研究者詳細 - 加来田　博貴

論文 - 加来田　博貴

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Modification at the acidic domain of RXR agonists has little effect on permissive RXR-heterodimer activation 査読

Shuji Fujii, Fuminori Ohsawa, Shoya Yamada, Ryosuke Shinozaki, Ryosuke Fukai, Makoto Makishima, Shuichi Enomoto, Akihiro Tai, Hiroki Kakuta

Bioorganic & medicinal chemistry letters 20 ( 17 ) 5139 - 5142 2010年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Retinoid X receptors (RXRs) function as homo-or heterodimers with other nuclear receptors, such as peroxisome proliferator-activated receptors (PPARs), which are targets for treatment of hyperlipidemia and type 2 diabetes, or liver X receptors (LXRs), which are involved in glucose/lipid metabolism. PPAR/RXR or LXR/RXR are known as permissive RXR-heterodimers because they are activated by RXR agonists alone. Interestingly, the pattern of RXR-heterodimer activation is different depending on the RXR agonist structure, but the structure-activity relationship has not been reported. Here we show that modification or replacement of the carboxyl group in the acidic domain of RXR agonists has little or no effect on permissive RXR-heterodimer activation. Phosphonic acid (9), tetrazole (10), and hydroxamic acid (12) analogues were synthesized from the common bromo intermediate 7. Except for 9, these compounds showed RXR full-agonistic activities in the concentration range of 1-10 mu M. The order of agonistic activity toward both PPAR gamma/RXR alpha and LXR alpha/RXR alpha was the same as it was for RXR, that is, 11 > 10 > 12. These results should be useful for the development of RXR agonists with improved bioavailability. (C) 2010 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2010.07.012

Replacing alkyl sulfonamide with aromatic sulfonamide in sulfonamide-type RXR agonists favors switch towards antagonist activity 査読

Ken-ichi Morishita, Nobumasa Yakushiji, Fuminori Ohsawa, Kayo Takamatsu, Nobuyasu Matsuura, Makoto Makishima, Masatoshi Kawahata, Kentaro Yamaguchi, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

Bioorganic & medicinal chemistry letters 19 ( 3 ) 1001 - 1003 2009年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Retinoid X receptor (RXR) ligands are attractive candidates for clinical application because of their activity against tamoxifen-resistant breast cancer, taxol-resistant lung cancer, metabolic syndrome, and allergy. Though several RXR ligands, especially RXR antagonists, have been reported, the rational molecular design of such compounds is not well advanced. 4-[N-Methanesulfonyl-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) amino] nicotinic acid (5a) is a moderately RXR alpha-preferential agonist, and we examined the feasibility of replacing the methyl group on the sulfonamide with a longer alkyl chain or an aromatic ring as an approach to produce new RXR antagonists. Several of the resulting benzenesulfonanilide-type compounds showed RXR antagonist activity. This design strategy should be a useful approach for addressing the lack of structure diversity of RXR antagonists. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmcl.2008.11.086

Design and synthesis of benzenesulfonanilides active against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus 査読

Kensuke Namba, Xiaoxia Zheng, Kazunori Motoshima, Hidetomo Kobayashi, Akihiro Tai, Eizo Takahashi, Kenji Sasaki, Keinosuke Okamoto, Hiroki Kakuta

Bioorganic & medicinal chemistry 16 ( 11 ) 6131 - 6144 2008年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Vancomycin is mainly used as an antibacterial agent of last resort, but recently vancomycin-resistant bacterial strains have been emerging. Although new antimicrobials have been developed in order to overcome drug-resistant bacteria, many are structurally complex beta-lactams or quinolones. In this study, we aimed to create new anti-drug-resistance antibacterials which can be synthesized in a few steps from inexpensive starting materials. Since sulfa drugs function as p-aminobenzoic acid mimics and inhibit dihydropteroate synthase (DHPS) in the folate pathway, we hypothesized that sulfa derivatives would act as folate metabolite-mimics and inhibit bacterial folate metabolism. Screening of our sulfonanilide libraries, including benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors, led us to discover benzenesulfonanilides with potent anti-methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant Enterococcus (VRE) activity, that is, N-3,5-bis(trifluoromethyl) phenyl-3,5-dichlorobenzenesulfonanilide (16b) [MIC = 0.5 mu g/mL (MRSA), 1.0 mu g/mL (VRE)], and 3,5-bis(trifluoromethyl)-N-(3,5-dichlorophenyl) benzenesulfonanilide (16c) [MIC = 0.5 mu g/mL (MRSA), 1.0 mu g/mL (VRE)]. These compounds are more active than vancomycin [MIC = 2.0 mu g/mL (MRSA), 125 mu g/mL (VRE)], but do not possess an amino group, which is essential for DHPS inhibition by sulfa drugs. These results suggested that the mechanism of antibacterial action of compounds 16b and 16c is different from that of sulfa drugs. We also confirmed the activity of these compounds against clinical isolates of Gram-positive bacteria. (C) 2008 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.bmc.2008.04.040

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

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

Cyclooxygenase-1-selective inhibitors are attractive candidates for analgesics that do not cause gastric damage. design and in vitro/in vivo evaluation of a benzamide-type cyclooxygenase-1 selective inhibitor 査読

Hiroki Kakuta, Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Kenji Sasaki, Akihiro Tai

Journal of medicinal chemistry 51 ( 8 ) 2400 - 2411 2008年

担当区分：筆頭著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：AMER CHEMICAL SOC

Although cyclooxygenase-1 (COX-1) inhibition is thought to be a major mechanism of gastric damage by nonsteroidal anti-inflammatory drugs (NSAIDs), some COX-1-selective inhibitors exhibit strong analgesic effects without causing gastric damage. However, it is not clear whether their analgesic effects are attributable to COX-1-inhibitory activity or other bioactivities. Here, we report that N-(5-amino-2-pyridinyl)-4(trifluoromethyl)benzamide (18f, TFAP), which has a structure clearly different from those of currently available COX-1-selective inhibitors, is a potent COX-1-selective inhibitor (COX-1IC(50) = 0.80 +/- 0.05 mu M, COX-2IC(50) = 210 I mu M). This compound causes little gastric damage in rats even at an oral dose of 300 mg/kg, though it has an analgesic effect at as low a dose as 10 mg/kg. Our results show that COX-1-selective inhibitors can be analgesic agents without causing gastric damage.

DOI： 10.1021/jm701191z

The first potent subtype-selective retinoid X receptor (RXR) agonist possessing a 3-isopropoxy-4-isopropylphenylamino moiety, NEt-3IP (RXRalpha/beta-dual agonist) 査読

Kayo Takamatsu, Atsushi Takano, Nobumasa Yakushiji, Kazunori Morohashi, Ken-ichi Morishita, Nobuyasu Matsuura, Makoto Makishima, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

ChemMedChem 3 ( 5 ) 780 - 787 2008年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：WILEY-BLACKWELL

Retinoid X receptor (RXR) agonists (rexinoids) ore attracting much attention for their use in treatment of cancers, including tomoxifen-resistant breast cancer and toxol-resistant lung cancer, and metabolic disease. However, known RXR agonists have a highly lipophilic character. In addition, no subtype-selective RXR agonists have been found. We previously reported on RXR alpha-preferential agonist 4-[N-methanesulfonyl-N-(5,5,8,8-tetromethyl-5,6,7,8tetrahydro-2-naphthyl)amino]benzoic acid (6a). The RXR agonistic activity is much less than that of well-known RXR agonists. To develop potent, less-lipophilic, and subtype-selective RXR agonists, we created new RXR agonists possessing alkoxy and isopropyl groups as a lipophilic domain of the common structure of well-known RXR agonists. As a result, compounds possessing branched alkoxy groups, 6-[N-ethyl-N-(3-isopropoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IP: 7a) and 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB: 7c), showed RXR agonistic activity as potent as, or more potent than, the activities of representative RXR agonists. Moreover NEt-3IP (7a) was found to be the first RXR alpha/beta-selective (or RXR alpha/beta-dual) agonist. Being potent, less lipophilic, and having RXR subtype-selective activity, NEt-3IP (7a) is expected to become a new drug candidate and to be a useful biological toot for clarifying each RXR subtype function.

DOI： 10.1002/cmdc.200700313

Pyridinium cationic-dimer antimalarials, unlike chloroquine, act selectively between the schizont stage and the ring stage of Plasmodium falciparum 査読

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

Bioorganic & medicinal chemistry 16 ( 11 ) 6027 - 6033 2008年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Malaria is a leading cause of death in developing countries, and the emergence of strains resistant to the main therapeutic agent, chloroquine, has become a serious problem. We have developed cationic-dimer type antimalarials, MAP-610 and PMAP-H10, which are structurally different from chloroquine. In this study, we introduced several substituents on the terminal phenyl rings of PMAP-H10. The electronic and hydrophobic properties of the substituents were correlated with the antimalarial activity and cytotoxicity of the compounds, respectively. Studies with synchronized cultures of malarial plasmodia showed that our cationic-dimers act selectively between the schizont stage and the ring stage of the parasitic cycle, unlike chloroquine, which has a stage-independent action. Thus, the mechanism of action of our antimalarials appears to be different from that of chloroquine, and our compounds may be effective against chloroquine-resistant strains. (C) 2008 Published by Elsevier Ltd.

DOI： 10.1016/j.bmc.2008.04.051

Effect of the oral absorption of benzenesulfonanilide-type cyclooxygenase-1 inhibitors on analgesic action and gastric ulcer formation 査読

Xiaoxia Zheng, Hiroyuki Oda, Shun Harada, Yukio Sugimoto, Akihiro Tai, Kenji Sasaki, Hiroki Kakuta

Journal of pharmaceutical sciences 97 ( 12 ) 5446 - 5452 2008年

担当区分：最終著者,　責任著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JOHN WILEY & SONS INC

A benzensulfonanilide-type cyclooxygenase-1 (COX-1)-selective inhibitor, ZXX2-77: 4-amino-4'-chloro-N-methylbenzenesulfonanilide (4a), has been reported as a novel analgesic that does not cause gastric damage. This compound has a weak analgesic effect but has potent in vitro COX-1 inhibitory activity. Since the reason for the weak analgesic effect in vivo was thought to be the low rate of oral absorption, the blood concentration of ZXX2-77 (4a) was measured in rats. It was found that the C(max) value (1.2 mu M) of ZXX2-77 (4a) at a dose of 30 mg/kg did not reach the COX-1 IC(50) value (3.2 mu M). On the other hand, ZXX2-79 (4b) (SO(2)NH derivative of ZXX2-77 (4a); 4-amino-4'-chlorobenzenesulfonanilide), which shows less potent COX inhibitory activities (COX-1 IC(50) = 12 mu M, COX-2 IC(50) = 150 mu M) than those of ZXX2-77 (4a) in vitro, was found to be more absorbable (C(max) - 16 mu M at a dose of 30 mg/kg in rats) than ZXX2-77 (4a). Furthermore, ZXX2-79 (4b) not only showed a potent analgesic effect in a formalin test but also caused little gastric damage. These findings indicate that demethylated sulfonamide compounds are more easily absorbed than are N-methylated sulfonamide compounds and suggest that COX-1-selective inhibitors will be useful as analgesics that do not cause gastric damage. (C) 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5446-5452, 2008

DOI： 10.1002/jps.21388

Necessity is the mother of invention: an ingenious method for leukocyte-targeted delivery of siRNA in stabilized nanoparticles demonstrates a role of cyclin D1 in inflammation

Hiroki Kakuta

ChemMedChem 2008年

Necessity is the mother of invention: An ingenious method for leukocyte-targeted delivery of siRNA in stabilized nanoparticles demonstrates a role of cyclin D1 in inflammation

Kakuta, H.

ChemMedChem 3 ( 7 ) 2008年

Analgesic agents without gastric damage: Design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors (vol 15, pg 1014, 2007) 査読

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 ( 9 ) 3299 - 3300 2007年5月

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

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

ChemMedChem 2 ( 10 ) 1527 - 1532 2007年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）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

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

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

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）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

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

Kanji Fujimoto, Daiki Morisaki, Munehiro Yoshida, Tetsuto Namba, Kim Hye-Sook, Yusuke Wataya, Hiroki Kourai, Hiroki Kakuta, Kenji Sasaki

Bioorganic & medicinal chemistry letters 16 ( 10 ) 2758 - 2760 2006年

記述言語：英語掲載種別：研究論文（学術雑誌）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

Membrane permeabilization by non-steroidal anti-inflammatory drugs 査読

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

Biochemical and biophysical research communications 323 ( 3 ) 1032 - 1039 2004年

記述言語：英語掲載種別：研究論文（学術雑誌）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

Cyclooxygenase inhibitors derived from thalidomide 査読

Mamiko Suizu, Yohei Muroya, Hiroki Kakuta, Hiroyuki Kagechika, Aya Tanatani, Kazuo Nagasawa, Yuichi Hashimoto

Chemical & pharmaceutical bulletin 51 ( 9 ) 1098 - 1102 2003年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Several N-3,5-dimethylphenylphthalimide analogs possessing more potent cyclooxygenase-inhibiting activity than that of aspirin were prepared during structural development studies based on thalidomide. Substituent effects on the activity were investigated.

DOI： 10.1248/cpb.51.1098

Fluorescent bioprobes for visualization of puromycin-sensitive aminopeptidase in living cells 査読

Hiroki Kakuta, Yukiko Koiso, Kazuo Nagasawa, Yuichi Hashimoto

Bioorganic & medicinal chemistry letters 13 ( 1 ) 83 - 86 2003年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

Non-peptide, small-molecular, non-competitive inhibitors of puromycin-sensitive aminopeptidase (PSA), that is, 3-(2,6-diethylphenyl)-2,4(1H,3 H)-quinazolinedione (PAQ-22, 3) and its 1N-methyl analogue (MPAQ-22 4), were structurally modified to afford fluorescent bioprobes, ANTAQ (5) and DAMPAQ-22 (6). The cellular localization of PSA could be visualized by the use of these fluorescent bioprobes. (C) 2002 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/s0960-894x(02)00845-4

DOI： 10.1016/S0960-894X(02)00845-4

Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton 査読

Hiroki Kakuta, Aya Tanatani, Kazuo Nagasawa, Yuichi Hashimoto

Chemical & pharmaceutical bulletin 51 ( 11 ) 1273 - 1282 2003年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PHARMACEUTICAL SOC JAPAN

Potent, specific, chemically stable and non-peptide/small-molecular inhibitors of puromycin-sensitive aminopeptidase, such as 3-(2,6-diethylphenyl)-2,4(1H,3H)-quinazolinedione (PAQ-22, 5), were prepared by the structural development of a potent PSA inhibitor, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22, 4). The design was carried out partly by applying electrostatic potential field information obtained from PIQ-22 (4) and its derivatives based on thalidomide (2). This information revealed that a positive electrostatic potential field around the benzylic methylene in the tetrahydroisoquinoline ring is necessary for potent activity. Lineweaver-Burk plot analysis showed that PAQ-22 (5) and its derivatives inhibit puromycin-sensitive aminopeptidase (PSA) in a non-competitive manner. These potent and specific PSA inhibitors showed dose-dependent cell invasion-inhibitory activity in a Matrigel assay using mouse melanoma B16F10/L5 cells, in spite of their low cell toxicity.

DOI： 10.1248/cpb.51.1273

Specific inhibitor of puromycin-sensitive aminopeptidase with a homophthalimide skeleton: Identification of the target molecule and a structure-activity relationship study 査読

M Komoda, H Kakuta, H Takahashi, Y Fujimoto, S Kadoya, F Kato, Y Hashimoto

BIOORGANIC & MEDICINAL CHEMISTRY 9 ( 1 ) 121 - 131 2001年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

2-(2,6-Diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (2: PIQ-22) was found to be a potent and specific inhibitor of puromycin-sensitive aminopeptidase (PSA). Lineweaver-Burk plot analysis showed that PSA is inhibited by PIQ-22 in a non-competitive manner. Structure-activity relationship studies indicated that tautomerism of the imidobenzoylketone group in the cyclic imide moiety of the PIQ-22 skeleton is important for the inhibitory activity. (C) 2000 Elsevier Science Ltd. All rights reserved.

DOI： 10.1016/S0968-0896(00)00231-5

Novel Specific Puromycin-sensitive Aminopeptidase Inhibitors: 3-(2,6-Diethylphenyl)-2,4(1H,3H)quinazolinedione and N-(2,6-Diethylphenyl)-2-amino-4H-3,1-benzoxazin-4-one 査読

Hiroki Kakuta, Yukiko Koiso, Hiroyasu Takahashi, Kazuo Nagasawa, and Yuichi Hashimoto

HETEROCYCLES 55 ( 8 ) 1433 - 1438 2001年

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Japan Institute of Heterocyclic Chemistry

Novel specific PSA (puromycin-sensitive aminopeptidase) inhibitors, 3-(2,6-diethylphenyl)-2,4(1H, 3H)-quinazolinedione (3: PAQ-22) and N-(2,6-diethylphenyl)-2-amino-4H-3,1-benzoxazin-4-one (4: PAZOX-22), were designed and synthesized. These compounds are chemically much more stable than the known specific PSA inhibitor PIQ-22 (2), and the enzyme specificity and inhibitory activity to PSA are similar to those of 2. The inhibitory manner of these compounds was found to be a non-competitive mode by Lineweaver- Burk plot analysis.

DOI： 10.3987/com-01-9247

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