Hiroshi Hamana

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.

Efficient Synthesis of Resin-Bound α-TMSdiazoketones and Their Use in Solid-Phase Organic Synthesis

Abstract α-TMSdiazoketones on a solid support could be simply and efficiently prepared by reaction of the corresponding resin-bound acid chlorides with excess TMSdiazomethane, without any bases. These α-TMSdiazoketones were used via carbenes or carbenoids for a variety of solid-phase reactions. These useful solid-phase reactions allow efficient construction of diverse compound libraries by use of combinatorial chemistry, due to the high reactivity and wide applications of the carbenes or carbenoids.

Design, synthesis, and binding mode prediction of 2-pyridone-based selective CB2 receptor agonists.

Selective CB2 agonists have the potential for treating pain without central CB1-mediated adverse effects. Screening efforts identified 1,2-dihydro-3-isoquinolone 1; however, this compound has the drawbacks of being difficult to synthesize with two asymmetric carbons on an isoquinolone scaffold and of having a highly lipophilic physicochemical property. To address these two major problems, we designed the 2-pyridone-based lead 15a, which showed moderate affinity for CB2. Optimization of 15a led to identification of 39f with high affinity for CB2 and selectivity over CB1. Prediction of the binding mode of 39f in complex with an active-state CB2 homology model provided structural insights into its high affinity for CB2.

Enhanced Accumulation of Sialyl Lewis X-Carboxymethylpullulan Conjugate in Acute Inflammatory Lesion

AbstractPurpose. E-selectin is a cell adhesion molecule that is specifically expressed in the inflammatory vascular endothelium in response to cytokines such as IL-1β and TNF-α, and interacts with specific ligands containing sialyl Lewis X (Neu5Acα2-3Galβl-4(Fucαl-3)GlcNAc-, SLex). In order to investigate the ability of E-selectin ligands to target the inflammatory site, the tissue distribution of carboxymethylpullulan (CMPul) modified with SLex was studied. Methods. CMPul conjugates with various saccharides containing SLex and monovalent SLex were intravenously administered to mice with ear edema induced by arachidonic acid, and their distributions to the inflamed ear and other tissues were studied. To determine the microdistributions of these compounds, the inflamed ear was subjected to microautoradiography. Results. After intravenous administration AUC0-24h of SLex-CMPul, which binds to E-selectin, in the inflamed ear was about 300-fold and 2.5-fold higher than that of monovalent SLex and CMPul conjugated with other saccharides, which can not serve as ligands for E-selectin. Microautoradiography also revealed SLex-CMPul accumulated at the microvessels in the inflammatory lesions. Conclusions. SLex-CMPul was found to have the potential to target drugs to the inflammatory lesion.

Selective CB2 agonists with anti-pruritic activity: Discovery of potent and orally available bicyclic 2-pyridones

The CB2 receptor has emerged as a potential target for the treatment of pruritus as well as pain without CB1-mediated side effects. We previously identified 2-pyridone derivatives 1 and 2 as potent CB2 agonists; however, this series of compounds was found to have unacceptable pharmacokinetic profiles with no significant effect in vivo. To improve these profiles, we performed further structural optimization of 1 and 2, which led to the discovery of bicyclic 2-pyridone 18e with improved CB2 affinity and selectivity over CB1. In a mouse pruritus model, 18e inhibited compound 48/80 induced scratching behavior at a dose of 100 mg/kg. In addition, the docking model of 18e with an active-state CB2 homology model indicated the structural basis of its high affinity and selectivity over CB1.

Sialyl Lewis X-polysaccharide conjugates: targeting inflammatory lesions.

A novel system for active targeting of inflammatory lesions has been established. A SLeX-CMPul conjugate (2) showed accumulation that was 2.5-fold higher in inflammatory lesions in vivo than a SLN-CMPul conjugate (4) and 300-fold higher than monovalent SLeX (6).

Highly Efficient Cyanosilylation of Aldehydes and Ketones under Microwave, Solvent‐Free, and Lewis Acid–Free Conditions

Abstract The addition of TMSCN to aldehydes and ketones under microwave irradiation in the absence of any Lewis or Brønsted acid and solvent yielded the corresponding cyanohydrins in good yields in short reaction times (less than 30 min).

Hilbert-johnson reaction under high pressure : A facile preparation of 2-pyridones

For the first time, a facile synthesis of 2-pyridones utilizing a classical Hilbert-Johnson reaction of 2-methoxypyridines with haloalkanes under high pressure has been achieved. The reactions were sensitive to steric hindrance of haloalkanes.

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.

Nitrogen 14 NMR and Correlations of Oxidation Potentials of Dibenzo[a,d]cycl[2.2.3]azines with the Corresponding HOMOs: Further Evidence for Peripheral Conjugate System

For the first time, 14 N NMR spectra of a novel type of heterocycles, dibenzo|a,d|cycl|2.2.3|azines were described. The chemical shifts are almost independent of substituents at position 2. The correlations of oxidation potentials with HOMO energies of dibenzo|a,d|cycl|2.2.3|azines also offer very good correlation coefficients (r 2 >0.92) regardless of calculation methods at various levels. Thus, it was concluded that the contribution of the unshared electron pairs of the central nitrogen to the peripheral conjugation in this system is almost negligible.