Kiyoto Goto

Tripterygium wilfordii var. regelii which are interleukin-1 inhibitors

Abstract Seven new quinoide-type diterpenes were isolated from the stems of Tripterygium wilfordii var. regelii and their structures were established on the basis of spectroscopic and chemical evidence. The isolated compounds showed extremely potent inhibitory activities against interleukin-lα and β releases for human peripheral mononticlear cells.

Triptoquinone A and B novel interleukin-1 inhibitors from Tripterygium wilfordii var Regeli

Abstract Novel interleukin-1 inhibitors, triptoquinone A (1) and B(2), have been isolated from Tripterygium wilfordii v a r regelli, and their structures were elucidated mainly by spectroscopic methods including X-ray.

Human Cytochrome P450 1A2 Involvement in the Formation of Reactive Metabolites from a Species-Specific Hepatotoxic Pyrazolopyrimidine Derivative, 5-n-Butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine

5-n-Butyl-7-(3,4,5-trimethoxybenzoylamino)pyrazolo[1,5-a]pyrimidine) (OT-7100) is a pyrazolopyrimidine derivative with potential analgesic effects. Exclusively limited elevations in serum levels of aspirate- and alanine-aminotransferase were abnormally observed in a clinical study, in contrast to no toxicological potential to experimental animals. The aim of this study was to clarify the mechanism responsible for species-specific hepatotoxicity of this model compound. OT-7100 was primarily metabolized to a carboxylic acid derivative and an amino derivative (5-n-butyl-pyrazolo[1,5-a]pyrimidine, M-5) by hydrolysis in humans and rats. In human liver, pyrazolo[1,5-a]pyrimidine derivative M-5 was further metabolized to mainly M-23OH (a C-3-position hydroxyl derivative, 3-hydroxy-5-n-butyl-pyrazolo[1,5-a]pyrimidine). Studies with recombinant cytochrome P450s (P450s), correlation analysis using a panel of human liver microsomes as well as immunoinhibition with anti-P450 antibodies collectively suggested that human liver microsomal P450 1A2 preferentially metabolized M-5 to predominantly M-23OH. Human liver microsomes were capable of activating M-5 to a covalently bound metabolite faster than rat liver microsomes: reduced glutathione prevented the bindings. A cysteine adduct derivative of M-23OH at the C-6-position was structurally confirmed. On the contrary, rat liver microsomal P450 1A2 could metabolize M-5 to equally M-23OH, M-22OH (a C-6-position hydroxyl derivative, 6-hydroxy-5-n-butyl-pyrazolo[1,5-a]pyrimidine), or an unknown metabolite. These results suggest that differences in the regiospecific metabolic function of human and rat P450 1A2 would be responsible for the human-specific metabolic activation of the primary metabolite of OT-7100 to a proximate form. It is presumed that hepatotoxicity associated with OT-7100 could be likely related to the formation of a human-specific reactive metabolite from M-23OH. OT-7100 activation by inducible P450 1A2 may therefore exhibit marked individual differences.

Coumarin derivatives in Coptis trifolia

Abstract Known compounds, epiberberine, groenlandicine, scopoletin and β-sitosterol were characterized in the whole plants of Coptis trifolia . By means of spectral analysis, the structures of two new compounds were determined to be glycosides of a 10-hydroxygeranyl residue which is linked with scopoletin (7-hydroxy-6-methoxycoumarin) through an ether linkage.

Total synthesis of (±)-triptoquinone A

Abstract A concise and practical total synthesis of (±)-triptoquinone A (1) , a novel interleukin-1 inhibitor isolated from Tripterygium wilfordii var. regelii , has been achieved in 11 steps from the known naphthol 2 .

Diastereoselective oxidation of mercapturates to mercapturate sulfoxides

Abstract An efficient and highly diastereoselective synthesis of mercapturate sulfoxides 2 based on the substrate contorolled asymmetric S-oxidation has been accomplished.

Enantioselective total synthesis and structure determination of the mercapturic acid sulfoxide conjugate

A practical and enantioselective total synthesis of the mercapturic acid sulfoxide 4, a metabolite of anti-inflammatory drug DUP 697 1, has been accomplished by employing the substratecontrolled diastereoselective oxidation of the sulfide 7 to the sulfoxide 8 as the key step. This led to the structure determination of 4.

Diastereoselective total syntheses of (±)-triptoquinone B and C

The first and efficient total syntheses of (±)-triptoquinone B 1 and C 2 have been achieved from the allyl ether 3; the key steps are the construction of the four contiguous stereogenic centres present in 2 by the MnIII mediated oxidative free radical cyclisation followed by metal hydride reduction.