研究者詳細 - 佐々木　健二

MISC - 佐々木　健二

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Reduction of lipophilicity at the lipophilic domain of RXR agonists enables production of subtype preference: RXR alpha-preferential agonist possessing a sulfonamide moiety

Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Ken-ichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Hamed Ismail Ali, Eiichi Akaho, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

CHEMMEDCHEM 3 ( 3 ) 454 - 460 2008年3月

記述言語：英語出版者・発行元：WILEY-V C H VERLAG GMBH

Retinoid X receptor agonists (RXR agonists, rexinoids) are interesting candidates for the treatment of cancers such as tomoxifen-resistant breast cancer and taxol-resistant lung cancer. However, well-known RXR agonists possess a strong lipophilic character. In addition, although RXR has three subtypes, no subtype-selective RXR agonists are known. Thus we aimed to produce less-lipophilic and subtype-selective RXR agonists. By designing sulfonamide-type RXR agonists, 4-[N-methanesulfonyl-N-(5,5,8,8-tetromethyl-5,6,7,8-tetrohydro-2-naphthyl)amino]benzoic acid (80) was found to prefer RXR alpha over RXR beta and RXR gamma, although the potency is less than the potencies of well-known RXR pan-agonists. Moreover, our results suggest that the reduction of lipophilicity at the hydrophobic interaction region of RXR agonists enables production of RXR subtype preference. Our finding will be useful for the creation of more potent and less-lipophilic subtype-selective RXR agonists aimed at the reduction of undesirable side effects.

DOI： 10.1002/cmdc.200700265

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Polycyclic N-heterocyclic compounds. Part 58: Rearrangement reactions of fused 3-(2-bromoethyl)pyrimidin-4(3H)-ones with primary amines and antidepressive evaluation of the products

Hiromi Ohtomo, Tsuyoshi Tagata, Kenji Sasaki, Takashi Hirota, Kensuke Okuda

TETRAHEDRON 63 ( 51 ) 12541 - 12546 2007年12月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Reaction of fused 3-(2-bromoethyl)pyrimidin-4(3H)-ones with primary alkylamines gave abnormal fused 3-alkyl-4-alkylimino-pyrimidines via a new rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives. Antidepressive evaluation of these compounds was performed by antireserpine action and one compound exhibited the positive activity comparable to imipramine. (c) 2007 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tet.2007.10.024

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Antimalarial cation-dimers synthesized in two steps from an inexpensive starting material, isonicotinic acid

Kazunori Motoshima, Yoshiko Hiwasa, Mai Yoshikawa, Kanji Fujimoto, Akihiro Tai, Hiroki Kakuta, Kenji Sasaki

CHEMMEDCHEM 2 ( 10 ) 1527 - 1532 2007年10月

記述言語：英語出版者・発行元：WILEY-V C H VERLAG GMBH

Malaria is one of the three major serious infectious diseases in the world. As the area affected by malaria includes a large proportion of developing countries, there is a need for new antimalarials that can be synthesized and supplied inexpensively. To generate low-cost antimalarials, the MAP series 6-10, bis-cation dimers, synthesized by amidating the carboxyl group of isonicotinic acid (11) with various amines and by cationizing the nitrogen atoms of the pyridine ring with the corresponding alkyl bromides, were designed. This design enabled expansion of the structural variations of bis-cation-type antimalarial compounds. The compounds bearing alkyl or phenyl groups in the amide moieties showed remarkable antimalarial activities in vitro. Moreover, 1, 1'-(1, 12-dodecanediyl)bis[4-[(buthylamino)carbonyl]pyridinium bromide], MAP-412 (6d), exhibited a potent antimalarial activity (ED50 = 8.2 mg kg-(1)). Being prepared at low cost our biscation-type antimalarial compounds may be useful as lead compounds for inexpensive antimalarials.

DOI： 10.1002/cmdc.200700107

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Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors

Xiaoxia Zheng, Hiroyuki Oda, Kayo Takamatsu, Yukio Sugimoto, Akihiro Tai, Eiichi Akaho, Hamed Ismail Ali, Toshiyuki Oshiki, Hiroki Kakuta, Kenji Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY 15 ( 2 ) 1014 - 1021 2007年1月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

In order to create novel analgesic agents without gastric disturbance, structurally simple cyclooxygenase-1 (COX-1) inhibitors with a benzenesulfonanilide skeleton were designed and synthesized. As a result, compounds 11f and 15a, which possess a p-amino group on the benzenesulfonyl moiety and p-chloro group on the anilino moiety, showed COX-1-selective inhibition. Moreover compound 11f, which is the most potent compound in this study showed more potent analgesic activity than that of aspirin at 30 mg/kg by po. The anti-inflammatory activity and gastric damage, however, were very weak or not detectably different from aspirin. Since the structure of our COX-1 inhibitors are very simple, they may be useful as lead compounds for superior COX-1 inhibitors as analgesic agents without gastric disturbance. (c) 2006 Published by Elsevier Ltd.

DOI： 10.1016/j.bmc.2006.10.029

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Antimalarial effect of bis-pyridinium salts, N,N '-hexamethylenebis(4-carbamoyl-1-alkylpyridinium bromide)

K Fujimoto, D Morisaki, M Yoshida, T Namba, K Hye-Sook, Y Wataya, H Kourai, H Kakuta, K Sasaki

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 16 ( 10 ) 2758 - 2760 2006年5月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

The in vitro antimalarial activity of bis-pyridinium salts, N,N'-hexamethylenebis(4-carbamoyl-1-decylpyridinium bromide) and their derivatives, against the Plasmodium falciparum FCR-3 strain (ATCC 30932, chloroquine-sensitive) was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 3.5 mu M to 10 nM. The chain length of the N1-alkyl moiety was found to be very beneficial in terms of antimalarial activity, and in this series of compounds, the most appropriate N1-alkyl chain length was found to be eight. (C) 2006 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2006.02.030

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Involvement of intracellular Ca2+ levels in nonsteroidal anti-inflammatory drug-induced apoptosis

Ken-Ichiro Tanaka, Wataru Tomisato, Tatsuya Hoshino, Tomoaki Ishihara, Takushi Namba, Mayuko Aburaya, Takashi Katsu, Keitarou Suzuki, Shinji Tsutsumi, Tohru Mizushima

Journal of Biological Chemistry 280 ( 35 ) 31059 - 31067 2005年9月

記述言語：英語

We recently reported that nonsteroidal anti-inflammatory drug (NSAIB)-induced gastric lesions involve NSAID-induced apoptosis of gastric mucosal cells, which in turn involves the endoplasmic reticulum stress response, in particular the up-regulation of CCAAT/enhancer-binding protein homologous transcription factor (CHOP). In this study, we have examined the molecular mechanism governing this NSAID-induced apoptosis in primary cultures of gastric mucosal cells. Various NSAIDs showed membrane permeabilization activity that correlated with their apoptosis-inducing activity. Various NSAIDs, particularly celecoxib, also increased intracellular Ca2+ levels. This increase was accompanied by K+ efflux from cells and was virtually absent when extracellular Ca2+ had been depleted. These data indicate that the increase in intracellular Ca2+ levels that is observed in the presence of NSAIDs is due to the stimulation of Ca2+ influx across the cytoplasmic membrane, which results from their membrane permeabilization activity. An intracellular Ca2+ chelator partially inhibited celecoxib-induced release of cytochrome c from mitochondria, reduced the magnitude of the celecoxib-induced decrease in mitochondrial membrane potential and inhibited celecoxib-induced apoptotic cell death. It is therefore likely that an increase in intracellular Ca2+ levels is involved in celecoxib-induced mitochondrial dysfunction and the resulting apoptosis. ATI inhibitor of calpain, a Ca2+-dependent cysteine protease, partially suppressed mitochondrial dysfunction and apoptosis in the presence of celecoxib. Celecoxib-dependent CHOP-induction was partially inhibited by the intracellular Ca2+ chelator but not by the calpain inhibitor. These results suggest that Ca2+-stimulated calpain activity and CHOP expression play important roles in celecoxib-induced apoptosis in gastric mucosal cells. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M502956200

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Transition-metal-catalyzed rearrangement of 5-alkynals to gamma-alkynylketones and 1-cyclopentenylketones

K Tanaka, K Sasaki, K Takeishi, K Sugishima

CHEMICAL COMMUNICATIONS ( 37 ) 4711 - 4713 2005年

Membrane permeabilization by non-steroidal anti-inflammatory drugs

W Tomisato, K Tanaka, T Katsu, H Kakuta, K Sasaki, S Tsutsumi, T Hoshino, M Aburaya, DW Li, T Tsuchiya, K Suzuki, K Yokomizo, T Mizushima

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 323 ( 3 ) 1032 - 1039 2004年10月

記述言語：英語出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE

The cytotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. The mechanism(s) behind these cytotoxic effects, however, is not well understood. We found here that several NSAIDs tested caused hemolysis when employed at concentrations similar to those that result in cytotoxicity. Moreover, these same NSAIDs were found to directly permeabilize the membranes of calcein-loaded liposomes. Given the similarity in NSAID concentrations for cytotoxic and membrane permeabilization effects, the cytotoxic action of these NSAIDs may be mediated through the permeabilization of biological membranes. Increase in the intracellular Ca2+ level can lead to cell death. We here found that all of NSAIDs tested increased the intracellular Ca2+ level at concentrations similar to those that result in cytotoxicity. Based on these results, we consider a possibility that membrane permeabilization by NSAIDs induces cell death through increase in the intracellular Ca2+ level. (C) 2004 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2004.08.205

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The synthesis of (±)-monomorine I starting with the palladium-catalyzed carbonylative 1,4-acylation of an organozinc chloride

Motoki Yuguchi, Masao Tokuda, Kenji Sasaki, Kazuhiko Orito

Bulletin of the Chemical Society of Japan 77 ( 5 ) 1031 - 1032 2004年5月

Winter cherry bugs feed on plant tropane alkaloids and de-epoxidize scopolamine to atropine.

Yoshie Kitamura, Yoshinori Tominaga, Kenji Sasaki, Toshihiko Ikenaga

Journal of Chemical Ecology 2004年

Synthesis of febrifugine derivatives and a solution to the puzzle of the structural determination of febrifugine

Y Takeuchi, K Azuma, M Oshige, H Abe, H Nishioka, K Sasaki, T Harayama

TETRAHEDRON 59 ( 10 ) 1639 - 1646 2003年3月

記述言語：英語出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

The stereo-structure of piperidine lactone (3), a synthetic intermediate of the antimalarial agent febrifugine ((+)-1) with a piperidine ring in the trans relative configuration, was re-revised to the cis-form. We determined that isomerization to the trans-form from the cis-form occurred in the stage (6 from 5) of deprotection in Baker's synthesis. (C) 2003 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0040-4020(03)00139-X

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Transglucosylation activities of multiple forms of α-glucosidase from spinach

Sugimoto, Manabu, Furui, Satoshi, Sasaki, Kenji, Suzuki, Yukio

Bioscience, Biotechnology, and Biochemistry 67 ( 5 ) 1160 - 1163 2003年1月

Synthesis and Characterization of 6-O-Acyl-2-O-a-D-Glucopyranosyl-L-ascorbic Acids with a Branched-acyl Chain

Akihiro Tai, Daisuke Kawasaki, Kenji Sasaki, Eiichi Gohda, Itaru Yamamoto

Chemical and Pharmaceutical Bulletin 2003年

Synthesis and characterization of a series of novel monoacylated ascorbic acid derivatives, 6-O-acyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acids, as skin antioxidants

Yamamoto, I, A Tai, Y Fujinami, K Sasaki, S Okazaki

JOURNAL OF MEDICINAL CHEMISTRY 45 ( 2 ) 462 - 468 2002年1月

記述言語：英語出版者・発行元：AMER CHEMICAL SOC

A series of novel monoacylated vitamin C derivatives were chemically synthesized with a stable ascorbate derivative, 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), and acid anhydrides in pyridine. Their solubility in organic phase, thermal stability, radical scavenging activity, and in vitro skin permeability was evaluated. These monoacylated derivatives were identified as 6-O-acyl-2-O-alpha-D-glucopyranosyl-L-ascorbic acids (6-Acyl-AA-2G) by UV spectra, elemental analyses, and nuclear magnetic resonance spectroscopy. The reactions afforded 6-Acyl-AA-2G in high yields (30-60%). 6-Acyl-AA-2G exhibited satisfactory stability in neutral solution comparable to that of atypical stable derivative, AA-2G, and also showed the radical scavenging activity. The lipid solubility of 6-Acyl-AA-2G was increased with increasing length of their acyl group. Increased skin permeability was superior to those of AA-2G and ascorbic acid (AsA). 6-Acyl-AA-2G that is susceptible to enzymatic hydrolysis by tissue esterase and/or alpha-glucosidase produces AA-2G and AsA, which is in the skin tissues. Thus, these findings indicate that the novel vitamin C derivatives presented here, 6-Acyl-AA-2G, may be effective antioxidants in skin care and medicinal use.

DOI： 10.1021/jm010379f

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Synthesis and Characterization of a Series of Novel Monoacylated Ascorbic Acid Derivatives, 6-O-Acyl-2-O-a-D-glucopyranosyl-L-ascorbic Acids, as Skin Antioxidants.

Itaru Yamamoto, Akihiro Tai, Yoshihito Fujinami, Kenji Sasaki, Shino Okazaki

J. Med. Chem. 2002年

Synthesis of Methylthiomaleimides for the Preparation of Pyridazines and Related Compound

Yoshinori Tominaga, Yasuhiro Shigemitsu, Kenji Sasaki

J. Heterocyclic Chem. 2002年

Synthesis of methylthiomaleimides for the preparation of pyridazines and related compounds

Yoshinori Tominaga, Yasuhiro Shigemitsu, Kenji Sasaki

Journal of Heterocyclic Chemistry 39 ( 3 ) 571 - 591 2002年

記述言語：英語出版者・発行元：HeteroCorporation

New functionalized maleimides (3-methylthio-2,5-dioxo-1H-pyrroles) were obtained by the reaction of ketene dithioacetals with nitromethane or the reaction of nitro ketene dithioacetal with active methylene compounds in the presence of the appropriate base in dimethyl sulfoxide followed by treatment with methanol. These maleimides reacted with various nucleophilic reagents such as electron-rich aromatic and heteroaromatic compounds like dialkylanilines, aminophenols, indoles, indolizines, and cyalazines to give the corresponding 3-aryl- or heteroaryl-1H-pyrole-2,5-diones. Styryl and merocyanine dyes, and polycyclic pyridazine-diones as chemiluminophors and succinimides were also obtained from these maleimides with good results.

DOI： 10.1002/jhet.5570390312

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Study on Glutathionesulfonic Acid Sodium Salt as Biodistribution Promoter for Thiopental Sodium

Yuhsuke Ohkawa, Tomonori Fujimoto, Kyohko Higashiyama, Hiroshi Maeda, Tomoyuki Asoh, Masateru Kurumi, Kenji Sasaki, Taiji Nakayama

Biological and Pharmaceutical Bulletin 2002年

Re-revision of the Stereo Structure of Piperidine Lactone, an Intermediate in the Synthesis of Febrifugine

Yasuo Takeuchi, Kumiko Azuma, Hiroshi Abe, Kenji Sasaki, Takasi Harayama

Chemical and Pharmaceutical Bulletin 2002年

A new dipeptide, O-phosphoserylethanolamine isolated from Agkistroden blomhoffi (mamushi)

Noriyoshi Masuoka, Jianying Zhang, Leila Partoo, Jun Ohta, Kenji Sasaki, Hideo Ebinuma, Hiroyuki Kodama

Archives of Biochemistry and Biophysics 2002年

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