Structure-activity relationship in advanced glycation end products formation inhibitory activity of phlorotannins.

The structure and inhibitory activity of advanced glycation end products (AGEs) formation were studied using six model compounds and seven phlorotannins isolated from brown alga Ecklonia stolonifera. As a result, it was inferred that AGEs formation inhibitory activity was stronger when electron-rich groups were present because of the addition of many oxygen atoms to the phlorotannins.

Halichonadins K and L, new dimeric sesquiterpenoids from a sponge Halichondria sp.

Two new structurally unique dimeric sesquiterpenoids, halichonadins K (1) and L (2), were isolated from an Okinawan marine sponge Halichondria sp. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis including a single crystal X-ray diffraction analysis and chemical conversion. Halichonadins K (1) and L (2) are homodimers of the eudesmane sesquiterpene linked with a piperidine ring through amide bonds. Halichonadin K (1) showed moderate cytotoxicity against KB cells.

Lyconadins D and E, and complanadine E, new Lycopodium alkaloids from Lycopodium complanatum.

Three new Lycopodium alkaloids, lyconadins D (1) and E (2), and complanadine E (3), were isolated from the club moss Lycopodium complanatum. Lyconadin D (1) was the first example of fastigiatine-type alkaloid isolated from Lycopodium complanatum. The structures and relative stereochemistry of 1-3 were elucidated on the basis of spectroscopic data. Complanadine E (3) enhanced mRNA expression for NGF.

Eudistomidin G, a new beta-carboline alkaloid from the Okinawan marine tunicate Eudistoma glaucus and structure revision of eudistomidin B.

A new beta-carboline alkaloid, eudistomidin G (1), has been isolated from the Okinawan marine tunicate Eudistoma glaucus, and the structure was elucidated from spectroscopic data. Furthermore, the structure of eudistomidin B (2), which has been isolated from the same tunicate, was revised from 2a to 2b by detailed analyses of spectroscopic data. Asymmetric synthesis of the revised structure (2b) of eudistomidin B (2) and its (1S,10S)-diastereomer (2c) has been accomplished with the Noyori catalytic asymmetric hydrogen-transfer reaction. The absolute configuration of eudistomidin B (2) was confirmed to be 2b possessing (1R,10S)-configuration, from comparison of the (1)H NMR data, CD spectra, [alpha](D) values, and HPLC analysis of 2b, 2c, and natural eudistomidin B.

Total synthesis of amphidinolide Q.

Asymmetric synthesis of amphidinolide Q, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished with Julia coupling, Myers alkylation, and Yamaguchi lactonization. The absolute configuration of amphidinolide Q was confirmed to be 1 from comparison of the NMR data and [alpha](D) values of synthetic and natural amphidinolide Q.

Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors.

Four bis-N-n-propyl analogues (3-6) in the uracil ring of two hybrid molecules (1 and 2) of caffeine and eudistomin D, a beta-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A(1), A(2A), and A(3) were examined. All the compounds (3-6) showed better potency as adenosine receptor ligands than caffeine. Bis-N-n-propylation (3 and 4, respectively) of the uracil ring in 1 and 2 resulted in higher affinity for A(1) and A(2A) adenosine receptors. Furthermore, it was found that a compound (5) possessing a n-propyloxy group at C-7 in compound 3 with a nitrogen at the beta-position of the pyridine ring (beta-N type) enhanced remarkably affinity for adenosine receptor A(3) subtype, while n-propyloxy substitution (compound 6) at C-5 in compound 4 with a nitrogen at the delta-position of the pyridine ring (delta-N type) reduced affinity for all the adenosine receptor, A(1), A(2A), and A(3). Among all the compounds (1-6) examined, compound 5 showed the most potent affinity for adenosine receptor A(3) subtype (K(i) value, 0.00382 microM).

Halichonadin F and the Cu(I) complex of halichonadin C from the sponge Halichondria sp.

A new sesquiterpenoid with an aromadendrane skeleton, halichonadin F (1), and the Cu(I) complex of haliconadin C (2) were isolated from a marine sponge Halichondria sp., and the structures and relative stereochemistries of 1 and the complex of 2 were elucidated on the basis of spectroscopic data and chemical methods.

Petiolins A-C, phloroglucinol derivatives from Hypericum pseudopetiolatum var. kiusianum.

Two new phloroglucinol derivatives possessing chromane skeleton, petiolins A (1) and B (2), and a new phloroglucinol derivative containing a dihydrofuran ring, petiolin C (3), were isolated from aerial parts of Hypericum pseudopetiolatum var. kiusianum. The gross structures of 1-3 were elucidated by spectroscopic data, and the relative stereochemistry of 3 was elucidated by NOESY data. Petiolins A-C (1-3) showed modest cytotoxicity, while petiolin C (3) exhibited antifungal activity.

Brianodins A-D, briarane-type diterpenoids from soft coral Pachyclavularia sp.

Four new briarane-type diterpenoids, brianodins A-D ( 1- 4), were isolated from a soft coral, Pachyclavularia sp., and the structures and relative stereochemistry of 1- 4 were elucidated on the basis of spectroscopic data. The absolute configurations of 3 and 4 were assigned by the MTPA method. Brianodin A ( 1) showed a modest cytotoxicity.

Synthesis of eudistomin D analogues and its effects on adenosine receptors.

Six analogues (1-6) of eudistomin D, a beta-carboline alkaloid from a marine tunicate Eudistoma olivaceum, were synthesized, and their affinity and selectivity for adenosine receptors A(1), A(2A), and A(3) were examined. All the synthetic compounds 1-6 did not show affinity to the adenosine A(1) receptor. Delta-carboline 3 exhibited the most potent affinity to the adenosine receptor A(3) among compounds 1-6. Delta-carbolines 3 and 4 showed better affinity than the corresponding beta-carbolines 1 and 2, respectively, while N-methylation (2, 4, and 6, respectively) of the pyrrole ring in 1, 3, and 5 resulted in the reduced affinity to the adenosine A(3) receptor. On the other hand, an eudistomin D derivative, BED, exhibited modest affinity to all the receptors A(1), A(2A), and A(3) but no selectivity.

Halichonadin E, a dimeric sesquiterpenoid from the sponge Halichondria sp.

A new dimeric sesquiterpenoid with eudesmane and aromadendrane skeletons linked through a urea fragment, halichonadin E ( 1), was isolated from a marine sponge Halichondria sp., and the gross structure and relative configuration of 1 were elucidated on the basis of spectroscopic data. Halichonadin E ( 1) is the first hetero-dimeric sesquiterpenoid with eudesmane and aromadendrane skeletons linked through a urea fragment.

Securinega alkaloids from the wood of Securinega suffruticosa var. amamiensis.

Three new Securinega alkaloids, secu'amamines B-D ( 1- 3), were isolated from the wood of the Japanese medicinal plant Securinega suffruticosa var. amamiensis, together with five known analogues ( 4, 6- 9). The structures 1- 3 were elucidated by spectroscopic methods including 2D NMR, and all eight compounds were evaluated for cytotoxicity against two cancer cell lines.

Synthesis of penaresidin derivatives and its biological activity.

A series of stereoisomers for the azetidine ring of penaresidin B was synthesized and their cytotoxic and antimicrobial activities were evaluated. Among six synthetic isomers 1-6, isomers 4 and 5 showed relatively potent cytotoxic activity against A549 (lung) and HT29 (colon) tumor cells as well as antibacterial activity.

Indole diterpene synthetic studies. Total synthesis of (+)-nodulisporic acid F and construction of the heptacyclic cores of (+)-nodulisporic acids A and B and (-)-nodulisporic acid D.

A first-generation strategy for construction of (+)-nodulisporic acids A (1) and B (2) is described. The strategy entails union of the eastern and western hemisphere subtargets via the indole synthesis protocol developed in our laboratory. Subsequent elaboration of rings E and F, however, revealed the considerable acid instability of the C(24) hydroxyl, thereby preventing further advancement. Nonetheless, preparation of the heptacyclic core of (+)-nodulisporic acids A and B, the total synthesis of (+)-nodulisporic acid F, the simplest member of the nodulisporic acid family, and elaboration of the heptacyclic core of (-)-nodulisporic acid D were achieved.

Synthesis of hybrid molecules of caffeine and eudistomin D and its effects on adenosine receptors.

Four hybrid molecules (1 and 12-14) of caffeine and eudistomin D, a beta-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A(1), A(2A), and A(3) were examined. It was found that all the compounds showed better potency as adenosine receptor ligands as compared with caffeine. Among them, a compound (13) possessing a nitrogen at the delta-position of the pyridine ring (delta-N type) showed the most potent affinity for adenosine receptor A(3) subtype, while N-methylation (14) of a pyrrole ring in 13 significantly lowered the potency as adenosine receptor ligands. Compounds (1 and 12) having a nitrogen at the beta-position of the pyridine ring (beta-N type) showed lower affinity than the corresponding delta-N type compounds (13 and 14), while compounds (10, 11, and 17) lacking a pyrrole ring between the pyridine and pyrimidine rings exhibited almost no affinity to the adenosine receptor subtypes examined.

Paratunamides A-D, oxindole alkaloids from Cinnamodendron axillare.

Four new oxindole alkaloids, paratunamides A-D (1-4), containing a secologanin unit, were isolated from the bark of Cinnamodendron axillare, and their structures and relative configurations were elucidated by spectroscopic data. The absolute configuration at C-7 in 1-4 was assigned as S, S, R, and S, respectively, on the basis of the CD spectra.

Absolute stereochemistry and antitumor activity of iejimalides.

The absolute configurations at five chiral centers, except for C-32(S) reported previously, in iejimalides A, C, and D, potent cytotoxic 24-membered macrolides isolated from a tunicate Eudistoma cf. rigida, were assigned as 4R, 9S, 17S, 22S, and 23S on the basis of detailed analysis of NMR data and chemical means. Furthermore, the structures proposed for iejimalides A, C, and D were revised to their 13Z-isomers. Iejimalides A-D (1-4) exhibited antitumor activity in vivo.

Absolute stereochemistry of citrinadins a and B from marine-derived fungus.

[Structure: see text]. Citrinadin A (2) is a pentacyclic indolinone alkaloid isolated from the cultured broth of a fungus, Penicillium citrinum, which was separated from a marine red alga. The absolute stereochemistry of the pentacyclic core in 2 and its new congener, citrinadin B (1), was elucidated by analysis of the ROESY spectrum for the chlorohydrin derivative (3) of 1 as well as comparison of the electronic circular dichroism (ECD) spectra for 1 and 2 with those of known spirooxiindole alkaloids. On the other hand, the absolute configuration at C-21 bearing an epoxide ring was assigned as S by comparison of the vibrational circular dichroism (VCD) spectra of 1 with those of model compounds 2S- and 2R-2,3-epoxy-3,3-dimethyl-1-phenylpropan-1-one (4a and 4b, respectively).

Brosimacutins J-M, four new flavonoids from Brosimum acutifolium and their cytotoxic activity.

Four new flavonoids, brosimacutins J-M (1 - 4), were isolated from the bark of Brosimum acutifolium Huber together with a known flavan, brosimine A (5). The structures of compounds 1-4 were elucidated by spectroscopic means. 27 constituents of this plant including compounds 1-5 were evaluated for their cytotoxic activity against murine leukemia P388 cells. Although no compounds tested had any reversal effect on vincristine resistance, brocimacutins J-M (1-4) were cytotoxic to vincristine-resistant P388 cells (IC50 4.4 - 19 microg/mL).

Gesashidine A, a beta-carboline alkaloid with an imidazole ring from a Thorectidae sponge.

A new beta-carboline alkaloid with an imidazole ring, gesashidine A (1), has been isolated from an Okinawan marine sponge of the family Thorectidae (SS-1035), and the structure was elucidated from the spectroscopic data.