111003-33-9

A new flavonoid glycoside, isoglucodistylin was isolated from Taxillus kaempferi, and (2R,3S)-taxifolin 3-β-D-glucopyranoside was assigned to this substance from studies on the hydrolysis products and on the isomerization products, and from analyses of the carbon-13 NMR spectra.

Anthocyanidin synthase from Vitis vinifera (VvANS) catalyzes the in vitro transformation of the natural isomer of leucocyanidin, 2R,3S,4S-cis-leucocyanidin, into 2R,4S-flavan-3,3,4-triol ([M + H]+, m/z 323) and quercetin. The C3-hydroxylation product 2R,4S-flavan-3,3,4-triol is first produced and its C3,C4-dehydration product is in tautomeric equilibrium with (+)-dihydroquercetin. The latter undergoes a second VvANS-catalyzed C3-hydroxylation leading to a 4-keto-2R-flavan-3,3-gem-diol which upon dehydration gives quercetin. The unnatural isomer of leucocyanidin, 2R,3S,4R-trans-leucocyanidin, is similarly transformed into quercetin upon C3,C4-dehydration, but unlike 3,4-cis-leucocyanidin, it also undergoes some C2,C3-dehydration followed by an acid-catalyzed hydroxyl group extrusion at C4 to give traces of cyanidin. Overall, the C3,C4-trans isomer of leucocyanidin is transformed into 2R,4R-flavan-3,3,4-triol (M + 1, m/z 323), (+)-DHQ, (-)-epiDHQ, quercetin, and traces of cyanidin. Our data bring the first direct observation of 3,4-cis-leucocyanidin- and 3,4-trans-leucocyanidin-derived 3,3-gem-diols, supporting the idea that the generic function of ANS is to catalyze the C3-hydroxylation of its substrates. No cyanidin is produced with the natural cis isomer of leucocyanidin, and only traces with the unnatural trans isomer, which suggests that anthocyanidin synthase requires other substrate(s) for the in vivo formation of anthocyanidins.

-

An efficient first total synthesis of highly polar ulmoside A and (2 R,3 R)-taxifolin-6- C -β- d -glucopyranoside, useful for the prevention of metabolic disorders, has been described. Key elements of the synthesis include a Sc(OTf) 3-catalyzed regio- and stereoselective C -glycosidation on taxifolin in 35percent yield with d -glucose and chiral semipreparative reverse-phase high-performance liquid chromatography (HPLC) for the separation of both taxifolins and the diastereomeric mixture of taxifolin-6- C -β- d -glucopyranosides. Correlation of the analytical data of synthetic ulmoside A and its diastereomer with a natural ulmoside A sample confirmed the assigned absolute stereochemistry of the natural products.

To explore the structure-activity relationships on the inhibitory activity of flavanonols against nitric oxide (NO) production in inflammatory cells, we synthesized 19 flavanonols which shared a common 3,5,7-trihydroxychroman scaffold. A range of substitutions was included in the B ring in order to investigate the structure-activity relationship. We also succeeded in isolating stereoisomers from 16 of the flavanonols using chiral column chromatography. The inhibitory effects of these compounds on NO production were examined in RAW 264.7 cells (a murine macrophage-like cell line), which were activated by lipopolysaccharide (LPS). We only observed inhibitory activity against NO production in (2R,3R) stereoisomers, while the inhibitory activities of (2S,3S) stereoisomers were significantly weaker. We also evaluated the free radical scavenging potential of the flavanonols using 1,1-diphenyl-2-picrylhydrazyl (DPPH). Each stereoisomer indicated the equivalent DPPH scavenging potential as expected. The radical scavenging activity was not correlated with the inhibitory activity against NO. The inhibition of NO production by flavanonols is stereospecific and cannot simply be explained by their radical scavenging activity. We propose the possible existence of a 'target' molecule for flavanonols which is involved in the production and/or regulation of NO in RAW 264.7 cells.

Silymarin, the seed extract of Silybium marianum, has preventive effects against Alzheimer's disease-like pathogenesis in vivo. We isolated (+)-taxifolin (4) from silymarin as an inhibitor of aggregation of the 42- residue amyloid -protein. Structure-activity relationship studies revealed the 30,40-dihydroxyl groups to be critical to the anti-aggregative ability, whereas the 7-hydroxyl group and the stereochemistry at positions 2 and 3 were not important.

A series of C7-O- and C20-O-amidated 2,3-dehydrosilybin (DHS) derivatives ((±)-1a-f and (±)-2), as well as a set of alkenylated DHS analogues ((±)-4a-f), were designed and de novo synthesized. A diesteric derivative ofDHS((±)-3) and two C23 esterifiedDHSanalogues ((±)-5a and (±)-5b) were also prepared for comparison. The cell viability of PC12 cells, Fe2+ helation, lipid peroxidation (LPO), free radical scavenging, and xanthine oxidase inhibition models were utilized to evaluate their antioxidative and neuron protective properties. The study revealed that the diether atC7-OHand C20-OHas well as the monoether at C7-OH, which possess aliphatic substituted acetamides, demonstrated more potent LPO inhibition and Fe2+chelation compared to DHS and quercetin. Conversely, the diallyl ether at C7-OH and C20-OH was more potent in protection of PC12 cells against H2O2-induced injury than DHS and quercetin. Overall, the more lipophilic alkenylated DHS analogues were better performing neuroprotective agents than the acetamidated derivatives. The results in this study would be beneficial for optimizing the therapeutic potential of lignoflavonoids, especially in neurodegenerative disorders such as Alzheimer's and Parkinson's disease.

-

Key Word Index-Pinus sylvestris; Pinaceae; cis- and trans-dihydroflavonol glycosides; flavanone glucoside; dihydroquercetin; dihydromyricetin; eriodictyol cis-trans isomerism; chemotypes. (-)-cis-2,3-Dihydroquercetin (presumably as the 3'-O-β-D-glucopyranoside); the 3'-O-D-glucopyranosides of (+)-trans-2,3-dihydroquercetin, dihydroquercetin, dihydromyricetin and eriodictyol; (+)-catechin and (+)-gallocatechin have been isolated from the needles of Pinus sylvestris.The dihydroquercetin aglycones interconvert in methanolic solution.Two chemotypes of Pinus sylvestris can be distinguished on the basis of their dihydroquercetin , dihydromyricetin and eriodictyol contents.

From the leaves of Thujopsis dolabrata SIEB. et ZUCC. ( Cupressaceae ) four new flavanonol glycosides, the 3-O-β-D-xylopyranosides (1->4) of (+)-taxifolin, (-)-taxifolin, (+)-epitaxifolin and (-)-epitaxifolin, together with (+)-catechin ( 5 ), (-)-epicatechin (6) and thirteen oligomeric procyanidins ( 7-19 ), were isolated and their chemical structures were characterized by spectroscopic and chemical investigations.Keywords - Thujopsis dolabrata; Cupressaceae; flavonol glycoside; taxifolin xyloside; oligomeric procyanidin

Stereocontrolled synthesis of the flavonoids (2, 4 and 5) is described.Racemic taxifolin (dihydroquercetin) (14) is synthesized by application of this method.