ABSTRACT
Five new macrolides, spirastrellolides C (3) to G (7), have been isolated from extracts of the marine sponge Spirastrella coccinea collected in Dominica. Their structures have been elucidated by a combination of spectroscopic analysis and chemical transformations.
Subject(s)
Enzyme Inhibitors/chemistry , Macrolides/chemistry , Porifera/chemistry , Animals , Enzyme Inhibitors/isolation & purification , Macrolides/isolation & purification , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Molecular Conformation , Reference Standards , StereoisomerismABSTRACT
The absolute configuration of strongylophorine-26 (1) was determined to be 4S, 5R, 8R, 9S, 10S, 13S, 14S by single-crystal X-ray diffraction analysis of the derivative 7 prepared from the co-occurring metabolite strongylophorine-8 (4) and chemical interconversion to the bislactone 8. Synthetic analogues (+)- and (-)-3 have been prepared in order to explore the structure-activity relationship for the anti-invasion pharmacophore of stronglylophorine-26. These studies revealed the unanticipated importance of the A ring lactone moiety for the anti-invasion activity of 1.
Subject(s)
Antineoplastic Agents/chemistry , Diterpenes/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Diterpenes/chemical synthesis , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , X-Ray DiffractionABSTRACT
The sequence positions of d and l Leu and Lys residues in bogorol A (1) have been defined by a simple and novel approach that utilizes small amounts of sample and focuses on detecting the order in which amino acids are liberated from the parent peptide during acid-catalyzed hydrolysis. This technique builds on a previously established relationship between the steric and electronic features of amino acids and their predilection for acidic liberation from polypeptides via dipeptides. The results, which complete the structure of bogorol A, have been confirmed by traditional degradation experiments. Utilizing the knowledge of the structure of bogorol A (1) as a template, we rapidly elucidated the structures of bogorols B-E (2-5) via analysis of ESI-MS and ESI-MS/MS data and GC analysis of degradation products. The bogorol cationic peptide antibiotics contain a number of unusual structural features, which include the reduction of the C-terminal residue to valinol, an N-terminal residue of 2-hydroxy-3-methylpentanoic acid, the incorporation of four d amino acids, and the presence of a dehydroamino acid. Bogorols show selective and relatively potent activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus spp., as well as moderate activity against Escherichia coli.
Subject(s)
Amino Acids/chemistry , Anti-Bacterial Agents/classification , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Peptides/classification , Peptides/chemical synthesis , Peptides/pharmacology , Amino Acid Sequence , Anti-Bacterial Agents/chemistry , Bacillus/chemistry , Hydrolysis , Microbial Viability/drug effects , Molecular Sequence Data , Peptides/chemistry , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Structure-Activity Relationship , Tandem Mass SpectrometryABSTRACT
[structure: see text] Laboratory cultures of an undescribed streptomycete obtained from the surface of a British Columbia lichen produce uncialamycin (1), a new enediyne antibiotic. The structure of uncialamycin (1) has been elucidated by analysis of spectroscopic data. Uncialamycin (1) exhibits potent in vitro antibacterial activity against gram-positive and gram-negative human pathogens, including Burkholderia cepacia, a major cause of morbidity and mortality in patients with cystic fibrosis.
Subject(s)
Anthraquinones , Anti-Bacterial Agents , Bacteria/drug effects , Burkholderia cepacia/drug effects , Streptomyces/chemistry , Anthraquinones/chemical synthesis , Anthraquinones/chemistry , Anthraquinones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Cystic Fibrosis/epidemiology , Cystic Fibrosis/mortality , Humans , Molecular StructureABSTRACT
Axinelloside A was isolated from the lipophilic extract of the Japanese marine sponge Axinella infundibula as a strong human telomerase inhibitor (IC(50) 2.0 microg/mL). It has the molecular weight of 4780.4 as the monoisotopic mass of the 19 sodium salt. The chemical structure was elucidated mainly by spectroscopic methods (2D NMR and MS). Axinelloside A consists of twelve sugars, e.g., a scyllo-inositol, a D-arabinose, 5 D-galactoses, and 5 L-fucoses, together with an (R)-3-hydroxy-octadecanoic acid, 3 (E)-2-hexadecenoic acids, and 19 sulfates.
Subject(s)
Lipopolysaccharides/pharmacology , Polysaccharides/pharmacology , Porifera/chemistry , Sulfates/chemistry , Telomerase/antagonists & inhibitors , Animals , Carbohydrate Conformation , Carbon Isotopes , HeLa Cells , Humans , Lipopolysaccharides/chemistry , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Polysaccharides/chemistry , Protons , Reference Standards , StereoisomerismABSTRACT
Strongylophorine-26, a new meroditerpenoid, was recently identified as an inhibitor of cancer cell invasion. This study was undertaken to characterize its mechanism of action. We find that strongylophorine-26 inhibits the motility of MDA-MB-231 breast carcinoma cells on a plastic surface. Upon addition of strongylophorine-26, rapid cell contraction and depolarization occurred, followed by spreading and flattening of the entire cell. Treated cells exhibited increased membrane ruffling throughout and extended lamellipodia in all directions. Strongylophorine-26 induced a decrease in actin stress fibers, a dramatic increase in the size and number of focal adhesions, and the appearance of a dense meshwork of actin filaments around the cell periphery. Strongylophorine-26 caused a transient activation of the small GTPase Rho and treatment with the Rho inhibitor C3 exoenzyme abrogated the anti-invasive activity of strongylophorine-26. These effects are distinct from those of many motility and angiogenesis inhibitors that seem to act by a common mechanism involving the induction of actin stress fibers. This difference in mechanism of action sets strongylophorine-26 apart as an experimental anticancer agent and indicates that pharmacologic inhibition of cell migration may be achieved by mechanisms not involving the stabilization of actin stress fibers.
Subject(s)
Actins/metabolism , Breast Neoplasms/metabolism , Cell Movement/drug effects , Diterpenes/pharmacology , Focal Adhesions/drug effects , Neoplasm Invasiveness/prevention & control , Stress Fibers/drug effects , rho GTP-Binding Proteins/physiology , ADP Ribose Transferases/metabolism , Botulinum Toxins/metabolism , Breast Neoplasms/pathology , Cell Membrane/metabolism , Female , Humans , Pseudopodia/metabolism , Tumor Cells, CulturedABSTRACT
Strongylophorine-26 (1), a new meroditerpenoid that shows activity in an anti-invasion assay, has been isolated from the marine sponge Petrosia (Strongylophora) corticata collected in Papua New Guinea. The structure of 1 was elucidated by analysis of spectroscopic data.
Subject(s)
Antineoplastic Agents/isolation & purification , Diterpenes/isolation & purification , Porifera/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Diterpenes/chemistry , Diterpenes/pharmacology , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Papua New Guinea , Tumor Cells, CulturedABSTRACT
Five new alkaloids, dictyodendrins A-E (1-5), were isolated from the Japanese marine sponge Dictyodendrilla verongiformis as telomerase inhibitors. Their structures were elucidated by spectroscopic and chemical methods. Dictyodendrins are tyramine-based pyrrolocarbazole derivatives containing three or four p-hydroxybenzene groups. They inhibited telomerase completely at a concentration of 50 microg/mL.
