Takahiro Nakazawa

Metabolites of orally administered Magnolia officinalis extract in rats and man and its antidepressant‐like effects in mice

As a part of our search for the active metabolite from the bark of Magnolia officinalis (Magnoliaceae), the aqueous extract was orally administered to rats, and metabolites in the urine were analysed by a high‐performance liquid chromatograph equipped with a photodiode array detector. When the extract was given to rats, five metabolites (sinapic acid‐4‐O‐sulfate (1), sinapic acid‐4‐O‐β‐glucuronide (2), sinapic acid (3), 3‐[2′,6‐dihydroxy‐5′‐(2‐propenyl)[1,1′‐biphenyl]‐3‐yl]‐(E)‐2‐propenoic acid (4), and an unchanged form, magnolol (5)) were detected in the urine. It was revealed that metabolites 1–3 and 4 were respectively derived from syringin and magnolol contained in the extract. In a human urine sample, metabolites 3–5 and dihydroxydihydromagnolol (6) were detected. These structures were identified by a combination of spectral methods and/or by comparison with authentic compounds obtained by synthesis. Among these free form metabolites (3–6), acute treatments with magnolol and dihydroxydihydromagnolol (50–100 mg kg−1, i.p.) attenuated the forced swim‐induced experimental depression in mice. The results indicated that magnolol and dihydroxydihydromagnolol were the antidepressant constituents of Magnolia officinalis.

Tetrahydrobostrycin and 1-Deoxytetrahydrobostrycin, Two New Hexahydroanthrone Derivatives, from a Marine-derived Fungus Aspergillus sp.

Two new hexahydroanthrones, tetrahydrobostrycin (1) and 1-deoxytetrahydrobostrycin (2), were isolated from a marine-derived fungus Aspergillus sp. strain 05F16 collected at the coral reef of Manado, Indonesia, together with bostrycin and abscisic acid. The structures of new compounds were determined on the basis of their spectral data. Compound 1 showed weak antibacterial activity against Staphylococcus aureus and Escherichia coli and 2 against S. aureus.

Inhibitory effects of urinary metabolites on platelet aggregation after orally administering Shimotsu‐To, a traditional Chinese medicine, to rats

Shimotsu‐To, which consists of four herbal extracts, has been used clinically for improving abnormal blood coagulation, fibrinolysis, atherosclerosis and chronic inflammation in Japan and China. We have investigated the pharmacological relationship between the effects and chemical components of Shimotsu‐To after oral administration to rats. The urinary constituents were separated and identified by three dimensional (3D‐) HPLC equipped with a photodiode array detector as a new tool and the chemical structures were determined by spectroscopic methods to be trans‐ferulic acid‐3‐O‐sulfate (1), vanillic acid (2), m‐hydroxyphenylpropionic acid (3), trans‐ferulic acid (4) and cis‐ferulic acid (5). Of these compounds, 2–5 strongly inhibited platelet aggregation induced by ADP and arachidonic acid. Compound 1, the sulfate conjugate of 4, did not show any inhibitory effect, which suggested that the inhibitory effect on platelet aggregation was inactivated by sulfate conjugation. These results indicated that compounds 2–5 partly contributed to the anti‐Oketsu effect of Shimotsu‐To through the inhibition of platelet aggregation.

Absence of morphine analgesia and its underlying descending serotonergic activation in an experimental mouse model of fibromyalgia.

Mice exposed to intermittent cold stress (ICS), but not constant cold stress (CCS) showed sustained thermal hyperalgesia for up to 12 days. Systemic or intracerebroventricular (i.c.v.) injection of morphine caused no significant analgesia in ICS mice, but induced dose-dependent analgesia in control mice. However, significant analgesic effects were achieved by intrathecal or intraplantar injection of morphine. The i.c.v. injection of morphine significantly increased the turnover ratio (5-HIAA/5-HT) in the dorsal half of the spinal cord of control mice, but not in ICS mice. Collectively, these results indicate that the loss of descending serotonergic activation seems to be a key mechanism underlying the absence of morphine-induced analgesia.

Euryspongins A-C, three new unique sesquiterpenes from a marine sponge Euryspongia sp.

Three new unique sesquiterpenes, euryspongins A-C (1-3), were isolated from a marine sponge Euryspongia sp. collected at Iriomote Island, Okinawa, Japan. Compound 1 possessed a bicyclic furanosesquiterpene structure with six- and eight-membered rings, whereas compounds 2 and 3 had an α,β-unsaturated-γ-lactone ring instead of the furan ring in 1. Only five natural products in this class have been reported, and compounds 1-3 are the sixth-eighth examples of natural products. Compounds 1-3 had no inhibition effect against PTP1B, an important target enzyme for the treatment of diabetes, while the dehydro derivative of 1 [dehydroeuryspongin A (4)] exhibited inhibitory activity (IC(50)=3.6 μM).

Absolute structures and bioactivities of euryspongins and eurydiene obtained from the marine sponge Euryspongia sp. collected at Iriomote Island.

Three unique sesquiterpenes, named euryspongins A-C (1-3), have been isolated from the marine sponge Euryspongia sp. The absolute configuration of 1 was assigned as (4R,6R,9S) by comparing its experimental Electronic Circular Dichroism (ECD) spectrum with the calculated ECD spectra of both enantiomers, and the absolute configurations of 2, 3 and artifact 4 were suggested on the basis of that of 1 by assuming common biogenesis of 1-3. These absolute configurations were opposite to those depicted in the previous communication. Further separation of the remaining fractions lead to the isolation of a new C11-polyketide, named as eurydiene (5), together with a known C11-polyketide, nakitriol (6). The structure of 5 was assigned on the basis of its spectroscopic data as a bicyclic alcohol with a diene side chain. Dehydroeuryspongin A (4) inhibited protein tyrosine phosphatase 1B (PTP1B), an important target enzyme for the treatment of type II diabetes and obesity, with an IC50 value of 3.58μM. Moreover, compound 4 did not inhibit the proliferation of human hepatoma Huh-7 cells at 100μM. One of the locations in which PTP1B has been detected is hepatocytes. Compounds 1-3, 5, and 6 were not active against PTP1B. The growth of human colon (HCT-15) and T-cell lymphoma (Jurkat) cells was not disturbed by compounds 1-6.

(25S)-cholesten-26-oic acid derivatives from an Indonesian soft coral Minabea sp.

(25S)-3-Oxocholesta-1,4-dien-26-oic acid (1) and a new (25S)-18-acetoxy-3-oxocholesta-1,4-dien-26-oic acid (2) were isolated from a soft coral Minabea sp. (cf. aldersladei) collected in North Sulawesi, Indonesia, together with two known cholic-acid-type compounds, 3-oxochol-1,4-dien-24-oic acid (3) and 3-oxochol-4-en-24-oic acid (4). The structures of these compounds were determined on the basis of their spectroscopic data. The absolute stereochemistry at C-25 of 2 was determined by comparative (1)H NMR study using chiral anisotropic reagents [(S)- and (R)-phenylglycine methyl esters]. This is the first to report compound 1 as a natural product.