Five new 2-(2-phenylethyl)chromone derivatives from agarwood.

Agarwood has been used as an incense and in traditional medicines as aphrodisiac, sedative, cardiotonic, and carminative. In this study, five new 2-(2-phenylethyl)chromones (2, 13-16) and eleven known compounds (1, 3-12) were isolated from the agarwood. The structures of the new compounds were determined by 1H-, 13C-, and two-dimensional NMR together with electronic circular dichroism (ECD) spectroscopy. All isolated compounds were evaluated for the phosphodiesterase (PDE) 3A and 5A1 inhibitory activity by the fluorescence polarization method. Dimeric 2-(2-phenylehyl)chromones (13, 14, 16) had potent inhibitory activity to PDE 5A1 with IC50 values of micro molar range (13: 4.2 µM, 14: 7.9 µM, 16: 4.3 µM), whereas they had weak activity to PDE 3A. In contrast, compound (15), which has a phenylpropionic acid moiety instead of the 2-(2-phenylethyl)chromone moiety in the dimers, showed moderate inhibition of both PDE 3A (IC50: 42.6 µM) and PDE 5A1 (IC50: 15.1 µM).

Three new 5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone derivatives enantiomeric to agarotetrol from agarwood.

Agarwood (jinkoh in Japanese) is a resinous wood from Aquilaria species of the family Thymelaeaceae and has been used as incense and in traditional medicines. Characteristic chromone derivatives such as agarotetrol have been isolated from agarwood. In previous study, we isolated two new 2-(2-phenylethyl)chromones together with six known compounds from MeOH extract of agarwood. Further chemical investigation of the MeOH extract led to isolation of eighteen 2-(2-phenylethyl)chromones, including three new 5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromones with stereochemistry enantiomeric to agarotetrol-type, viz. (5R,6S,7S,8R)-2-[2-(3'-hydroxy-4'-methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone (2), (5R,6S,7S,8R)-2-[2-(4'-methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone (6), and (5R,6S,7S,8R)-2-[2-(4'-hydroxy-3'- methoxyphenyl)ethyl]-5,6,7,8-tetrahydroxy-5,6,7,8-tetrahydrochromone (13). The absolute configurations of the new compounds were determined by exciton chirality method. All isolated compounds were tested for their phosphodiesterase (PDE) 3A inhibitory activity by fluorescence polarization method. Compounds 8, 12-15, 21-24 showed moderate PDE 3A inhibitory activity.

Effects of saffron and its constituents, crocin-1, crocin-2, and crocetin on α-synuclein fibrils.

Saffron, the stigma of Crocus sativus Linné (Iridaceae family), has been known to inhibit aggregation of ß-amyloid, a nerve tissue protein. α-Synuclein (αS) is a 140-amino acid protein found abundantly in various regions of the brain. Its abnormal aggregation and accumulation in nerve tissue are said to cause neurodegenerative diseases such as Parkinson's disease, Lewy body dementia, and multiple-system atrophy. This study (part of this study was presented at the 137th Annual Meeting of the Pharmaceutical Society of Japan) examined the effects of saffron, its constituents (crocin-1, crocin-2, crocetin, and safranal), and crocetin structural analogs (hexadecanedioic acid, norbixin, and trans, trans-muconic acid) on αS aggregation, and αS fibril dissociation. Saffron dose-dependently inhibited αS aggregation and dissociated αS fibrils by thioflavin T fluorescence assay. These effects were observed by transmission electron microscopy, which showed reduced and shortened αS fibrils. Crocin-1, crocin-2, and crocetin showed anti-aggregation and fibril dissociation effects, with crocetin being the most potent. The effects of norbixin were weaker than those of crocetin, and the other crocetin structural analogs showed no effects. These results show that saffron and its constituents (crocin-1, crocin-2, and crocetin) can be effective in preventing and treating diseases caused by abnormal αS aggregation.

Agarwood Inhibits Histamine Release from Rat Mast Cells and Reduces Scratching Behavior in Mice: Effect of Agarwood on Histamine Release and Scratching Behavior.

OBJECTIVES: This study was conducted to clarify the effects of agarwood on histamine release from mast cells in rats and on the scratching behaviors in mice. METHODS: Histamine release from rat mast cells induced by compound 48/80 or concanavalin A (Con A) and compound 48/80-induced scratching behavior in mice were examined to investigate the effects of agarwood. The hyaluronidase activity and the 3',5'-cyclic adenosine monophosphate (cAMP) levels in mast cells were examined to investigate the mechanisms for the inhibition of histamine release. The correlation between the inhibitory effects of agarwood on histamine release and the content of its typical ingredients, a 2-(2-phenylethyl)chromone derivatives, was analyzed using thin-layer chromatography. RESULTS: Agarwood showed an inhibitory effect on mast-cell histamine release induced by compound 48/80 or Con A without any effect on hyaluronidase activity; this effect involves an increase in the cAMP levels in mast cells. Oral administration of agarwood showed an inhibitory effect on compound 48/80-induced scratching behavior in mice. The inhibitory effects of agarwood on histamine release were quite different, depending on the area where the agarwood was produced, its quality, and its market price. No correlation was found between the inhibitory effects of agarwood on histamine release and the typical ingredients of agarwood, which are 2-(2-phenylethyl)chromone derivatives. CONCLUSION: These results show that agarwood inhibits histamine release from mast cells partially through an increase in the cAMP levels in cells. We suggest that some active ingredients of agarwood must be effective on oral intake and that agarwood can be used to treat patients with a number of conditions, including urticaria, atopic dermatitis, and bronchial asthma, in which an increase in histamine release occurs. Differences in the pharmacological effects of this crude drug among markets may provide important information for the quality control of this herbal medicine.

New 2-(2-Phenylethyl)chromone Derivatives and Inhibitors of Phosphodiesterase (PDE) 3A from Agarwood.

The MeOH extract of agarwood showed inhibitory activity against phosphodiesterase (PDE) 3A. Fractionation of the extract led to the isolation of two new 2-(2-phenylethyl)chromones, 6,8-dihydroxy-2-[2-(4'-methoxyphenyl)ethyl]chromone (6), and 6,7-dihydroxy-2-(2-phenylethyl)chromone (8), together with six known compounds. All isolated compounds were tested for their PDE 3A inhibitory activity using fluorescence polarization method. Compound 7 showed PDE 3A inhibitory activity with IC50 of 4.83 µM.

Analgesic Effects of Toad Cake and Toad-cake-containing Herbal Drugs: Analgesic effects of toad cake.

OBJECTIVES: This study was conducted to clarify the analgesic effect of toad cake and toad-cake-containing herbal drugs. METHODS: We counted the writhing response of mice after the intraperitoneal administration of acetic acid as a nociceptive pain model and the withdrawal response after the plantar surface stimulation of the hind paw induced by partial sciatic nerve ligation of the mice as a neuropathic pain model to investigate the analgesic effect of toad cake and toad-cake-containing herbal drugs. A co-treatment study with serotonin biosynthesis inhibitory drug 4-chloro- DL-phenylalanine methyl ester hydrochloride (PCPA), the catecholamine biosynthesis inhibitory drug α-methyl- DL-tyrosine methyl ester hydrochloride (AMPT) or the opioid receptor antagonist naloxone hydrochloride was also conducted. RESULTS: Analgesic effects in a mouse model of nociceptive pain and neuropathic pain were shown by oral administration of toad cake and toad-cake-containing herbal drugs. The effects of toad cake and toad-cake-containing herbal drugs disappeared upon co-treatment with PCPA, but not with AMPT or naloxone in the nociceptive pain model; the analgesic effect of toad-cake-containing herbal drugs also disappeared upon co-treatment with PCPA in the neuropathic pain model. CONCLUSION: Toad cake and toad-cake-containing herbal drugs have potential for the treatments of nociceptive pain and of neuropathic pain, such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and postoperative or posttraumatic pain, by activation of the central serotonin nervous system.

Synthesis and biological activities of glycosphingolipid analogues from marine sponge Aplysinella rhax.

A novel glycosphingolipid, beta-D-GalNAcp(1-->4)[alpha-D- Fucp(1-->3)]-beta-D-GlcNAcp(1-->)Cer (1), isolated from the marine sponge Aplysinella rhax, has a unique structure, with D-fucose and N-acetyl-D-galactosamine attached to a reducing-end N-acetyl-D-glucosamine through an alpha1-->3 and beta1-->4 linkage, respectively. We synthesized glycolipid analogues carrying a 2-branched fatty alkyl residue or a 2-trimethylsilyl ethyl residue in place of ceramide (2 and 3), non-natural type trisaccharide analogue containing an L-fucose residue (4), and other analogues (5 and 6). Among these prepared compounds, 2 showed the most potent nitric oxide (NO) production inhibitory activity against LPS-activated J774.1 cells. In addition, their structure-activity relationships were established.