Yasuoki Murakami

4-Phenylbutyric acid protects against neuronal cell death by primarily acting as a chemical chaperone rather than histone deacetylase inhibitor.

This letter describes the mechanism behind the protective effect of 4-phenylbutyric acid (4-PBA) against endoplasmic reticulum (ER) stress-induced neuronal cell death using three simple 4-(p-substituted phenyl) butyric acids (4-PBA derivatives). Their relative human histone deacetylase (HDAC) inhibitory activities were consistent with a structural model of their binding to HDAC7, and their ability to suppress neuronal cell death and activity of chemical chaperone in vitro. These data suggest that 4-PBA protects against neuronal cell death mediated by the chemical chaperone activity rather than by inhibition of histone deacetylase.

Regiospecific Acetylation of Substituted α,α′‐Benzylidenedimethanols with Vinyl Acetate using Porcine Pancreas Lipase

Abstract Acetylation of substituted α,α′‐benzylidenedimethanols with 10 equivalents of vinyl acetate in the presence of 50 w/w% of porcine pancreas lipase (PPL) type II regiospecifically proceeded to afford only the corresponding E‐monoacetates in excellent yields without Z‐monoacetates, diacetate, or the starting materials.

Orally active factor Xa inhibitors: investigation of a novel series of 3-amidinophenylsulfonamide derivatives using an amidoxime prodrug strategy.

A series of novel and potent 3-amidinophenylsulfonamide derivatives of factor Xa inhibitors were designed and synthesized using an amidoxime prodrug strategy. We focused on systemic clearance of parent compounds in rats, and performed in vivo pharmacokinetic screening. Incorporation of a carboxymethoxy group markedly improved systemic clearance (compound 43), and the related amidoxime 44 showed sufficient prodrug conversion. Compound 45, the double prodrug of 43, exhibited practicable bioavailability after oral administration in rats. Among the various compounds under investigation, KFA-1982 was selected for clinical development.

Evaluation of synthetic naphthalene derivatives as novel chemical chaperones that mimic 4-phenylbutyric acid

The chemical chaperone 4-phenylbutyric acid (4-PBA) has potential as an agent for the treatment of neurodegenerative diseases. However, the requirement of high concentrations warrants chemical optimization for clinical use. In this study, novel naphthalene derivatives with a greater chemical chaperone activity than 4-PBA were synthesized with analogy to the benzene ring. All novel compounds showed chemical chaperone activity, and 2 and 5 possessed high activity. In subsequent experiments, the protective effects of the compounds were examined in Parkinsons disease model cells, and low toxicity of 9 and 11 was related to amphiphilic substitution with naphthalene.

Peculiarity of methoxy group-substituted phenylhydrazones in Fischer indole synthesis

We found that the Fischer indole synthesis of ethyl pyruvate 2-methoxyphenylhydrazone (5) with HCl/EtOH gave an abnormal product, ethyl 6-chloroindole-2-carboxylate (7), as the main product, with a smaller amount of ethyl 7-methoxyindole-2-carboxylate (6) as the normal product. This abnormal reaction was the result of a cyclization on the side with the substituent (methoxy group) of a benzene ring on phenylhydrazone, which was not previously observed. In this initial investigation, we focused on 1) the application of the above-mentioned abnormal Fischer indole synthesis, 2) the details of this reaction of phenylhydrazone with other kinds of substituents, 3) the mechanism of the first step of the Fischer indole synthesis, 4) the abnormal reaction in methoxydiphenylhydrazones, and 5) a synthetic device to avoid an abnormal reaction. The results of these studies are summarized herein.

A new methodology for functionalization at the 3-position of indoles by a combination of boron Lewis acid with nitriles.

We discovered that a reagent comprising a combination of PhBCl2 and nitriles was useful for syntheses of both 3-acylindoles and 1-(1H-indol-3-yl)alkylamine from indoles. The reaction proceeded selectively at the 3-position of indoles providing 3-acylindoles in moderate to high yields on treatment with the above reagent. Furthermore, the reaction provided the corresponding amine products in moderate to high yields after the intermediate imine was reduced by NaBH3CN. These reactions proceeded under mild conditions and are applicable to the formation of indoles functionalized at the 3-position.

Chemical confirmation of the structure of a mutagenic aminophenylnorharman, 9-(4'-aminophenyl)-9H-pyrido〔3,4-b〕indole: an authentic synthesis of 9-(4'-nitrophenyl)-9H-pyrido〔3,4-b〕indole as its relay compound

9-(4-Aminophenyl)-9H-pyrido[3,4-b]indole 2 is a mutagenic compound produced by non-mutagenic norharman 1 and aniline in the presence of S9 mix. 9-(4-Nitrophenyl)-9H-pyrido[3,4-b]indole 4, the relay compound for synthesis of 2, was synthesized starting from ethyl indole-2-aldehyde 12 via initial N-(4-nitro)phenylation of the indole nucleus, elongation of the 2-aldehyde substituent, and then construction of the pyridine nucleus in order to ensure the nitrogen substitution in 2.