Salarins a and B and tulearin a: new cytotoxic sponge-derived macrolides

Three novel nitrogenous macrolides designated salarin A and B (1 and 2) and tulearin A (3) were isolated from the Madagascar Fascaplysinopsis sp. sponge. The structures of the compounds were elucidated by interpretation of MS and 1D and 2D NMR spectra. Both salarins carry an acetylcarbamate moiety, and in addition, 1 contains a triacylamine group and 2 a methoxymethylketone lactam. Tulearin A carries the naturally rare carbamate ester. The compounds were found to be toxic to brine shrimp larvae, and salarin A and tulearin A were also cytotoxic to leukemia cells.     

Structures and cytotoxic properties of sponge-derived bisannulated acridines

A reinvestigation of sponge natural products from additional Indo-Pacific collections of Xestospongiacf. carbonaria and X. cf. exigua has provided further insights on the structures, biological activities, and biosynthetic origin of bisannulated acridines. These alkaloids include one known pyridoacridine, neoamphimedine (2), and three new analogues, 5-methoxyneoamphimedine (4), neoamphimedine Y (5), and neoamphimedine Z (6). A completely new acridine, alpkinidine (7), was also isolated. A disk diffusion soft agar assay, using a panel of five cancer cell lines (solid tumors and leukemias) and two normal cells, was used to evaluate the differential cytotoxicity (solid tumor selectivity) of the sponge semipure extracts and selected compounds including amphimedine (1), 2, 4, and 7. While all four compounds were solid tumor selective, 1 and 2 were the most potent and 4 was the most selective. The rationale used to characterize the new structures is outlined along with the related biosynthetic pathways envisioned to generate 2 and 7.     

Tedanolide C: a potent new 18-membered-ring cytotoxic macrolide isolated from the Papua New Guinea marine sponge Ircinia sp

Cytotoxicity-guided fractionation of the crude methanol extract of a marine sponge, Ircinia sp., yielded tedanolide C (1), a new 18-membered macrolide. The structure was solved by interpreting NMR and MS data, and the relative stereochemistry was determined from a combination of homo- and heteronuclear coupling constants in conjunction with molecular modeling. Compound 1 exhibited potent cytotoxicity against HCT-116 cells in vitro. Cell cycle analysis showed that treatment of cells with compound 1 arrested cells in the S-phase.     

Palmerolide A, a cytotoxic macrolide from the antarctic tunicate Synoicum adareanum

Palmerolide A, a 20-membered macrocyclic polyketide bearing carbamate and vinyl amide functionality, was isolated from the tunicate Synoicum adareanum collected from the vicinity of Palmer Station on the Antarctic Peninsula. Palmerolide A displays potent and selective cytotoxicity toward melanoma (UACC-66 LC50 = 0.018 muM) and appears to operate via inhibition (IC50 = 2 nM) of V-ATPase.     

Iriomoteolide-3a, a cytotoxic 15-membered macrolide from a marine dinoflagellate amphidinium species

A 15-membered macrolide, iriomoteolide-3a (1), with an allyl epoxide has been isolated from a marine benthic dinoflagellate Amphidinium sp. (strain HYA024), and the structure was assigned by detailed analyses of 2D NMR data. Relative and absolute configurations were elucidated on the basis of conformational studies of 1 and its acetonide (2) and modified Mosher's method of 1, respectively. Iriomoteolide-3a (1) and the acetonide (2) exhibited potently cytotoxic activity against antitumor cells.     

Peloruside A: a potent cytotoxic macrolide isolated from the new zealand marine sponge Mycale sp

A novel, polyoxygenated, pyranose ring containing 16-membered macrolide peloruside A (1) exhibiting cytotoxic activity in the nanomolar range was isolated from the New Zealand marine sponge Mycale sp. The structure of 1 and relative stereochemistry of the 10 stereogenic centers were determined on a 3 mg sample using a variety of spectroscopic methods. Compound 1 was isolated along with the previously reported cytotoxins mycalamide A (2) and pateamine (3) from a single specimen of this sponge.     

Unusual spirocyclic macroline alkaloids, nitrogenous derivatives, and a cytotoxic bisindole from Alstonia

The bark extract of the Malayan A. macrophylla provided several novel indoles with unprecedented carbon skeletons, an unusual nitrogenous compound, a cytotoxic bisindole, several new macroline alkaloids, in addition to other known alkaloids. The structures of the new compounds were established by spectroscopic analysis.     

Unusual C25 steroids produced by a sponge-derived Penicillium citrinum

[structure: see text] Structurally unique steroids, isocyclocitrinol A (1) and 22-acetylisocyclocitrinol A (2), were isolated from the extract of a saltwater culture of sponge-derived Penicilliun citrinum. The structures were established by analysis of 1D and 2D NMR data. The absolute structures were determined on the basis of X-ray structure analysis and application of modified Mosher's method. Furthermore, the structure of cyclocitrinol (3a) previously isolated from a terrestrial P. citrinum was revised as 3b. Compounds 1 and 2 showed weak antibacterial activity against Staphylococcus epidermidis and Enterococcus durans.     

Additional cytotoxic substances isolated from the sponge-derived Gymnascella dankaliensis

A continuous investigation of secondary metabolites produced by the sponge-derived fungus, Gymnascella dankaliensis, has yielded a new polyketide tyrosine derivative, dankastatin C (3) and the known steroid, demethylincisterol A₃ (4), which was originally found from a Homaxinella marine sponge. The stereostructure of the new compound has been determined based on the analysis of 1D and 2D NMR data. Dankastatin C (3) showed potent cell growth inhibitory activity against the murine P388 cell line.     

Iriomoteolide-1a, a potent cytotoxic 20-membered macrolide from a benthic dinoflagellate amphidinium species

A potent cytotoxic 20-membered macrolide, iriomoteolide-1a (1), has been isolated from a benthic dinoflagellate Amphidinium sp. (strain HYA024), and the structure was elucidated on the basis of detailed analyses of 2-D NMR data. The relative and absolute stereochemistries were assigned by the combination of conformational analyses using NMR data and modified Mosher's method of 1.     

The structure of tetramycin,a new polyene macrolide antibiotic

The structure of the tetraene antifungal antibiotic tetramycin has been established by detailed studies of mass, ¹H and ¹³C NMR spectra as well as by chemical degradation. A newly developed mass analysis has been introduced for determining the carbon skeleton of the aglycone.     

Iriomoteolide-13a,a cytotoxic 22-membered macrolide from a marine dinoflagellate Amphidinium species

Iriomoteolide-13a (1) has been isolated from a benthic dinoflagellate Amphidinium sp. (strain KCA09053) as a new 22-membered macrolide containing one hexahydrofuro[3,2-b]furan ring, one tetrahydropyran ring, two tetrahydrofuran rings, three one-carbon branches, and three hydroxyl groups including two hemiketals. The structure of 1 was assigned on the basis of a detailed 2D NMR analysis. Compound 1 exhibited cytotoxic activity against human cervix adenocarcinoma HeLa cells (IC₅₀: 0.5 μg/mL).     

Stereoselective synthesis of the cytotoxic macrolide FD-891

[reaction: see text] A total synthesis of the naturally occurring, cytotoxic macrolide FD-891 is described. Three fragments were first stereoselectively constructed using mainly asymmetric aldol and allylation reactions. The complete framework was then assembled using two Julia-Kocienski olefinations to connect the three fragments and a Yamaguchi reaction to close the macrolactone ring.     

Hypocrol A,a new tyrosol derivative from a sponge-derived strain of the fungus Hypocrea koningii

In continuation of our search for new antibacterial and antioxidant metabolites from sponge-derived fungi, one new tyrosol derivative, hypocrol A (1), together with four known congeners, trichodenol B (2), 4-hydroxyphenethyl acetate (3), 4-hydroxyphenethyl tetradecanoate (4) and 1-oleyltyrosol (5), was isolated from the strain Hypocrea koningii PF04. Their planar structures were unequivocally elucidated by spectroscopic methods and comparison with the literature data. All the compounds displayed weak antibacterial activities against Staphylococcus aureus, methicillin-resistant S. aureus and Escherichia coli, whereas compounds 1 and 2 exhibited a moderate antioxidant efficacy in the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging assay with IC₅₀ values of 48.5 and 97.4 μg/mL, respectively.     

Stereoselective synthesis of the cytotoxic macrolide aspergillide B

A total, stereoselective synthesis of the cytotoxic macrolide aspergillide B has been performed. A cross metathesis and a C-glycosidation via a Mukaiyama-type aldol reaction were key features of the synthesis. The macrocyclic lactone ring was created by means of the Yamaguchi procedure.     

Amphidinolide h, a potent cytotoxic macrolide, covalently binds on actin subdomain 4 and stabilizes actin filament

The actin-targeting toxins have not only proven to be invaluable tools in studies of actin cytoskeleton structure and function but they also served as a foundation for a new class of anticancer drugs. Here, we describe that amphidinolide H (AmpH) targets actin cytoskeleton. AmpH induced multinucleated cells by disrupting actin organization in the cells, and the hyperpolymerization of purified actin into filaments of apparently normal morphology in vitro. AmpH covalently binds on actin, and the AmpH binding site is determined as Tyr200 of actin subdomain 4 by mass spectrometry and halo assay using the yeast harboring site-directed mutagenized actins. Time-lapse analyses showed that AmpH stimulated the formation of small actin-patches, followed by F-actin rearrangement into aggregates via the retraction of actin fibers. These results indicate that AmpH is a novel actin inhibitor that covalently binds on actin.     

Amphidinolide W, a new 12-membered macrolide from dinoflagellate Amphidinium sp

A new cytotoxic 12-membered macrolide, amphidinolide W (1), has been isolated from a marine dinoflagellate Amphidinium sp., and the structure was elucidated by spectroscopic data including (13)C-(13)C INADEQUATE correlations for its (13)C-enriched sample. The absolute stereochemistry of 1 was assigned by combination of J-based configuration analysis and modified Mosher method. Amphidinolide W (1) is the first macrolide without an exomethylene unit among all amphidinolides obtained so far.     

Ternifolide A, a new diterpenoid possessing a rare macrolide motif from Isodon ternifolius

Ternifolide A (1), a new diterpenoid featuring a unique 10-membered lactone ring formed between C-6 and C-15, along with ternifolide B (2), a nor-diterpenoid, and ternifolide C (3) were isolated from the leaves of Isodon ternifolius. Both H-8 and H-9 being α-orientations in compound 1 were found for the first time. The absolute configurations of 1 and 3 were confirmed by X-ray diffraction study. Compounds 1 and 3 were evaluated for their cytotoxicity.     

Phylattrin, a new cytotoxic xanthone from Calophyllum soulattri

Our continuing studies on secondary metabolites from the stem bark of Calophyllum soulattri has led to the isolation of another new diprenylated xanthone, phylattrin (1), in addition to five other xanthones and two common sterols. The xanthones are soulattrin (2), caloxanthone C (3), macluraxanthone (4), brasixanthone B (5) and trapezifolixanthone (6) while the sterols are stigmasterol (7) and β-sitosterol (8). The structures of these compounds were determined on the basis of spectroscopic analyses such as 1D and 2D-NMR, HRESIMS, IR and UV. Compounds 1-7 exhibited moderate cytotoxic activities against SNU-1, HeLa, Hep G2, NCI-H23, K562, Raji, LS174T, IMR-32 and SK-MEL-28 cells.