 7–9 represent the first cancer cell growth inhibitory cyclic decapeptides isolated from a marine sponge.
[Show abstract][Hide abstract] ABSTRACT: Phakellistatin 6 (7), a trace (7.5 × 10−7% yield) constituent of the marine sponge Phakellia costata located in the Federated States of Micronesia has been found to significantly inhibit growth of certain human cancer cell lines (GI50, 0.1 to 0.01 μg/ml). The structure of phakellistatin 6 (7) was deduced as cyclo (Pro-Trp-Leu-Pro-Ile-Pro-Phe) employing a combination of MS/MS and high field (500 MHz) 2D-NMR procedures followed by chiral (all S amino acids) assignments using hydrolysis → derivatisation → chiral chromatographic techniques.
[Show abstract][Hide abstract] ABSTRACT: The Federated State of Micronesia (Chuuk) marine sponge Phakellia costada has been found to contain (9.6 x 10−6 % yield) a new human cancer cell growth inhibitor designated phakellistatin 5 (3). Structural elucidation was accomplished employing high resolution FAB tandem MS/MS and high field (500 MHz) 2D-NMR techniques. Extension of the NMR experiments over the temperature range −25 to 25°C allowed the principal solution conformation of phakellistatin 5 to be assigned (Figure 2). The absolute configuration was found to correspond to S-amino acid units except for R-Asn.