Naturally occurring biflavonoids with amyloid ß aggregation inhibitory activity for development of anti-Alzheimer agents.

Amyloid ß (Aß) aggregation plays an essential role in promoting the progression of Alzheimer's disease (AD). Therefore, the inhibition of Aß aggregation is a potential therapeutic approach for AD. Herein, twenty-seven biflavonoids with different inter-flavonyl linkages and methoxy substitution patterns were isolated from several plants, and their Aß40 aggregation inhibitory activity was evaluated by the thioflavin-T fluorescence assay. Amentoflavone (1) and its monomethoxy derivatives (2, 3, and 5) exhibited the most potent inhibitory activity, with IC50 values of approximately 5 µM. It was clarified that increasing the number of methoxy substituents on the biflavonoid structures attenuated the inhibitory activity. Moreover, the linkage and the methoxy substitution pattern had a marked influence on the inhibitory activity. Our investigation strongly supports that biflavonoids can be considered a new type of anti-Alzheimer agents that may be successfully developed for AD patients.

Inhibitory activities of biflavonoids against amyloid-ß peptide 42 cytotoxicity in PC-12 cells.

A major hallmark of Alzheimer's disease is the cerebral accumulation and resulting cytotoxicity of amyloid-ß peptides, particularly Aß42. In this study, we used an MTT assay to investigate the inhibitory activity of biflavonoids 1-22 against Aß42 cytotoxicity in PC-12 cell cultures. Cytoprotective effects were observed for the following amentoflavone type biflavonoids: podocarpusflavone B 8, isoginkgetin 10, sciadopitysin 13, and kayaflavone 15. These biflavonoids exhibited strong activity in tested compounds, with EC50 values of 5.18, 10.77, 9.84, and 5.29 µM, respectively. Cell viability tests of PC-12 cells revealed that biflavonoids 13 and 15 had stronger inhibitory activities than apigenin 23 and (-)-epigallocatechin gallate 24.

Epoxyquinophomopsins A and B from endophytic fungus Phomopsis sp. and their activity against tyrosine kinase.

Two new quinone derivatives, epoxyquinophomopsins A (1) and B (2), were purified from the EtOAc extract of endophytic fungus Phomopsis sp isolated from Morus cathayana. The structures of both compounds were determined based on 1D and 2D NMR and mass spectral data, as well as by x-ray diffraction analysis for 1. Compounds 1 and 2 were screened against eight receptor- (RTKs) and eight non-receptor tyrosine kinases (nRTKs). Both compounds showed strong inhibitory properties against Bruton's Tyrosine Kinase (nRTK) with their kinase activity were 19% and 20%, respectively. Only compound 1 that showed strong inhibitory properties against RTKs EGFR and HER-4 with its kinase activity were 16 and 15%, respectively. Thus, both compounds have potential as tyrosine kinase inhibitors.

beta-Secretase (BACE-1) inhibitory effect of biflavonoids.

Here, we describe amentoflavone-type biflavonoids, which were isolated from natural sources and were found to inhibit beta-secretase (BACE-1). The structure-activity relationship was studied, and compounds 1-8, 10, 17, and 18 showed BACE-1 inhibitory activity. Among these compounds, 2,3-dihydroamentoflavone 17 and 2,3-dihydro-6-methylginkgetin 18 exhibited potent inhibitory effects with IC(50) values of 0.75 and 0.35 microM, respectively.

An oxepinoflavone from Artocarpus elasticus with cytotoxic activity against P-388 cells.

A new oxepinoflavone, artoindonesianin E1 (1), was isolated from the wood of Artocarpus elasticus, along with four known prenylated flavones: artocarpin (2), cycloartocarpin (3), cudraflavones A (4) and C (5). The structure of the new compound was identified by spectroscopic methods. Upon cytotoxic evaluation against murine leukemia P-388 cells, the new compound showed IC(50) 5.0 microg/mL.

Macagigantin, a farnesylated flavonol from Macaranga gigantea.

A new farnesylated flavonol derivative, macagigantin (1), together with two known flavonoids, glyasperin A (2) and apigenin (3), had been isolated from the acetone extract of the leaves of Macaranga gigantea. The structure of the new compound was elucidated as 6-farnesylkaempferol based on its spectroscopic data, including UV, IR, 1D and 2D NMR, and HR-EI-MS spectra. Compounds 1-3 were evaluated for their cytotoxic properties against P-388 cells, their IC(50) values being 11.3, 6.0, and 5.1 microM, respectively.

Phenolic constituents from the wood of Morus australis with cytotoxic activity.

A new methylated flavonol, 5,7,2',4'-tetrahydroxy-3-methoxyflavone (1), had been isolated from the methanol extract of the wood of Morus australis, along with nine known compounds, kuwanon C (2), morusin (3), morachalcone A (4), oxyresveratrol (5), 4'-(2-methyl-2-buten-4-yl)oxyresveratrol (6), moracins M (7) and C (8), alboctalol (9), and macrourin B (10). The structures of these compounds were determined based on spectral evidence, including UV, IR, NMR, and mass spectra. Cytotoxic properties of compounds 1-10 were evaluated against murine leukemia P-388 cells. The prenylated stilbene 6 and 2-arylbenzofuran 8, and morusin (3) were found to have strong cytotoxic effects with IC50 values of 6.9, 8.7, and 10.1 microM, respectively.

Flavonoid and stilbene derivatives from Macaranga trichocarpa.

A new farnesylated flavonol (4'-O-methylmacagigantin) and a new geranylated stilbene (macatrichocarpin H), together with eight known phenolic compounds, have been isolated from the leaves of Macaranga trichocarpa. Structures of these compounds were determined based on NMR and mass spectrroscopic data. Cytotoxic properties of the isolated compounds were tested against P-388 cells showing that mactrichocarpin G was the most active compound with IC50 was 3.5µM.

Cytotoxic resveratrol oligomers from the tree bark of Dipterocarpus hasseltii.

A new resveratrol tetramer, named diptoindonesin E, was isolated from the acetone extract of the tree bark of Dipterocarpus hasseltii, together with five known resveratrol oligomers (-)-epsilon-viniferin, laevifonol, (-)-alpha-viniferin, vaticanol B, (-)-hopeaphenol, and a coumarin, scopoletin. The structures of these compounds were determined from spectroscopic evidence. Cytotoxicity test of the isolated compounds showed that hopeaphenol strongly inhibited murine leukemia P-388 cells.

Cytotoxic chalcones and flavanones from the tree bark of Cryptocarya costata.

A new flavanone, 7-hydroxy-5,6-dimethoxyflavanone (1), together with three other flavonoids, didymocarpin (2), 2',4'-dihydroxy-5',6'-dimethoxychalcone (3), and isodidymocarpin (4), had been isolated from the methanol extract of the tree bark of Cryptocarya costata. The structures of these compounds were determined based on spectral evidence, including UV, IR, 1-D and 2-D NMR, and mass spectra. Cytotoxic properties of compounds 1-4 were evaluated against murine leukemia P-388 cells. The chalcones 3 and 4 were found to have substantial cytotoxicity with IC50 of 5.7 and 11.1 microM, respectively.

Cytotoxic properties of oligostilbenoids from the tree barks of Hopea dryobalanoides.

A new modified stilbene dimer, diptoindonesin D (1), was isolated from the acetone extract of the tree bark of Hopea dryobalanoides, together with seven known compounds, parviflorol (2), (-)-balanocarpol (3), heimiol A (4), hopeafuran (5), (+)-alpha-viniferin (6), vaticanol B (7) and (-)-hopeaphenol (8). Cytotoxic properties of compounds 1-8 were evaluated against murine leukemia P-388 cells. Compound 8 was found to be the most active with IC50 of 5.7 microM.

Artoindonesianins Q-T, four isoprenylated flavones from Artocarpus champeden Spreng. (Moraceae).

Four isoprenylated flavones, artoindonesianins Q-T, were isolated from the heartwood of Artocarpus champeden Roxb. The structures of these compounds were elucidated on the basis of their spectroscopic data.

Artoindonesianins X and Y, two isoprenylated 2-arylbenzofurans, from Artocarpus fretessi (Moraceae).

Two isoprenylated 2-arylbenzofurans, artoindonesianins X and Y (1-2), together with seven known flavonoids, have been isolated from the roots and tree bark of Artocarpus fretessi. Their structures were established on the basis of spectral analysis. Compounds 1 and 2 showed moderate activity against the brine shrimp Artemia salina.

Two oligostilbenes, cis- and trans-diptoindonesin B, from Dryobalanops oblongifolia.

Two oligostilbenes, cis- and trans-diptoindonesin B, have been isolated from the tree bark of Dryobalanops oblongifolia (Dipterocarpaceae). The structures and relative configurations of both compounds were determined on the basis of spectroscopic evidence, including 2D-NMR spectroscopic analysis.

Two new cytotoxic isoprenylated flavones, artoindonesianins U and V, from the heartwood of Artocarpus champeden.

Two new isoprenylated flavones, artoindonesianins U (1) and V (2), have been isolated from the heartwood of Artocarpus champeden together with three known isoprenylated flavonoids, 5'-hydroxycudraflavone A, cyclocommunin and artonin B. The structures of the new flavones were elucidated on the basis of spectroscopic evidence. Both compounds 1 and 2 showed strong cytotoxic activity against P-388 cell lines.

Diptoindonesin A, a new C-glucoside of epsilon-viniferin from Shorea seminis (Dipterocarpaceae).

A new C-glucoside of epsilon-viniferin, named diptoindonesin A (1), was isolated from the ethyl acetate extract of the tree bark of Shorea seminis, together with the known stilbene oligomers (-)-ampelopsin A (2), (-)-alpha-viniferin (3), and (-)-hopeaphenol (4). The structure of 1 was determined from spectroscopic evidence.

Dihydroflavonol and flavonol derivatives from Macaranga recurvata.

Two new dihydroflavonol derivatives, macarecurvatins A and B, have been isolated from the leaves of Macaranga recurvata (Euphorbiaceaae), along with the known compounds diisoprenylaromadendrin, glyasperin A and broussoflavonol F. The structures of the new compounds were determined on the basis of spectroscopic evidence. Upon cytotoxic evaluation against P-388 cells, macarecurvatin B showed strong activity with an IC50 of 0.83 microM.

Geranylated flavonols from Macaranga rhizinoides.

Two geranylated and methylated flavonol derivatives, macarhizinoidins A (1) and B (2), along with a known phenolic compound methyl 4-isoprenyloxycinnamate (3), have been isolated from the methanol extract of the leaves M. rhizinoides. The structures of these compounds were identified based on their spectroscopic data. On cytotoxic evaluation against murine leukemia P-388 cells, compounds 1-2 showed IC50 values of 11.4 and 13.9 microM, respectively, while compound 3 was inactive.

Phenolic compounds from Cryptocarya konishii: their cytotoxic and tyrosine kinase inhibitory properties.

Two chalcone derivatives, 2'-hydroxychalcone (1) and desmethylinfectocaryone (2), together with five known phenolic compounds infectocaryone (3), cryptocaryone (4), kurzichalcolactone A (5), pinocembrin (6) and trans-N-feruloyltyramine (7), were isolated from the methanol extract of the wood of Cryptocarya konishii. The structures of the new compounds were determined based on the analysis of spectroscopic data, including UV, IR, 1D and 2D NMR, and mass spectra. Evaluation of the cytotoxic and tyrosine kinase inhibitory activities of compounds 1-7 showed that compounds 2-4 strongly inhibited the growth of murine leukemia P-388 cells, whereas compound 4 significantly inhibited the enzyme.

A modified oligostilbenoid, diptoindonesin C, from Shorea pinanga Scheff.

A new oligostilbenoid, diptoindonesin C, has been isolated from the tree bark of Shorea pinanga Scheff., along with the two known oligostilbenoids gnetin H and hopeaphenol, and a known coumarin scopoletin. The new oligostilbenoid was moderately active against brine shrimps Artemia salina.