研究者詳細 - 佐々木　健二

MISC - 佐々木　健二

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Polycyclic N-heterocyclic compounds. Part 74. Rearrangement reaction of 5-amino-1,2-dihydrofuro[2,3-c]isoquinolines with α,ω-dibromoalkanes and evaluation of product bronchodilator activity

Kensuke Okuda, Masahiko Yoshida, Takashi Hirota, Kenji Sasaki

Synthetic Communications 42 ( 6 ) 865 - 871 2012年

Quercetin diacylglycoside analogues showing dual inhibition of DNA gyrase and topoisomerase IV as novel antibacterial agents （共著）

「Hossion Abugafar M, L」「Zamami Yoshito」「Kandahary Rafiya K」「Tsuchiya Tomofusa」「Ogawa Wakano」「Iwado Akimasa」「Sasaki Kenji」

Journal of Medicinal Chemistry 54 ( 11 ) 3686 - 3703 2011年6月

Polycyclic N-heterocyclic compounds. Part 70: synthesis of 5-amino-1,2-dihydrofuro[2,3-b]pyrido[3',2':4,5]-thieno[3,2-d]pyridines and related compounds. Evaluation of effects on lipoprotein lipase mRNA expression （共著）

Heterocycles 83 ( 6 ) 1315 - 1328 2011年6月

Polycyclic N-heterocyclic compounds. Part 66: Synthesis of N-[2-([1,2,4]oxadiazol-5-yl)cyclopenten-1-yl]formamide oximes and their evaluation as inhibitors of platelet aggregation （共著）

「Okuda, Kensuke, 」「Zhang, Ying-Xue」「Ohtomo, Hiromi」「Hirota, Takashi」「Sasaki, Kenji」

Journal of Heterocyclic Chemistry 48 ( 3 ) 715 - 719 2011年5月

Polycyclic N-Heterocyclic Compounds, Part 68: Reactions of 3-(2-Bromoethyl)quinazolin-4(3H)-one and 3-(2-Bromoethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one with Primary Alkylamines via a Dimroth-Type Rearrangement

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

SYNTHETIC COMMUNICATIONS 41 ( 6 ) 812 - 819 2011年

記述言語：英語出版者・発行元：TAYLOR & FRANCIS INC

[image omitted] The reaction of 3-(2-bromoethyl)quinazolin-4(3H)-one with ethyl- and n-propylamine gave abnormal fused 3-alkyl-4-alkyliminoquinazolines via a Dimroth-type rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives in methanol. The reaction of 3-(2-bromoethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one with primary alkylamines was also investigated for the scope of this rearrangement reaction.

DOI： 10.1080/00397911003668570

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7-Chloro-1,2-dihydrofuro[2,3-c]isoquinolin-5-amine

Kensuke Okuda, Takashi Hirota, Kenji Sasaki, Hiroyuki Ishida

ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE 66 ( 11 ) O2949 - U1351 2010年11月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

In the title compound, C11H9ClN2O, the fused-ring system is essentially planar, with a maximum deviation of 0.0323 (16) angstrom. In the crystal, molecules are connected by N-H center dot center dot center dot O hydrogen bonds forming a zigzag chain along the c axis. Molecules are further stacked along the a axis through weak pi-pi interactions, the shortest being 3.6476 (8) angstrom.

DOI： 10.1107/S160053681004273X

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Design, synthesis, and biological evaluation of a novel series of quercetin diacylglucosides as potent anti-MRSA and anti-VRE agents （共著）

「Hossion Abugafar M L」「Otsuka Nao」「Kandahary, Rafiya K」「Tsuchiya Tomofusa」「Ogawa Wakano」「Iwado Akimasa」「Zamami Yoshito」「Sasaki Kenji」

Bioorganic & Medicinal Chemistry Letters 20 ( 17 ) 5349 - 5352 2010年9月

Polycyclic N-Heterocyclic Compounds. Part 64: Synthesis of 5-Amino-1,2,6,7-tetrahydrobenzo[f]furo[2,3-c]isoquinolines and Related Compounds. Evaluation of Their Bronchodilator Activity and Effects on Lipoprotein Lipase mRNA Expression

Kensuke Okuda, Hiroshi Deguchi, Setsuo Kashino, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 5 ) 685 - 689 2010年5月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

Reaction of 1-(3-cyanopropoxy)-3,4-dihydronaphthalene-2-carbonitriles with potassium tert-butoxide gave 5-amino-1,2,6,7-tetrahydrobenzo[f]furo[2,3-c]isoquinolines via a Truce Smiles rearrangement. The 5-amino group was transformed to the bromo derivatives which were allowed to react with aliphatic cyclic amines to produce amino derivatives. In contrast, a combination of imidazole and NaH gave a dihydrofuran ring cleaved product, the structure of which was confirmed by X-ray crystallographic analysis. Effects of the newly synthesized compounds on carbamylcholine chloride-induced contractions of trachea and lipoprotein lipase mRNA expression were also evaluated and found one promising bronchodilator.

DOI： 10.1248/cpb.58.685

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Polycyclic N-Heterocyclic Compounds. Part 65: Ring Cleavage Reactions of Fused Furo[2,3-c]isoquinolines and Related Compounds with Various Nucleophiles

Kensuke Okuda, Hiroshi Deguchi, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 5 ) 755 - 757 2010年5月

Polycyclic N-Heterocyclic Compounds. Part 62: Reaction of N-(Quinazolin-4-yl)amidine Derivatives with Hydroxylamine Hydrochloride and Anti-platelet Aggregation Activity of the Products

Kensuke Okuda, Ying-Xue Zhang, Hiromi Ohtomo, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 3 ) 369 - 374 2010年3月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

The reactions of N-(5,6,7,8-tetrahydroquinazolin-4-yl)amidines and their amide oximes with hydroxylamine hydrochloride gave abnormal cyclization products via a ring cleavage of pyrimidine component accompanied with a ring closure of 1,2,4-oxadiazole to give N-[2-([1,2,4]oxidiazol-5-yl)cyclohexen-1-yl]formamide oximes. Similarly, N-(quinazolin-4-yl)amidines reacted with hydroxylamine hydrochloride gave the same results. The evaluation of inhibitory activities against platelet aggregation in vitro is also described to show one derivative has potent activity.

DOI： 10.1248/cpb.58.369

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Polycyclic N-Heterocyclic Compounds. Part 63 Improved Synthesis of 5-Amino-1,2-dihydrofuro[2,3-c]isoquinolines via Truce-Smiles Rearrangement and Subsequent Formation to Furo[2,3-c]isoquinoline

Kensuke Okuda, Masahiko Yoshida, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 58 ( 3 ) 363 - 368 2010年3月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

An improved synthesis of 5-amino-1,2-dihydrofuro[2,3-c]isoquinoline has been achieved using a slight niodification of reaction Conditions for the Truce-Smiles rearrangement. Acid treatment of the obtained 5-amino-1,2-dihydrofuro [2,3-c]isoquinolines gave unexpected ring-opened spiro ring compounds. The previously unreported Parent compound, furo[2,3-c]isoquinoline, was also synthesized.

DOI： 10.1248/cpb.58.363

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Polycyclic N-heterocyclic compounds. Part 61: A novel Truce-Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2-d]furo[2,3-b]pyridines

Kensuke Okuda, Norimasa Watanabe, Takashi Hirota, Kenji Sasaki

TETRAHEDRON LETTERS 51 ( 6 ) 903 - 906 2010年2月

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

The cycloalkeno[1,2-d]furo[2,3-b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyanovinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, p-elimination and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce-Smiles type rearrangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good yields. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.tetlet.2009.12.010

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Polycyclic N-Heterocyclic Compounds. Part 60: Reactions of 3-(2-Cyanophenyl)quinazolin-4(3H)-ones with Primary Amines

Kensuke Okuda, Tsuyoshi Tagata, Setsuo Kashino, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 57 ( 11 ) 1296 - 1299 2009年11月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

The reaction of 3-(2-cyanophenyl)quinazolin-4(3H)-one with various primary alkylamines gave 3-alkylquinazolin-4(3H)-ones via an addition of the nucleophile, ring opening, and ring closure (ANRORC) mechanism. This type of reaction required hydroxy group functionality in either the solvent or reagent. When hydroxylamine was used as nitrogen nucleophile, the intermediate of this reaction was isolated and found to be an amide oxime. When ethylenediamine was used as the lie nucleophile, the amidine moiety of the intermediate decomposed to give a benzanilide.

DOI： 10.1248/cpb.57.1296

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Polycyclic N-Heterocyclic Compounds. Part 59(1)): Rearrangement Reactions of Fused Tricyclic 3-(2-Bromoethyl)pyrimidin-4(3H)-ones with Primary Amines via a Dimroth-Type Rearrangement

Kensuke Okuda, Hiromi Ohtomo, Fumiaki Tanaka, Takashi Hirota, Kenji Sasaki

CHEMICAL & PHARMACEUTICAL BULLETIN 57 ( 7 ) 755 - 758 2009年7月

記述言語：英語出版者・発行元：PHARMACEUTICAL SOC JAPAN

Reaction of some fused tricyclic 3-(2-bromoethvl)pyrimidin-4(3H)-ones with primary alkyl amines gave abnormal fused 3-alkyl-4-alkyliminopyrimidines via a Dimroth-type rearrangement, as well as normal substituted 3-(2-alkylaminoethyl) derivatives in methanol. This abnormal rearrangement reaction depended on reaction solvent.

DOI： 10.1248/cpb.57.755

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

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2月

記述言語：英語出版者・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

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Effect of the Oral Absorption Benzenesulfonanilide-Type Cyclooxygenase-1 Inhibitors on Analgesic Action and Gastric Ulcer Formation

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

JOURNAL OF PHARMACEUTICAL SCIENCES 97 ( 12 ) 5446 - 5452 2008年12月

記述言語：英語出版者・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

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

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

BIOORGANIC & MEDICINAL CHEMISTRY 16 ( 11 ) 6027 - 6033 2008年6月

記述言語：英語出版者・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

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

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6月

記述言語：英語出版者・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

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

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

CHEMMEDCHEM 3 ( 5 ) 780 - 787 2008年5月

記述言語：英語出版者・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

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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

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

JOURNAL OF MEDICINAL CHEMISTRY 51 ( 8 ) 2400 - 2411 2008年4月

記述言語：英語出版者・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

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