Search

The production and accumulation of advanced glycation end products (AGEs) have been implicated in diabetes and diabetic complication. This study was conducted as a search for an AGE inhibitor from brown alga, Sargassum macrocarpum. Separation and purification were performed using AGEs inhibitory activity as an index, yielding isolation of 11 meroterpenoids, of which 3 were new compounds: macrocarquinoids A (1), B (6), and C (9). Their structures were elucidated using NMR spectral analysis with 2D techniques. All tested compounds showed AGEs inhibitory activity. Particularly, macrocarquinoid C (9) possessed the strongest activity (IC50: 1.0 mM) of isolated compounds. This activity was stronger than that of aminoguanidine (positive control).

Two new polyacetylene glycosides, kamiohnoyneosides A and B, were isolated from the flowers of edible Chrysanthemum "Kamiohno", along with a known polyacetylene glycoside and two known monoterpene glycosides. The structures of new compounds were elucidated on the basis of spectroscopic data. Kamiohnoyneoside A and three known compounds moderately inhibited formation of Ne-(carboxymethyl)lysine, one of the representative advanced glycation endproducts.

Background Some dinoflagellates cause harmful algal blooms, releasing toxic secondary metabolites, to the detriment of marine ecosystems and human health. Our understanding of dinoflagellate toxin biosynthesis has been hampered by their unusually large genomes. To overcome this challenge, for the first time, we sequenced the genome, microRNAs, and mRNA isoforms of a basal dinoflagellate, Amphidinium gibbosum, and employed an integrated omics approach to understand its secondary metabolite biosynthesis. Results We assembled the ~ 6.4-Gb A. gibbosum genome, and by probing decoded dinoflagellate genomes and transcriptomes, we identified the non-ribosomal peptide synthetase adenylation domain as essential for generation of specialized metabolites. Upon starving the cells of phosphate and nitrogen, we observed pronounced shifts in metabolite biosynthesis, suggestive of post-transcriptional regulation by microRNAs. Using Iso-Seq and RNA-seq data, we found that alternative splicing and polycistronic expression generate different transcripts for secondary metabolism. Conclusions Our genomic findings suggest intricate integration of various metabolic enzymes that function iteratively to synthesize metabolites, providing mechanistic insights into how dinoflagellates synthesize secondary metabolites, depending upon nutrient availability. This study provides insights into toxin production associated with dinoflagellate blooms. The genome of this basal dinoflagellate provides important clues about dinoflagellate evolution and overcomes the large genome size, which has been a challenge previously.

The production and accumulation of advanced glycation end products (AGEs) have been implicated in diabetes and diabetic complication. This study was conducted as a search for an AGE inhibitor from brown alga, Sargassum macrocarpum. Separation and purification were performed using AGEs inhibitory activity as an index, yielding isolation of 11 meroterpenoids, of which 3 were new compounds: macrocarquinoids A (1), B (6), and C (9). Their structures were elucidated using NMR spectral analysis with 2D techniques. All tested compounds showed AGEs inhibitory activity. Particularly, macrocarquinoid C (9) possessed the strongest activity (IC

The manzamine alkaloids are absolutely one of the most fascinating marine natural products. The representative manzamine alkaloids, manzamines A-C, were isolated from a marine sponge Haliclona sp. collected off Cape Manzamo, Okinawa, Japan. The manzamine alkaloids are a unique class of alkaloids possessing a characteristic heterocyclic system, and exhibit a diverse range of bioactivities including cytotoxicity, antimicrobial activity, antimalarial activity, antiviral and antiinflammatory activities, antiinsecticidal activity, and proteasome inhibitory activity. About 100 manzamine alkaloids have been isolated from more than 16 species of marine sponges belonging to 5 families. The unusual ring systems, an intriguing suggested biogenetic pathway, and promising biological activities of manzamine alkaloids have attracted great interest as challenging targets for the total synthesis. This review is the continuation of the previous review published in volume 60 of The Alkaloids and covers isolation, structure elucidation, biosynthesis and biogenesis, chemical synthesis, and biological activity of manzamine alkaloids reported from 2003 to 2018.

A new 12-membered macrolide, symbiodinolactone A, was isolated from the culture broth of symbiotic marine dinoflagellate Symbiodinium sp. The gross structure of symbiodinolactone A was elucidated by spectroscopic analyses, and the relative configuration was elucidated by the J-based configuration analysis and density-functional theory calculations. Symbiodinolactone A is the new 12-membered macrolide possessing an E double bond between C-4 and C-5, a branched methyl group at C-7, and a 1,2,3-trihydroxybutyl group at C-11. Symbiodinolactone A is the first usual size macrolide and the first non-nitrogen-containing macrolide from dinoflagellate Symbiodinium sp. Symbiodinolactone A might be generated by the unexplained dinoflagellate polyketide biosynthetic machinery.

The manzamine alkaloids are absolutely one of the most fascinating marine natural products. The representative manzamine alkaloids, manzamines A-C, were isolated from a marine sponge Haliclona sp. collected off Cape Manzamo, Okinawa, Japan. The manzamine alkaloids are a unique class of alkaloids possessing a characteristic heterocyclic system, and exhibit a diverse range of bioactivities including cytotoxicity, antimicrobial activity, antimalarial activity, antiviral and antiinflammatory activities, antiinsecticidal activity, and proteasome inhibitory activity. About 100 manzamine alkaloids have been isolated from more than 16 species of marine sponges belonging to 5 families. The unusual ring systems, an intriguing suggested biogenetic pathway, and promising biological activities of manzamine alkaloids have attracted great interest as challenging targets for the total synthesis. This review is the continuation of the previous review published in volume 60 of The Alkaloids and covers isolation, structure elucidation, biosynthesis and biogenesis, chemical synthesis, and biological activity of manzamine alkaloids reported from 2003 to 2018.

A new indole alkaloid with the canthin-6-one skeleton, ishigadine A, has been isolated from an Okinawan marine sponge Hyrtios sp. The structure of ishigadine A was elucidated on the basis of spectroscopic analyses. Ishigadine A is a new canthin-6-one alkaloid possessing a hydroxy group, a 1,3-dimethyl-4-methylthioimidazolium, and a 1-propylguanidine. Ishigadine A is the third canthin-6-one alkaloid from sponges. Ishigadine A might be generated from l -arginine, l -histidine, and l -tryptophan. Ishigadine A exhibited moderate cytotoxicity against L1210 murine leukemia cells.

Two new bromotyrosine alkaloids, ma'edamines C and D, were isolated from an Okinawan marine sponge Suberea sp. The structures of ma'edamines C and D were elucidated on the basis of spectroscopic data. Ma'edamines C and D were the first natural products possessing a unique tetrasubstituted pyridinium moiety such as N-alkyl-3,5-diethyl-2-propylpyridinium and N-alkyl-3,5-diethyl-4-propylpyridinium, respectively. Ma'edamines C and D exhibited moderate cytotoxicity against murine leukemia cell line L1210 in vitro.

Culturable fungal communities were investigated in marine subsurface sediment cores obtained at three different sites in Suruga Bay. Sediment core samples were examined at five different depths, namely 3 m, 12 m, 21 m, 31 m and 40 m below the seafloor (mbsf) at each site. Although the occurrence and diversity of culturable fungi in subsurface sediments appeared extremely low, fungi were successfully cultured from 5 out of 15 samples, including a sample taken from 40 m below the seafloor. The most frequently detected fungal species were Aspergillus spp. followed by Pichia and Cadophora. Two possible novel spp. belonging to the phylum Ascomycota were also isolated. Although the presence of fungi in deep subsurface environments has been suggested in some recent reports, there has been only limited information available describing the identification and diversity of culturable fungi from deep subsurface sediments. Our results provide further evidence to support that fungi persist in deep marine subsurface biospheres. Also, it was suggested that marine subsurface biospheres can be a new fungal resource. Further investigation on cultured deep subsurface fungi will provide a better understanding of the ecology and physiology of extremotolerant fungi and their potential for biotechnological application.

A novel, anaerobic bacterium, strain MO-SEDIT, was isolated from a methanogenic microbial community, which was originally obtained from marine subsurface sediments collected from off the Shimokita Peninsula of Japan. Cells were Gram-stain-negative, non-motile, non-spore-forming rods, 0.4–1.4 μm long by 0.4–0.6 μm wide. The cells also formed long filaments of up to about 11 μm. The strain grew on amino acids (i.e. valine, leucine, isoleucine, methionine, glycine, phenylalanine, tryptophan, lysine and arginine), pyruvate and melezitose in the presence of yeast extract. Growth was observed at 4–37 °C (optimally at 30 °C), at pH 6.0 and 8.5 (optimally at 7.0–7.5) and in 0–60 g l− 1 NaCl (optimally 20 g NaCl l− 1). The G+C content of the DNA was 32.0 mol%. The polar lipids of strain MO-SEDIT were phosphatidylglycerol, phosphatidyl lipids and unknown lipids. The major cellular fatty acids (>10 % of the total) were C14 : 0, C16 : 1ω9 and C16 : 0 dimethyl aldehyde. Comparative sequence analysis of the 16S rRNA gene showed that strain MO-SEDIT was affiliated with the genus Sedimentibacter within the phylum Firmicutes. It was related most closely to the type strain of Sedimentibacter saalensis (94 % sequence similarity). Based on the phenotypic and genetic characteristics, strain MO-SEDIT is considered to represent a novel species of the genus Sedimentibacter, for which the name Sedimentibacter acidaminivorans sp. nov. is proposed. The type strain is MO-SEDIT ( = JCM 17293T = DSM 24004T).

The total synthesis of 7,10-epimer of the proposed structure of amphidinolide N was accomplished. The requisite chiral C17-C29 subunit was assembled stereoselectively via Keck allylation, Shi epoxidation, diastereoselective 1,3-reduction, and a later oxidative synthesis of the THF framework. The C1-C13 and C17-C29 subunits were successfully coupled using a Enders RAMP "linchpin" as the C14-C16 three carbon unit, thereby controlling the chirality at C14 and C16. The labile allyl epoxy moiety was successfully constructed by Grieco-Nishizawa olefination at a final stage of the synthesis.

Amphidinolide N, the structure of which has been recently revised, is a 26-membered macrolide featuring allyl epoxide and tetrahydropyran moieties with 13 chiral centers. Due to its challenging structure and extraordinary potent cytotoxicity, amphidinolide N is a highly attractive target of total synthesis. During our total synthesis studies of the 7,10-epimer of the proposed structure of amphidinolide N, we have synthesized the C1-C13 subunit enantio- and diastereoselectively. Key reactions include an l-proline catalyzed enantioselective intramolecular aldol reaction, Evans aldol reaction, Sharpless asymmetric epoxidation and Tamao-Fleming oxidation. To aid late-stage manipulations, we also developed the 4-(N-benzyloxycarbonyl-N-methylamino)butyryl group as a novel ester protective group for the C9 alcohol.

New bisindole alkaloids, hyrtinadines C (1) and D (2), have been isolated from an Okinawan marine sponge Hyrtios sp. The structures of hyrtinadines C (1) and D (2) were elucidated based on analyses of the spectral data. Hyrtinadines C (1) and D (2) were the relatively rare alkaloids possessing a 3,4-fused azepinoindole skeleton. Hyrtinadines C (1) and D (2) showed antimicrobial activity.

Speradine A is a derivative of cyclopiazonic acid (CPA) found in culture of an Aspergillus tamarii isolate. Heterologous expression of a predicted methyltransferase gene, cpaM, in the cpa biosynthesis gene cluster of A. tamarii resulted in the speradine A production in a 2-oxoCPA producing A. oryzae strain, indicating cpaM is involved in the speradine A biosynthesis.

A β-1,3-glucanase (LpGluA) of deep subseafloor Laceyella putida JAM FM3001 was purified to homogeneity from culture broth. The molecular mass of the enzyme was around 36 kDa as judged by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). LpGluA hydrolyzed curdlan optimally at pH 4.2 and 80 °C. In spite of the high optimum temperature, LpGluA showed relatively low thermostability, which was stabilized by adding laminarin, xylan, colloidal chitin, pectin, and its related polysaccharides. The gene for LpGluA cloned by using degenerate primers was composed of 1236 bp encoding 411 amino acids. Production of both LpGluA and a chitinase (LpChiA; Shibasaki et al. Appl Microbiol Biotechnol 98, 7845-7853, 2014) was induced by adding N-acetylglucosamine (GluNAc) to a culture medium of strain JAM FM3001. Construction of expression vectors containing the gene for LpGluA and its flanking regions showed the existence of a putative repressor protein.

A new linear polyketide, amphidinin G (1), has been isolated from a symbiotic marine dinoflagellate Amphidinium sp. The planar structure of 1 was established mainly based on the 2D NMR data and the stereochemistry was elucidated by the combination of J-value analysis, modified Mosher’s method, and NMR chemical shift comparison with synthetic analogues. Amphidinin G (1) was expected to be a biosynthetic precursor of amphidinin A (2), a known linear dinoflagellate polyketide. Amphidinin G (1) showed antifungal activity against Trichophyton mentagrophytes.

The investigation of the Vietnamese marine sponge Spongia sp. led to the isolation of three new sesquiterpene phenols, langconols A-C (1-3), and one new sesquiterpene hydroxyquinone, langcoquinone C (4), together with two known meroterpenoids (5 and 6). Their structures were determined on the basis of spectroscopic analyses and comparisons with published data. Furthermore, the antibacterial assays of the isolates 1-6 suggested that 4 and 6 had significant antibacterial activities against Bacillus subtilis and Staphylococcus aureus, with MICs ranging from 6.25 to 25.0µM, while 1 and 3 possessed significant antibacterial activities against B. subtilis with MICs of 12.5 and 25.0µM, respectively. In contrast, cytotoxic assays of the isolated compounds 1-6, as well as compounds 7-15 previously isolated from this sponge, indicated that 1 and the previously reported anti-B. subtilis and anti-S. aureus sesquiterpene phenol 9 lacked cytotoxic activities against three human cancer cell lines (A549, lung cancer; MCF7, breast cancer; HeLa, cervix cancer) and a human normal cell line (WI-38 fibroblast).

A new manzamine alkaloid, zamamidine D (1), was isolated from an Okinawan Amphimedon sp. marine sponge. The structure of zamamidine D (1) including the relative configuration was elucidated on the basis of spectroscopic data. Zamamidine D (1) is the first manzamine alkaloid possessing a 2,2′-methylenebistryptamine unit as the aromatic moiety instead of a β-carboline unit. Zamamidine D (1) showed antimicrobial activity against several bacteria and fungi.

New dimeric bromopyrrole-imidazole alkaloids, nagelamide I (1) and 2,2'-didebromonagelamide B (2), have been isolated from an Okinawan marine sponge Agelas species. The structures of 1 and 2 were elucidated based on analyses of the spectral data. Nagelamide I (1) was the first symmetric dimeric bromopyrrole-imidazole alkaloid consisting of two subunits connected with a single bond.

New meroterpenoids, nakijiquinone S (1) and nakijinol C (2), have been isolated from an Okinawan marine sponge of the family Spongiidae. The gross structures and relative stereochemistries of 1 and 2 were elucidated on the basis of their spectral data. Nakijiquinone S (1) and nakijinol C (2) were new meroterpenoids consisting of a clerodane-type decalin ring connected to a 2-butoxy-5-hydroxy-benzoquinone unit or methyl 2,3,4-trihydroxybenzoate unit through a methylene, respectively. Nakijiquinone S (1) and nakijinol C (2) showed antimicrobial activities against several bacteria and fungi.

Two new acetylenic fatty acid derivatives possessing a taurine amide residue, taurospongins B (1) and C (2), have been isolated from an Okinawan marine sponge of the family Spongiidae. The gross structures of 1 and 2 were elucidated on the basis of their spectral data, especially 2D NMR and FABMS/MS data. The absolute configurations for 1 and 2 were established by chemical means. Taurospongin C (2) showed inhibitory activity against Cryptococcus neoformans.

Theonezolides A–C (1–3) are cytotoxic 37-membered macrolides with a long side chain isolated from an Okinawan marine sponge Theonella sp. The relative stereochemistry of 1–3 was investigated by combination of NMR analysis including application of a JBCA method, a Universal NMR database, and a 13C-acetonide method. Furthermore, the absolute configurations at 14 chiral centers in 1–3 were found to be 19S, 22R, 24S, 28S, 44S, 45S, 47R, 49S, 53R, 55S, 57S, 59S, 60S, and 63S by application of a modified Mosher’s method.

Three new bis-3-alkylpyridine alkaloids, pyrinodemins G–I (1–3), were isolated from an Okinawan marine sponge Amphimedon sp. and the structures of 1–3 were elucidated on the basis of spectroscopic data. Pyrinodemins G–I (1–3) were novel bis-3-alkylpyridine alkaloids possessing an N-methoxy amide moiety, an α,β-unsaturated 3,5-disubstituted γ-lactone moiety, and a 2,3-di-substituted acrolein at a junction of two 3-alkylpyridines, respectively. Pyrinodemins G (1) and H (2) showed cytotoxicity against P388 murine leukemia cells.

New bisindole alkaloids, hyrtinadines C (1) and D (2), have been isolated from an Okinawan marine sponge Hyrtios sp. The structures of hyrtinadines C (1) and D (2) were elucidated based on analyses of the spectral data. Hyrtinadines C (1) and D (2) were the relatively rare alkaloids possessing a 3,4-fused azepinoindole skeleton. Hyrtinadines C (1) and D (2) showed antimicrobial activity.

New bisindole alkaloids, hyrtinadines C (1) and D (2), have been isolated from an Okinawan marine sponge Hyrtios sp. The structures of hyrtinadines C (1) and D (2) were elucidated based on analyses of the spectral data. Hyrtinadines C (1) and D (2) were the relatively rare alkaloids possessing a 3,4-fused azepinoindole skeleton. Hyrtinadines C (1) and D (2) showed antimicrobial activity.

The biogenetic origins of amphidinin A (1) and amphidinolide P (2) were investigated by feeding experiments with (13)C-labeled acetates. (13)C-NMR data of (13)C-enriched samples revealed that the all carbons of 1 and 2 were derived from acetates. The polyketide chain of 1 was formed from one triketide chain, two diketide chains, and three unusual isolated C1 units derived from C-2 of cleaved acetates, while the polyketide chain of 2 was formed from one pentaketide chain, two acetate units, and three unusual isolated C1 units derived from C-2 of cleaved acetates. The all branched C1 units of 1 and 2 were derived from C-2 of cleaved acetates.

Microorganisms that utilize various D-amino acids (DAAs) were successfully isolated from deep-sea sediments. The isolates were phylogenetically assigned to Alphaproteobacteria, Gammmaproteobacteria, and Bacilli. Some of the isolates exhibited high enantioselective degradation activities to various DAAs. In particular, the Alphaproteobacteria Nautella sp. strain A04V exhibited robust growth in minimal medium supplemented with D-Val as a sole carbon and nitrogen source, whereas its growth was poor on minimal medium supplemented with L-Val instead of D-Val. Its growth was facilitated most when racemic mixtures of valine were used. In contrast, the Nautella strains isolated from shallow-sea grew only with L-Val. No significant differences were found among the strains in the genome sequences including genes possibly related to DAA metabolisms., 深海にひろがる鏡の向こうの微生物世界－Dアミノ酸を好む深海微生物を発見－. 京都大学プレスリリース. 2016-04-27.

Two new bromotyrosine alkaloids, tyrokeradines G (1) and H (2), have been isolated from an Okinawan marine sponge of the order Verongida. The structures of 1 and 2 were elucidated on the basis of spectroscopic data. Tyrokeradine G (1) is the first bromotyrosine alkaloid possessing a β-alanine unit, while tyrokeradine H (2) is a rare bromotyrosine alkaloid possessing a N-substituted pyridinium ring. Tyrokeradines G (1) and H (2) showed antifungal activity.

New diterpene alkaloids, agelasines O–U (1–7), have been isolated from an Okinawan marine sponge Agelas sp. The gloss structures and relative stereochemistries of 1–7 were elucidated from the spectroscopic data. Agelasines O–R (1–4) were the third examples of diterpene alkaloid with a 9-N-methyladenine and a pyrrole units. Agelasine O (1) has a halimane skeleton, while agelasines P–R (2–4) have a clerodane skeleton. Agelasines S–U (5–7) were new diterpene alkaloids with a 9-N-methyladenine unit consisting of a halimane skeleton, a labdane skeleton, and a clerodane skeleton, respectively. Agelasines O–R (1–4) and T (6) showed antimicrobial activities against several bacteria and fungi.

The structures of seven new secondary metabolites isolated from an Okinawan marine sponge Suberites sp., nakijinamines A (1), B (2), and F–I (3–6) and 6-bromoconicamin (7), have been elucidated on the basis of spectroscopic analysis, chemical conversion, and conformational analysis. These analyses disclosed that 1–6 were heteroaromatic alkaloids having the hybrid structures of an aaptamine-type alkaloid and an indole alkaloid, while 7 was a bromoindole alkaloid. Nakijinamine I (6) is the first example of an aaptamine-type alkaloid possessing a 1,4-dioxane ring. Antimicrobial activities of 1–7 were evaluated.

Four new β-carboline alkaloids, eudistomidins H-K (1-4), were isolated from an Okinawan marine tunicate Eudistoma glaucus and the structures of 1-4 were elucidated on the basis of spectroscopic data. Eudistomidins H (1) and I (2) were new β-carboline alkaloids possessing a unique fused-tetracyclic ring system consisting of a tetrahydro β-carboline ring and a hexahydropyrimidine ring. Eudistomidin J (3) showed relatively potent cytotoxicity against murine leukemia cells P388 and L1210, and human epidermoid carcinoma cells KB in vitro.

Three new heteroaromatic alkaloids, nakijinamines C-E (1-3), which are a hybrid of the aaptamine-type and bromoindole alkaloids possessing a taurine- or histidine-derived residue, have been isolated from an Okinawan marine sponge Suberites species. The structures of 1-3 were elucidated on the basis of spectroscopic data and chemical conversions. Nakijinamines C (1) and E (3) are the first natural products possessing a 1H-oxazolo[4',5':4,5]benzo[1,2,3-de][1,6]naphthyridine ring system.

New Lycopodium alkaloids, lyconadins C ( 1 ) and F ( 2 ), were isolated from the club moss Lycopodium complanatum . Lyconadin C ( 1 ) is a new C 16 N 2 -type Lycopodium alkaloid possessing unique fused-tetracyclic ring system consisting of a cycloheptene ring fused to a decahydroquinoline and pyridone rings. Lyconadin F ( 2 ) possesses a primary amide moiety in its molecular, which is the first example of Lycopodium alkaloids. Biogenetically, lyconadins C ( 1 ) and F ( 2 ) might be related to lyconadins A ( 4 ) and B ( 5 ). The structures and relative stereochemistry of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute stereochemistry of 2 was elucidated by chemical correlations with lyconadin B ( 5 ) through hemiaminal form of lyconadin F ( 3 ).

Two new bromotyrosine alkaloids, ceratinadins D (1) and E (2), were isolated from an Okinawan marine sponge Pseudoceratina sp. as well as a known bromotyrosine alkaloid, psammaplysin F (3). The gross structures of 1 and 2 were elucidated on the basis of spectroscopic data. The absolute configurations of 1 and 2 were assigned by comparison of the NMR and ECD data with those of a known related bromotyrosine alkaloid, psammaplysin A (4). Ceratinadins D (1) and E (2) are new bromotyrosine alkaloids possessing an 8,10-dibromo-9-methoxy-1,6-dioxa-2-azaspiro[4.6]undeca-2,7,9-trien-4-ol unit with two or three 11-N-methylmoloka&rsquo, iamine units connected by carbonyl groups, respectively. Ceratinadin D (1) exhibited antimalarial activities against a drug-resistant and a drug-sensitive strains of Plasmodium falciparum (K1 and FCR3 strains, respectively).

Three new tricyclic terpenoids, yezo’otogirins A–C ( 1 – 3 ), were isolated from aerial parts of Hypericum yezoense. The structures including absolute stereochemistry of 1 – 3 were elucidated from the spectroscopic data and conformational analysis.

Two new Lycopodium alkaloids, lycopladines F (1) and G (2), have been isolated from the club moss Lycopodium complanatum, and the structures and relative stereochemistries of 1 and 2 were elucidated on the basis of spectroscopic data. Lycopladine F (1) is a rare C16N2-type Lycopodium alkaloid possessing an amino acid residue (C4N).