M. Suzuki
Gifu University
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Featured researches published by M. Suzuki.
Tetrahedron Letters | 1980
T. Tsunoda; M. Suzuki; Ryoji Noyori
Abstract Carbonyl compounds are readily acetalized by alkoxysilanes in the presence of trimethylsilyl trifluoromethanesulfonate catalyst.
Pharmacology & Therapeutics | 2002
Yasuharu Sasaki; M. Suzuki; Hiroyoshi Hidaka
We have developed several kinds of protein kinase inhibitors, which are classified as isoquinolinesulfonamides and characterized as ATP competitive inhibitors of Ser/Thr protein kinases. These include H9, H89, KN62, and 1-(5-isoquinolinesulfonyl)-homopiperazine (HA-1077) against protein kinase C (PKC), protein kinase A, Ca(2+)/calmodulin-dependent protein kinase II, and Rho-kinase, respectively, and they have been used widely to confirm the involvement of the target protein kinase in biological or physiological reaction(s). In some cases, inhibitors have predicted the involvement of the target protein kinase in cell or tissue before its precise mechanism or its effector was defined. On a clinical level, we developed the Rho-kinase inhibitor HA-1077 as an anti-spastic that effectively suppresses the spasm of cerebral arteries after subarachnoid hemorrhage. We have improved HA-1077 to obtain (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinoline)sulfonyl]-homopiperazine (H-1152P), which is a more selective inhibitor of Rho-kinase, with a K(i) value of 1.6 nM for Rho-kinase, 630 nM for protein kinase A, and 9270 nM for PKC. This inhibitor suppressed the phosphorylation of myristoylated alanine-rich C-kinase substance (MARCKS) in neuronal cells stimulated with lysophosphatidic acid, whose phosphorylation site was confirmed to be the Ser159 residue, using a phosphorylation site-specific antibody. In contrast, phorbol 12-myristate 13-acetate-induced phosphorylation of MARCKS was scarcely inhibited by H-1152P. Furthermore, lysophosphatidic acid-stimulated phosphorylation in neuronal cells was characterized as a C3 toxin-sensitive event. Our results show that the Rho-kinase inhibitor targets a protein with a well-known function, MARCKS in neuronal cells. Although MARCKS is widely recognized as a substrate of PKC, our results raise the possibility that MARCKS is a target protein of Rho-kinase in neuronal cells. In this review, we address the possible role of Rho-kinase in neuronal functions, using the Rho-kinase specific inhibitor H-1152P.
Journal of Neurochemistry | 2002
Mami Ikenoya; Hiroyoshi Hidaka; Takamitsu Hosoya; M. Suzuki; Naoki Yamamoto; Yasuharu Sasaki
The functions of small Gu2003protein Rho‐associated kinase (Rho‐kinase) have been determined in muscle and non‐muscle cells, but, particularly in neuronal cells, its effector(s) has not been well known. Recently, we preliminarily reported that Rho‐kinase phosphorylates the Ser159 residue in myristoylated alanine‐rich Cu2003kinase substrate (MARCKS) in vitro, but it remains obscure in vivo. To further clarify this point, we developed an isoquinolinesulfonamide derivative, H‐1152, that is a more specific, stronger and membrane‐permeable inhibitor of Rho‐kinase with a Ki value of 1.6u2003nm, but poor inhibitor of other serine/threonine kinases. H‐1152 dose‐ dependently inhibited the phosphorylation of MARCKS in human neuroteratoma (NT‐2) cells stimulated by Rho‐activator lysophosphatidic acid (LPA), which was determined by phosphorylation site‐specific antibody against phospho‐Ser159 in MARCKS, whereas it hardly inhibited the phosphorylation stimulated by phorbol‐12,13‐dibutyrate (PDBu). In contrast, two other Rho‐kinase inhibitors, HA‐1077 at 30u2003µm and Y‐27632 at 10–30u2003µm, inhibited the phosphorylation of MARCKS in the cells stimulated by LPA and PDBu. A PKC inhibitor Ro‐31‐8220 selectively inhibited PDBu‐induced phosphorylation of MARCKS. Taken together with our previous results, the present findings strongly suggest that Rho/Rho‐kinase phosphorylates MARCKS at Ser159 residue in neuronal cells in response to LPA stimulation and that H‐1152 is a useful tool to confirm Rho‐kinase function(s) in cells and tissues.
Tetrahedron | 1988
Shizuaki Murata; M. Suzuki; Ryoji Noyori
Abstract Trimethylsilyl triflate with or without added hindered tertiary amines catalyzes directed condensation of enol trimethylsllyl ethers with acetals, orthoformate, or 2-acetoxytetrahydrofuran or -pyrans to give the corresponding β-alkoxy carbonyl compounds. Reaction of enol silyl ethers and carboxonium triflate ion-pair intermediates occurs via acyclic transition states and exhibits moderate to high erythro selectivity independent of the geometry ( E / Z ) of the enol silyl ethers.
Tetrahedron Letters | 1980
T. Tsunoda; M. Suzuki; Ryoji Noyori
Abstract In the presence of a catalytic amount of trimethylsilyl trifluoromethanesulfonate, allyltrimethylsilane reacts with acetals to give the corresponding homoallyl ethers in high yields.
Journal of Biological Chemistry | 1996
Hajime Takechi; Kiyoshi Matsumura; Yumiko Watanabe; Kazuyoshi Kato; Ryoji Noyori; M. Suzuki
By use of several prostacyclin analogs and an in vitro autoradiographic technique, we have found a novel subtype of the prostacyclin receptor, one having different binding properties compared with those of the known prostacyclin receptor in the rat brain. Isocarbacyclin, which is a potent agonist for the known prostacyclin receptor, had high affinity for the novel subtype (dissociation constant (K) of 7.8 nM). However, iloprost, which is usually used as a stable prostacyclin analog, showed low affinity binding (K = 159 nM) for the subtype. Other prostaglandins showed no or little affinity for the subtype. [3H]Isocarbacyclin binding was high in the thalamus, lateral septal nucleus, hippocampus, cerebral cortex, striatum, and dorsal cochlear nucleus. Although the nucleus of the solitary tract and the spinal trigeminal nucleus showed a high density of [3H]isocarbacyclin binding, [3H]iloprost also had high affinity in these regions, and the binding specificity was similar to that for the known prostacyclin receptor. Hemilesion studies of striatal neurons lesioned by kainate or of dopaminergic afferents lesioned by 6-hydroxydopamine revealed that the binding sites of the novel subtype exist on neuronal cells in the striatum, but not on the presynaptic terminal of afferents or on glial cells. Electrophysiological studies carried out in the CA1 region of the hippocampus revealed that prostacyclin analogs have a facilitatory effect on the excitatory transmission through the novel prostacyclin receptor. The widespread expression of the prostacyclin receptor in the central nervous system suggests that prostacyclin has important roles in neuronal activity.
Tetrahedron | 1990
M. Suzuki; Yasushi Morita; Hiroshi Koyano; Masahiro Koga; Ryoji Noyori
Abstract In the presence of dimethylzinc, ( R)-tert -butyldimethylsiloxy-2-cyclopentenone can be linked with ( S,E )-1-lithio-3- tert -butyldimethylsiloxy-1-octene and methyl 7-1odo-5-heptynoate, giving a protected 5,6didehydroprostaglandin E 2 - Use of an ω side-chain aldehyde or nitroalkene in place of the propargylic iodide affords the C-7 and C-6 functionalized prostaglandins, respectively. This new protocol constitutes the simplest three-component method for the synthesis of various natural and unnatural prostaglandins.
Clinical Chemistry and Laboratory Medicine | 2000
Toshihisa Ishikawa; M. Tien Kuo; Kyoji Furuta; M. Suzuki
Abstract The ATP-binding cassette transmembrane proteins play an important role in transport of drugs as well as of biologically active endogenous substances. The human multidrug resistance-associated protein (MRP) subfamily consists of at least six members, exhibiting a wide spectrum of biological functions. MRP1 operates as an ATP-dependent primary active transporter for substrates conjugated with glucuronide, sulfate or glutathione. Leukotriene C4 is an important endogenous substrate for MRP1. Glutathione serves as a cofactor in MRP1-mediated drug transport as well. Genes encoding both MRP1 and the catalytic subunit of γ-glutamylcysteine synthetase (γ-GCS) are coordinately regulated in cultured cancer cell lines as well as colorectal cancer tissues from colon cancer patients. The induction of MRP1 and γ-GCS expression by oxidative stress varies among different cell lines, and p53 mutations are associated with elevated levels of induction. To modulate the transport function of MRP1, we have synthesized novel glutathione derivatives as photoreactive biochemical probes targeting the transporter protein. GIF-0019 restored the cellular sensitivity of MRP1-overexpressing drug-resistant cancer cells to anticancer prostaglandins in vitro, which was characterized by enhanced mRNA levels of the cyclin-dependent kinase inhibitor p21, suppressed c-myc expression and G1 arrest.
Journal of Neurochemistry | 2002
Takumi Satoh; Kyoji Furuta; Keiichiro Tomokiyo; Daisaku Nakatsuka; Motoki Tanikawa; Makoto Nakanishi; Maki Miura; Shuuitsu Tanaka; Tetsuro Koike; Hiroshi Hatanaka; Kazuyoshi Ikuta; M. Suzuki; Yasuyoshi Watanabe
Abstract: Cyclopentenone prostaglandins (PGs) are known to arrest the cell cycle at the G1 phase in vitro and to suppress tumor growth in vivo. However, their effects on neurons are unclear. Here, we report that some cyclopentenone PGs function as neurite outgrowth‐promoting factors. They promoted neurite outgrowth from PC12 cells and from dorsal root ganglion explants but only in the presence of nerve growth factor (NGF). We refer to these PGs as neurite outgrowth‐promoting PGs (NEPPs). Through study of the structure‐function relationship of NEPP1‐10 and related compounds, we found that the cross‐conjugated dienone moiety of NEPPs was essential for promoting neurite outgrowth, and NEPP10 was concluded to be the best candidate for drug development. We also investigated the intracellular mechanism of the promotion by NEPPs and obtained evidence that immunoglobulin heavy chain binding protein/glucose‐regulated protein 78 (BiP/GRP78) plays a role in the promotion, based on the following observations: Antisense nucleotides for BiP/GRP78 gene blocked the promotion of neurite outgrowth; BiP/GRP78 protein level increased in response to NEPPs; and overexpression of BiP/GRP78 protein by adenoviral gene transfer promoted the neurite outgrowth by NGF.
Tetrahedron Letters | 1981
M. Suzuki; T. Kawagishi; Ryoji Noyori
Abstract A one-pot procedure for α-alkoxyalkylation of α,β-unsaturated ketones has been devised, which by combination with the organocopper conjugate addition reaction provides a new tool for vicinal carba-condensation of enones.