Daphniphyllum alkaloids are a structually diverse group of natural products with unique fused-heterocyclic skeletons, which are elaborated by trees of the genus Daphniphyllum (Daphniphyllaceae). These unusual ring systems have been challenging targets for total synthesis as well as biosynthetic studies. We have isolated novel types of Daphniphyllum alkaloids from Daphniphyllum macropodum, D. humile, D. teijsmanni, and D. glaucescense. In our continuing search for structually unique and biogenetically interesting new alkaloids, calyciphyllines C-G (1-5) have been isolated from D. calycinum, and their structures and relative stereochemistry were elucidated on the basis of spectroscopic data. Calyciphylline C (1) is a novel Daphniphyllum alkaloid with an unprecedented fused-hexacyclic skeleton having an azetidine ring. Calyciphyllines D (2) and F (4) are novel alkaloids containing a unique fused-pentacyclic skeleton with a 8-azatricyclo[4.2.1.0.^<4,8>]nonane ring system. Calyciphylline E (3) is a new alkaloid with a fused-heptacyclic ring system, while calyciphylline G (5) is a novel alkaloid possessing an unprecedented fused-hexacyclic skeleton containg 5-azatricyclo[6.2.1.0]undecane ring system. Effects of these alkaloids on neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells were examined by a semiquantitative RT-PCR method to find that the mRNA expressions for NGF were enhanced.

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Diffusion-ordered NMR spectroscopy (DOSY) is a versatile and powerful NMR technique and a noninvasive analytical method for mixture analysis that does not require prior physical separation of the analysis. In our search for new metabolites from natural resources, DOSY was applied for constituent analysis of crude bromopyrrole fractions separated from an Okinawan marine sponge Agelas sp. (SS-1056) so that two new bromopyrrole alkaloids, agesamides A (1) and B (2), have been isolated. The structures and relative stereochemistry of 1 and 2 were elucidated fromspectroscopic data. Furthermore, two new bromopyrrole alkaloids, nagelamides J (3) and K (4), have been isolated from another Okinawan marine sponge Agelas sp. (SS-1077), and the structures and relative stereochemistries were elucidated from spectroscopic data. Nagelamide J (3) is the first bromopyrrole alkaloid possessing a cyclopentane ring fused to an amino imidazole ring and nagelamide K (4) is a unique dimeric bromopyrrole alkaloid containing an ester linkage. Nagelamide J (3) exhibited antimicrobial activity against Staphylococcus aureus (MIC, 8.35μg/ml) and antifungal activity against Cryptococcus neoformans (MIC, 16.7μg/ml), while nagelamide K (4) exhibited antimicrobial activity against Micrococcus luteus (MIC, 16.7μg/ml).

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Sesquiterpenoid quinines and hydroquinones are representative marine natural products with unique structures and interesting biological activities. In our continuous search for bioactive compounds having unique structures from Okinawan marine sponges, we have isolated new sesquiterpenoid quinones, nakijiquinones E〜I (1〜5) and metachromins L-Q (6〜11), from three collections of Okinawan marine sponges. The structures of 1〜5 were elucidated on the basis of 2D NMR data, while those of 6〜11 were established by chemical correlations. Furthermore, biological activities for 1〜11 and synthetic metachromin analogs 15〜26 were examined. Nakijiquinones E (1) and F (2) were the first dimeric sesquiterpenoid quinones possessing a 3-aminobenzoate moiety, while nakijiquinones G〜I (3〜5) were new sesquiterpenoid quinones having a histamine unit, an agmatine unit, and 3-(methylsulfinyl) propan-1-amino group, respectively. Metachromins L〜Q (6〜11) were new sesquiterpenoid quinones containing a different amino group derived from amino acids. Most of nakijiquinones E〜I (1〜5), metachromins L〜Q (6〜11), and synthetic metachromin analogs (15〜26) showed modest cytotoxicity against murine leukaemia P388 and L1210 cells, and human epidermoid carcinoma KB cells (IC_<50>, 1〜10μg/mL). Inhibitory activity of 15〜26 against several tyrosine kinases are currently investigated.

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Bromopyrrole alkaloids are known to be one of the most common metabolites contained in marine sponges. During our search for bioactive substances from marine organisms, we have isolated bromopyrrole alkaloids with unique cyclic skeletons from sponges of the genus Agelas or Hymeniacidon. Recently, three new bromopyrrole alkaloids, nagelamides K, M, and N (1-3), have been isolated from an Okinawan marine sponge Agelas sp. (SS-1134). The structures and relative stereochemistry of 1〜3 were elucidated on the basis of spectroscopic data. Nagelamide K (1) is a new dimeric bromopyrrole alkaloid possessing a rare piperidinoiminoimidazolone ring with an aminoimidazole ring and a taurine unit. Nagelamide M (2) is a novel bromopyrrole alkaloid possessing an 2-amino-octahydropyrrolo[2,3-d]imidazol ring with a taurine unit, while nagelamide N (3) is a new bromopyrrole alkaloid consisting of an 2-amino-tetrahydroimidazol-4-one ring with a taurine unit and 3-(dibromopyrrole-2-carboxamido)propanoic acid moiety. Nagelamides K, M, and N (1-3) showed modest antimicrobial activity.

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Amphezonol A (1), a novel polyhydroxyl compound, was isolated from a marine dinoflagellate Amphidinium sp. (Y-72), and the structure was elucidated on the basis of 2D NMR data including HSQC-TOCSY and INADEQUATE spectra (920MHz) using the ^<13>C-enriched sample. Amphezonol A (1), C_<62>H_<114>O_<24>, was the first member of a new class of polyketide natural products consisting of a C_<60>-linear aliphatic chain with twenty-one hydroxyl groups, and two tetrahydropyran and a tetrahydrofuran rings. Cloning of polyketide synthase (PKS) gene from a dinoflagellate Amphidinium sp. was attempted and PKS gene fragments were obtained by PCR amplification from degenerated primer sets designed on the basis of the conserved amino acid sequences in known type I PKSs. The PCR analysis, using primer sets designed from these PKS gene fragments, revealed that these DNA sequences exist only in the dinoflagellates producing polyketides.

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Complanadine A was isolated from club moss Lycopodium complanatum by J. Kobayashi group. Its structure was characterized by a dimeric motif of lycodine-type C_<16>N_2 skeleton. So far complanadines B, D and E, which consist of the lycodine skeleton, were also reported as dimeric Lycopodium alkaloids. Interestingly complanadines A, B, D, and E induced mRNA expression level for nerve growing factor (NGF) in 1321N1 human astrocytoma cells. Because of the intriguing biological activity and complex structure, we started a synthetic program toward complanadines. The total syntheses of lycodine (5), complanadines A (1) and B (2) are described. For synthesis of lycodine, notable transformations include diastereoselective Diels-Alder and Mizoroki-Heck reactions to access a bicycle[3.3.1]nonane core in the lycodine skeleton. In the total syntheses of complanadines, C-H functionalization of pyridine N-oxide is a key feature for construction of the dimeric structure. Further synthetic studies toward natural enantiomer of complanadines as well as biological studies are now in progress, the results will be discussed in the presentation.

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Club moss (Lycopodiaceae) is known to be a rich source of Lycopodium alkaloids possessing unique heterocyclic ring systems such as C_<16>N, C_<16>N_2, and C_<27>N_3, which have attracted great interest from biogenetic, synthetic, and biological points of view. In our continuing efforts to find new Lycopodium alkaloids, lycopladine H (1), lyconadins C-E (2-4), lycoplaidines F-G (5-6), and complanadine E (7) were isolated from Lycopodium domplanatum. The structures for 1-7 were elucidated on the basis of spectral data. Lycopladine H (1) is an unprecedented C_<16>N-type Lycopodium alkaloid possessing a novel fused-tetracyclic ring system consisting of an azocane ring fused to a [2,2,2,]-bicyclooctane ring and 3-piperidinone ring, Lyconadin C (2) is a new tetracyclic Lycopodium alkaloid consisting of cyclohexane, cycloheptane, pyperidine, and pyridone rings. Lyconadin C (2) might be a biosynthetic precursor of lyconadin A. Lyconadins D (3) and E (4) are the first fastigiatine-type alkaloids isolated from Lycopodium complanatum. Lycopladine F (5) is a rare C_<16>N_2-type Lycopodium alkaloid possessing an amino acid residue (C_4N), while lycopladine G (6) is a 17-keto and 20-methylester form of lycopladine F (5). Complanadine E (7) is a new dimeric Lycopodium alkaloid consisting of two C_<16>N_2-type skeletons, which corresponds to 1,2,3,4,5,N-1-hexahydro complanadine A.

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Club moss (Lycopodiaceae) is known to be a rich source of Lycopodium alkaloids posessing unique heterocyclic ring systems such as C_<16>N, C_<16>N_2, and C_<27>N_3, which have attracted great interest from biogenetic, synthetic, and biological points of view. In our continuing efforts to find new Lycopodium alkaloids, lycopladines A-D (1-4), lyconadin B (5), and complanadines C (6), D (7) were isolated from the club moss Lycopodium complanatum. The structures for 1-7 were elucidated on the basis of spectral data. Lycopladine A (1) obtained as colorless amourphous solid, showed the pseudomolecular ion peak at m/z 260 (M+H)^+ in the ESIMS, and the molecular formula, C_<16>H_<21>NO_2, was established by HRESIMS [m/z 260.1653, (M+H)^+, △+0.2mmu]. The gross structure of 1 was elucidated on the basis of 2D NMR data. The relative stereochemistry of 1 was elucidated from NOESY data. Lycopladine A (1) possesses an unprecedented skeleton different from known C_<16>N-type Lycopodium alkaloids. The stuructures of lycopladines B-D (2-4) were elucidated on the basis of spectroscopic data and modified Mosher's method. Lycopladine B (2) was 5-hydroxyl, △_<8,15>, △_<13,14>, and 17-methyl ester form of fawcettidane skeleton. Lycopladine C (3) was assigned as 5-O-acetyl form of 2. Lycopladine D (4) had fawcettidane skeleton with hydroxyl group at C-5 and lactone ring (C-13〜C-16). The absolute stereochemistry of 2 and 4 were elucidated by modified Mosher's method. The absolute configuration at C-5 of 2 and 4 were assigned to be S and R, respectively. Lyconadin B (5) was assigned as dihydro form of lyconadin A. Complanadines C (6) and D (7) were obtained as colorless amorphous solids. The structures and relative stereochmistry of 6 and 7 were elucidated on the basis of spectroscopic data. Complanadine C (6) was assigned as the dimer of 9-keto, △_<10,11> form of lycopodine and △_<9,10> form of lycopodine. The dimer of lycopodane skeleton has not been reported previously. Complanadine D (7) was tetrahydro form of complanadine A. A plausible biogenetic path of lyconadin A (8) was proposed on the basis of structure of lycopladine A (1). Biogenetically, lyconadines A (8) and B (5) might be derived from L-lysine via pelletierine, phlegmarane skeleton, and an intermediate X from which lycopladine A (1) might be provided. Effects of lycopladines A-D (1-4), and lyconadins A (8) and B (5) on neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells were examined. The mRNA expressions of NGF in 1321N1 cells were examined by a semiquantitative RT-PCR method. The mRNA expressions for NGF were enhanced by lyconadins A (8) and B (5).

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Amphidinolide C (1) is a unique 25-membered macrolide isolated from a marine dinoflagellate Amphidinium sp. (strain Y-5). The gross structure of 1 has been elucidated by 2D-NMR data, whereas the stereochemistry remains undefined. During our search for bioactive metabolites from marine dinoflagellates, relatively large amounts of 1 have been recently isolated from two strains (Y-56 and Y-71) of the genus Amphidinium, which allowed us to investigate the stereochemistry of 1 Absolute configurations at C-12, C-13, C-20, C-23, C-24, and C-29 of amphidinolide C (1) were assigned by combination of NMR analyses including J-based configuration analysis and Mosher's method, while absolute configurations at C-7 and C-8 of 1 were assigned by application of Mosher's method for erythro glycol and comparison of ^1H-NMR data of natural specimen with those of synthetic C-1-C-10 segments. Absolute configurations at C-3, C-4, C-6, and C-16 of 1 were elucidated by comparison of NMR data of degradation products of 1 with synthetic C-1-C-7 and C-16-C-18 segments. On the other hand, five new 19-membered macrolides amphidinolides T1-T5 (2-6) have been isolated from the Y-56 and Y-71 strains of the genus Amphdinium. The gross structures were elucidated by 2D-NMR analyses. Absolute configurations at C-2, C-13, C-14, and C-18 of amphidinolide T1 (2) were assigned on the basis of NMR data of the MTPA esters of 2 and those of degradation products of 2, while absolute configurations at C-7, C-8, and C-10 of 2 were elucidated by comparison of ^1H-NMR data of C-1-C-12 segment with those of synthetic model compounds for tetrahydrofuran portion. The absolute stereochemistry of amphidinolides T2-T5 (3-6) were also elucidated by similar methods. The stereostructure of 2 was also confirmed by a single crystal X-ray diffraction analysis.

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  In our continuing search for structurally and biologically interesting metabolites from marine organisms and plants, we investigated the constituents of Okinawan marine sponges and Hypericum plants, resulting in the isolation of several new and unique natural products. Their structures were elucidated on the basis of spectroscopic analyses and chemical conversions. Novel bromopyrrole alkaloids, nagelamides X-Z, were isolated from a sponge Agelas sp. Heteroaromatic alkaloids, hyrtimomines A and B, were isolated from a sponge Hyrtios sp. together with bisindole alkaloids, hyrtimomines C-E. An oxylipin with a trimeric structure, manzamenone O, was obtained from a sponge Plakortis sp. Dimeric eudesmane sesquiterpenes connected through various linker moieties, halichonadins K-L, were isolated from a sponge Halichondria sp., and isomalabaricane triterpenes, stelliferins J-N, were obtained from a sponge Rhabdastrella sp. The investigation for the extracts of Hypericum plants gave new meroterpenes, acylphloroglucinols, and xanthones. Biyoulactones A-E are meroterpenoids from the roots of Hypericum chinense. Acylphloroglucinols, chipericumines A-D, and highly prenylated xanthones, biyouxanthones A-D, were also isolated from the same origin. Tricyclic meroterpenes, yezo'otogirins A-C, and liner meroterpenos, yojironins A and B, were isolated from Hypericum yezoense and Hypericum yojiroanum, respectively.

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Marine dinoflagellates of the genus Amphidinium have been recognized as a rich source of novel bioactive substances with unique structures. We previously isolated a series of cytotoxic macrolides, designated amphidinolides, possessing unique structural features from several strains of the dinoflagellates Amphidinium sp., among which the strain Y-5 was the richest source of the amphidinolides. Further search for metabolites from the strain Y-5, which was a symbiont of Okinawan marine acoel flatworm Amphiscolops sp., resulted in the isolation of two novel polyhydoroxyl compounds, colopsinols A (1) and B (2), belonging to a new class of polyketide metabolites. The structures of 1 and 2 were elucidated on the basis of extensive NMR techniques including a newly developed 2D NMR experiments such as CH_2-selected editing HSQC (E-HSQC) as well as FABMS/MS data. Colopsinols A (1) and B (2) are new class of polyketide natural products consisting of C_<56> and C_<53>-liner carbon chains, respectively, possessing a gentiobioside (β-D-glucopyranosyl-(1-6)-β-D-glucopyranoside) moiety and a sulfate ester. From this strain (Y-5), 13 cytotoxic macrolides, amphidinolides A-D, J, K, and M-S, have been isolated so far. Biosynthetically it is interesting that quite different type of polyketides such as colopsinols and amphidinolides are produced from the same dinoflagellate. Colopsinol A (1) showed inhibitory activity against DNA polymerase α and β with IC_<50> values of 13 and 7μM, respectively.

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