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Callyazepin (1) and (3R)-methylazacyclodecane (2), nitrogenous macrocycles, were isolated from a tropical Callyspongia sp. sponge. The combined spectroscopic analyses revealed that the structure of 1 is a bicyclic azepane ammonium salt of a novel structural class derived from mixed biogenetic origins. The configuration of the whole molecule and the conformation of the formamide group were assigned by proton-proton coupling constants, a NOESY analysis, and the application of the phenylglycine methyl ester method. The structure of 2 was identified using combined spectroscopic analyses and ECD measurements. These compounds exhibited moderate cytotoxic activities against the K562 and A549 cell lines.

Six new meroterpenoids (1-6), along with arenarol (7), a known rearranged drimane sesquiterpene hydroquinone, were isolated from a Dysidea sp. sponge collected from the Federated States of Micronesia. On the basis of the results of combined spectroscopic analysis, compound 1 was determined to be the cyclic ether derivative of 7, whereas 2 and 3 were assigned as the corresponding sesquiterpene quinones containing taurine-derived substituents. Compounds 4-6 possess a novel tetracyclic skeleton formed by a direct linkage between the quinone and sesquiterpene moieties. The configurations of these new compounds were assigned on the basis of combined NOESY and ECD analysis. These compounds exhibited cytotoxic and antimicrobial activities and weak inhibition against Na(+)/K(+)-ATPase.

The suvanines, a new suvanine salt, five new (2, 4-8) and two known sesterterpenes from the same structural class, and two new modified lipids (9 and 10) were isolated from a Coscinoderma sp. sponge collected from Chuuk Island, Micronesia. On the basis of the results of combined spectroscopic and chemical analyses, a new suvanine salt was determined to be the suvanine N,N-dimethyl-1,3-dimethylherbipoline salt (2) and suvanine-lactam derivatives (4-8) formed by condensations between an oxidized furan moiety and amino acids. The lipid metabolites were found to be new derivatives of the taurine-containing deacyl irciniasulfonic acid class. The suvanines exhibited moderate cytotoxicities against the K562 and A549 cell lines, while the new suvanine salt (2) had significant antibacterial activity.

Five new nortriterpene glycosides, along with eight known compounds of the sarasinoside class, were isolated from the tropical sponge Lipastrotethya sp. collected from Chuuk, Micronesia. The structures of these new compounds, designated as sarasinosides N-R (9-13), were determined by combined spectroscopic and chemical methods. The aglycone portions of 10-13 were found to be unprecedented among nortriterpeneoids on the basis of extensive NMR analyses. Several of these compounds exhibited cytotoxicity against A549 and K562 cell lines as well as weak inhibitory activity against Na(+)/K(+)-ATPase.

Nine new triterpene galactosides and aglycones, along with three known compounds from the rare pouoside class, were isolated from the tropical sponge Lipastrotethya sp. collected from Micronesia. The structures of these new compounds were determined by combined spectroscopic methods and designated as pouosides F-I (4, 8, 10, and 12) and pouogenins A-E (5-7, 9, and 11). The absolute configurations of the asymmetric centers and the cyclohexenone moiety, which had been previously undetermined, were assigned by NOESY analyses and Mosher's methods. Several of these compounds exhibited weak cytotoxicity against the K562 cell line.

Eight new sesterterpenes (2, 5, and 10-15), including structurally related pentaprenyl hydroquinones (2 and 5), and seven known ones of the same structural classes were isolated from the sponge Coscinoderma sp., collected from Chuuk Island, Micronesia. On the basis of the results of combined spectroscopic analyses, the new compounds were determined to be derivatives of the halisulfates and suvanine. These compounds exhibited moderate cytotoxicity against the K562 cell line and inhibitory activities against isocitrate lyase, sortase A, and Na+/K+-ATPase; significant structure-activity relationships were evident.

Cyclotides, the largest known family of head-to-tail cyclic peptides, have approximately 30 amino acid residues with a complex structure containing a circular peptide backbone and a cystine knot. They are found in plants from the Violaceae and Rubiaceae families and are speculated to function in plant protection. In addition to their insecticidal properties, cyclotides display cytotoxic, anti-HIV, antimicrobial, and inhibition of neurotensin binding activities. Although cyclotides are present in all violaceous species hitherto screened, their distribution and expression in Rubiaceae are not fully understood. In this study, we show that Psychotria leptothyrsa var. longicarpa (Rubiaceae) contains a suite of different cyclotides. The cyclotide fractions were isolated by RP-HPLC, and sequences of six new peptides, named psyles A-F, were determined by MS/MS sequencing. One of these, psyle C, is the first rubiaceous linear variant known. Psyles A, C, and E were analyzed in a fluorometric microculture assay to determine cytotoxicity toward the human lymphoma cell line U937-GTB. The IC(50) values of psyles A, C, and E were 26, 3.50, and 0.76 muM, respectively. This study expands the number of known rubiaceous cyclotides and shows that the linear cyclotide maintains cytotoxicity.

A new highly unsaturated macrolide lactam, termed mirabilin ( 1), was isolated from the aqueous extract of the marine sponge Siliquariaspongia mirabilis. Mirabilin is characterized by the presence of a 35-membered macrolide lactam ring bearing a pentadiene conjugated system and a tetrasubstituted tetrahydropyran ring. A linear polyketide moiety is attached to the macrocyclic ring through an amide linkage. The structure of mirabilin was determined using extensive 2D NMR and ESIMS and tandem MS techniques. Mirabilin inhibits the growth of the tumor cell line HCT-116 with an IC 50 value of 0.27 +/- 0.09 microM and is noncytotoxic to several other cell lines.

A new polybrominated diphenyl ether ( 9), together with eight known compounds, were isolated from the crude organic extract of the marine sponge Dysidea sp. collected from the Federated States of Micronesia. Their structures were elucidated on the basis of various NMR spectroscopic data. These compounds exhibited inhibitory activities against Streptomyces 85E in the hyphae formation inhibition (HFI) assay and displayed antiproliferative activities against the human breast adenocarcinoma cancer cell line MCF-7. Compound 6 was selected for further evaluation in a cell cycle progression study.

Three new pentaketides, aspinotriols A ( 1) and B ( 3) and aspinonediol ( 5), were isolated together with two known compounds, aspinonene ( 7) and dihydroaspyrone ( 9), from the marine fungus Aspergillus ostianus strain 01F313, which was collected in Pohnpei and cultured with bromine-modified artificial seawater. The structures of the new compounds were determined by spectroscopic analyses including 1D and 2D NMR. Although 1 and 3 are diastereomers, they show nearly superimposable (1)H and (13)C NMR spectra. The absolute configurations of compounds 1, 3, 5, and 9 were elucidated by the modified Mosher's method.

Four new cyclic depsipeptides termed mirabamides A-D (1-4) have been isolated from the marine sponge Siliquariaspongia mirabilis and shown to potently inhibit HIV-1 fusion. Their structures were elucidated by NMR and ESIMS, and absolute stereochemistry of the amino acids was determined using advanced Marfey's methods and NMR. Mirabamides contain two new entities, including 4-chlorohomoproline in 1-3 and an unusual glycosylated amino acid, beta-methoxytyrosine 4'-O-alpha-L-rhamnopyranoside (in 1, 2, and 4), along with a rare N-terminal aliphatic hydroxy acid. These elements proved to be useful for anti-HIV structure-activity relationship studies. Mirabamide A inhibited HIV-1 in neutralization and fusion assays with IC50 values between 40 and 140 nM, as did mirabamides C and D (IC50 values between 140 nM and 1.3 microM for 3 and 190 nM and 3.9 microM for 4), indicating that these peptides can act at the early stages of HIV-1 entry. The potent activity of depsipeptides containing the glycosylated beta-OMe Tyr unit demonstrates that beta-OMe Tyr itself is not critical for activity. Mirabamides A-C inhibited the growth of B. subtilis and C. albicans at 1-5 microg/disk in disk diffusion assays.

Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor (NHR) family, are ligand-activated transcription factors. Ligands (agonists) of PPARgamma have been shown to inhibit growth, promote terminal differentiation, and induce apoptosis in human breast tumor cells. A cell-based reporter assay was developed to examine extracts of terrestrial and marine organisms for the ability to activate PPARgamma. Bioassay-guided fractionation and isolation of an active extract from Pseudoceratina rhax yielded the known histone deacetylase (HDAC) inhibitor psammaplin A (1). Compound 1 activates PPARgamma in a MCF-7 cell-based reporter assay and induces apoptosis in human breast tumor cells in vitro. Molecular modeling studies suggest that 1 may interact with binding sites within the PPARgamma ligand-binding pocket. Therefore, in addition to its known effects on HDAC-mediated processes, activation of PPARgamma-regulated gene expression may play a role in the ability of 1 to induce apoptosis.

Investigations of the marine sponge Prianos osiros, collected in Pohnpei, gave a new cytotoxic acetylenic carotenoid, (3R,3'R,5S)-3,3',5,19'-tetrahydroxy-7',8'-didehydro-gamma,epsilon-carotene-8-one. The absolute configuration of this carotenoid was solved by interpretation of IR, MS, and 2D NMR spectra and application of the modified Mosher's method. Compound 1 is cytotoxic toward cultured human colon tumor cells, HCT 116 (IC(50) 4.38 microg/mL).

A new cycloheptapeptide, phakellistatin 14, was isolated in 8.8 x 10(-7)% yield from Phakellia sp., a marine sponge from Chuuk, Federated States of Micronesia. The structure (1), cyclo-Phe-beta-OMe-Asp-Ala-Met(SO)-Ala-Ile-Pro, was elucidated by 1D and 2D NMR spectral analyses augmented by HRFABMS. The chirality of each amino acid unit was determined to be S using chiral HPLC methods. Phakellistatin 14 showed cancer cell growth inhibitory activity (ED(50) 5 microg/mL) against the murine lymphocytic leukemia P388 cell line.

Two novel cholic acid derivatives and three known steroids were isolated from an octocoral Eleutherobiasp. from Pohnpei Micronesia along with the known briareins minabein-1 (6), minabein-4 (7), minabein-6 (8), minabein-8 (9), and minabein-9 (10). X-ray crystallographic analysis of the known compound minabein-4 allowed assignment of its correct relative and absolute stereochemistry. Consequently, a different structure proposed for the same compound (named independently as nui-inoalide-D) is incorrect.

Cyclonellin (1), a new cyclic octapeptide, was isolated from an aqueous extract of the marine sponge Axinella carteri. Its structure was elucidated by interpretation of NMR spectral data of the intact compound and N-terminal Edman sequencing of linear peptide fragments obtained by partial hydrolysis of 1. The absolute configurations of the constituent amino acids were determined by acid hydrolysis, derivitization with FDAA, and LC-MS analyses.

The bioassay-guided fractionation of the water-soluble extract of the marine sponge Cribrochalina olemda collected in Palau resulted in the isolation of a new amino acid cribronic acid (1): (2S,4R,5R)-5-hydroxy-4-sulfooxypiperidine-2-carboxylic acid. However, aqueous extracts of Stylotella aurantium and Axinella carteri collected in Yap State, Micronesia, afforded a known N-methyl-d-aspartic acid (NMDA)-type glutamate receptor agonist, (2S,4S)-4-sulfooxypiperidine-2-carboxylic acid (2), as a common active principle. Both 1 and 2 induced convulsive behaviors in mice upon intracerebroventricular (icv) injection with ED(50) values of 29 +/- 3.0 and 20 +/- 2.8 pmol/mouse, respectively. Radioligand binding assay using rat cerebrocortical membrane demonstrated that 1 and 2 inhibit the binding of the labeled NMDA receptor ligand [(3)H]CGP39653 at IC(50) values of 83 +/- 15 and 214 +/- 20 nM, respectively. However, 1 and 2 did not displace [(3)H]kainic acid or [(3)H]AMPA. These data indicated that 1 is a selective NMDA-type glutamate receptor ligand with potent convulsant activity in mice.

Three new sesquiterpene quinols (1, 2, and 5) and two known ones (3 and 4) were isolated along with halistanol sulfate (6) from a marine sponge of the genus Aka collected from Yap Island, Federated States of Micronesia. Their structures were determined from spectral data, and the structure of siphonodictyal C (3) was revised. Sulfates 3 and 6 inhibit CDK4/cyclin D1 complexation, whereas 1 and 4 do not.

Chemical investigation of the Micronesian ascidian Eudistoma sp. afforded two new eudistomin congeners, which were designated eudistomins W (1) and X (2). The structures of the new compounds were unambiguously established on the basis of NMR spectroscopic ((1)H, (13)C, COSY, (1)H detected direct, and long-range (13)C-(1)H correlations) and mass spectrometric (EI and ESIMS) data. Compound 2 exhibited antibiotic activity toward Bacillus subtilis, Staphyloccocus aureus, and Escherichia coli and was also found to be fungicidal against Candida albicans in an agar diffusion assay. Compound 1 was selectively active against C. albicans but showed no antibacterial activity.

Twelve new briarane diterpenes, designated milolides (1-12), and one known diterpene, 9-deacetylstylatulide lactone (13), were isolated from the Micronesian octocoral Briareum stechei collected at Yap, Federated States of Micronesia. Their structures were determined from spectral data.

A MeOH/CH(2)Cl(2) extract of the bud covers of Artocarpus altilis collected in Micronesia showed activity in a cathepsin K inhibition assay. In addition to the three known flavonoids isolated from the bud covers of this species, two new compounds have been identified whose structures were determined on the basis of spectral data. These compounds include a dimeric dihydrochalcone, cycloaltilisin 6 (2), and a new prenylated flavone, cycloaltilisin 7 (3). Novel compounds 2 and 3 have IC(50) values of 98 and 840 nM, respectively, in cathepsin inhibition.

Obyanamide (1) was isolated from a variety of the marine cyanobacterium Lyngbya confervoides collected in Saipan, Commonwealth of the Northern Mariana Islands. Gross structure elucidation of this novel cyclic depsipeptide relied on extensive application of 2D NMR techniques. The absolute stereochemistry was deduced by chiral chromatography of the hydrolysis products and comparison with authentic and synthetic standards. Obyanamide (1) was cytotoxic against KB cells with an IC(50) of 0.58 microg/mL.

Eleven new briarane-type diterpene lactones, designated milolides (1--8, 10--12), together with four known diterpene lactones (9, 13--15), were isolated from the Micronesian octocoral Briareum stechei collected at Yap, Federated States of Micronesia. One aspect of the stereochemistry of one of the known compounds, solenolide C (9), is revised. Structures of the new compounds were determined from spectral data.

Two new sesquiterpenes, pelorol (1) and 5-epi-smenospongine (2), and seven known ones (3-9) were isolated from the sponge Petrosaspongia metachromia, collected from Yap, Federated States of Micronesia. Their structures were determined from spectral data. Pelorol (1) possesses a new carbon skeleton.

Four new imidazole alkaloids, 2-5, along with the known isonaamidine B (1) were isolated from a Pacific sponge, Leucetta cf. chagosensis, collected from Yap, Federated States of Micronesia. Among these, 4 and 5 are zinc complexes derived from isonaamidine B and isonaamidine D. The structures of the new compounds were elucidated from spectral data. Isonaamidine D (3) showed weakly antifungal activity against Aspergillus niger with MIC = 100 micrograms/mL.