Hideyuki Kuno

Lactone synthesis from 16-hydroxyhexadecanoic acid ethyl ester in organic solvents catalyzed with polyethylene glycol-modified lipase

Lipase from Pseudomonas cepacia was coupled with 2,4-bis[O-methoxypoly(ethylene glycol)]-6-chloro-s-triazine (activated PEG2) to form PEG-modified lipase. The PEG-lipase becomes soluble and active in organic solvents. 16-Hexadecanolide was synthesized with PEG-lipase from 16-hydroxyhexadecanoic acid ethyl ester via intramolecular ester exchange reaction. The lactone was effectively obtained in high concentrations of the substrate; the yield was 92% at 1 mM, 48% at 10 mM and 11% at 100 mM substrate.

Polyethylene glycol-modified lipase catalyzes asymmetric alcoholysis of δ-decalactone in n-decanol

SummaryLipase from Pseudomonas cepacia was modified with 2,4-bis[O-methoxypoly(ethylene glycol)]-6-chloro-s-triazine(activated PEG2) to form PEG-lipase. The PEG-lipase, soluble and active in organic solvents, catalyzes asymmetric alcoholysis of racemic δ-decalactone in alcohols to form (R)-5-hydroxydecanoic acid alkyl esters. The yield was 69% with 83% enantiomeric excess after 3 hr-reaction in n-decanol at 50°C. The advantage of this reaction is that the alcoholysis proceeds efficiently in straight hydrophobic substrates without any organic solvents.

Usefulness of in vitro combination assays of mitochondrial dysfunction and apoptosis for the estimation of potential risk of idiosyncratic drug induced liver injury

Drug-induced liver injury (DILI) is one of the serious and frequent drug-related adverse events. This adverse event is a main reason for regulatory action pertaining to drugs, including restrictions in clinical indications and withdrawal from clinical trials or the marketplace. Idiosyncratic DILI especially has become a major clinical concern because of its unpredictable nature, frequent hospitalization, need for liver transplantation and high mortality. The estimation of the potential for compounds to induce idiosyncratic DILI is very difficult in non-clinical studies because the precise mechanism of idiosyncratic DILI is still unknown. Recently, many in vitro assays which indicate a possibility of the prediction of the idiosyncratic DILI have been reported. Among these, some in vitro assays focus on the effects of compounds on mitochondrial function and the apoptotic effects of compounds on human hepatocytes. In this study, we measured oxygen consumption rate (OCR) and caspase-3/7 activity as an endpoint of mitochondrial dysfunction and apoptosis, respectively, with human hepatocytes after treatment with compounds causing idiosyncratic DILI (troglitazone, leflunomide, ranitidine and diclofenac). Troglitazone and leflunomide decreased the OCR but did not affect caspase-3/7 activity. Ranitidine increased caspase-3/7 activity but did not affect the OCR. Diclofenac decreased the OCR and increased caspase-3/7 activity. Acetaminophen and ethanol, which are also hepatotoxicants but do not induce idiosyncratic DILI, did not affect the OCR or caspase-3/7 activity. These results indicate that a combination assay of mitochondrial dysfunction and apoptosis is useful for the estimation of potential risk of compounds to induce idiosyncratic DILI.

Regioselective hydrogenation using platinum-support zeolite modified by CVD-method

Abstract Platinum-support zeolites coupled with silicon alkoxides were prepared by the Chemical Vapor Deposition (CVD) method. With this catalyst system, it was demonstrated that the terminal carbon-carbon double bond is preferentially hydrogenated in the case of several unsaturated hydrocarbons. Further, it was elucidated that highly regioselective hydrogenation of alkadiene could also be achieved in this catalyst system.

Synthesis of a useful chiral building block, (S)-5-acetoxy-2-penten-4-olide from D-glucose

A new method for preparation of (S)-5-acetoxy-2-penten-4-olide starting from D-glucose with 5 steps is described