Papers - Obata, Rika

Quantum yield improvement of red-light-emitting firefly luciferin analogues for in vivo bioluminescence imaging

Masahiro Kiyama, Satoshi Iwano, Satoshi Otsuka, Shijia W. Lu, Rika Obata, Atsushi Miyawaki, Takashi Hirano, Shojiro A.Maki

Tetrahedron 74 ( 6 ) 652 - 660 2017.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0040-4020

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Discovery of benzo[g]indoles as a novel class of non-covalent Keap1-Nrf2 protein-protein interaction inhibitor

Daisuke Yasuda, Akihiro Yuasa, Rika Obata, Mao Nakajima, Kyoko Takahashi, Tomoyuki Ohe, Yoshinobu Ichimura, Masaaki Komatsu, Masayuki Yamamoto, Riyo Imamura, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Tadahiko Mashino

Bioorganic and Medicinal Chemistry Letters (ELSEVIER)  27 ( 22 ) 5006 - 5009 2017.11

Research paper (scientific journal), Joint Work, Accepted

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Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein inter- action inhibitors and their inhibitory activity

Daisuke Yasuda, Mao Nakajima, Akihiro Yuasa, Rika Obata, Kyoko Takahashi, Tomoyuki Ohe, Yoshinobu Ichimura, Masaaki Komatsu, Masayuki Yamamoto, Riyo Imamura, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Tadahiko Mashino

Bioorganic and Medicinal Chemistry Letters (ELSEVIER)  26 ( 24 ) 5956 - 5959 2016.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming

Tetsuya Saito, Yoshinobu Ichimura, Keiko Taguchi, Takafumi Suzuki, Tsunehiro Mizushima, Kenji Takagi, Yuki Hirose, Masayuki Nagahashi, Tetsuro Iso, Toshiaki Fukutomi, Maki Ohishi, Keiko Endo, Takefumi Uemura, Yasumasa Nishito, Shujiro Okuda, Miki Obata, Tsuguka Kouno, Riyo Imamura, Yukio Tada, Rika Obata, Daisuke Yasuda, Kyoko Takahashi, Tsutomu Fujimura, Jingbo Pi, Myung-Shik Lee, Takashi Ueno, Tomoyuki Ohe, Tadahiko Mashino, Toshifumi Wakai, Hirotatsu Kojima, Takayoshi Okabe, Tetsuo Nagano, Hozumi Motohashi, Satoshi Waguri, Tomoyoshi Soga, Masayuki Yamamoto, Keiji Tanaka, Masaaki Komatsu

Nature Communications 7 2016.06

Research paper (scientific journal), Joint Work, Accepted

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Multicolor bioluminescence obtained using firefly luciferin

Masahiro Kiyama, Ryohei Saito, Satoshi Iwano, Rika Obata, Haruki Niwa, Shojiro A. Maki

Current Topics in Medicinal Chemistry 16 ( 24 ) 2648 - 2655 2016

Research paper (scientific journal), Joint Work, Accepted

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Crystal structure of 5,5′-dibromo-3,3′-di-tert-butyl-6,6′-dimethylbiphenyl-2,2′-diol

Obata Rika, Ohba Shigeru, Einaga Yasuaki, Nishiyama Shigeru

Acta Crystallographica Section E: Structure Reports Online 71 ( Pt 5 ) o278 - o279 2015.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1600-5368

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<p>The whole molecule of the title compound, C&lt;inf&gt;22&lt;/inf&gt;H&lt;inf&gt;28&lt;/inf&gt;Br&lt;inf&gt;2&lt;/inf&gt;O&lt;inf&gt;2&lt;/inf&gt;, is generated by twofold rotation symmetry. The dihedral angle of the biphenyl moiety is 85.05 (11)°. The hydroxy groups show intramolecular O - H⋯π interactions without any other hydrogen-bond acceptors. In the crystal, there are no other significant intermolecular interactions present.</p>

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Cathodic reductive coupling of methyl cinnamate on boron-doped diamond electrodes and synthesis of new neolignan-type products

Kojima, Taiki, Obata, Rika, Saito, Tsuyoshi, Einaga, Yasuaki, Nishiyama, Shigeru

Beilstein Journal of Organic Chemistry (Beilstein-Institut zur Foerderung der Chemischen Wissenschaften)  11   200 - 203 2015.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1860-5397

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The electroredn. reaction of Me cinnamate on a boron-doped diamond (BDD) electrode was investigated. The hydrodimer, di-Me 3,4-diphenylhexanedioate (racemate/meso = 74:26), was obtained in 85% yield as the major product, along with small amts. of cyclic Me 5-oxo-2,3-diphenylcyclopentane-1-carboxylate. Two new neolignan-type products were synthesized from the hydrodimer.

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Synthesis and luminescence properties of biphenyl-type firefly luciferin analogs with a new, near-infrared light-emitting bioluminophore

Miura Chihiro, Kiyama Masahiro, Iwano Satoshi, Ito Kazuto, Obata Rika, Hirano Takashi, Maki Shojiro, Niwa Haruki

Tetrahedron 69 ( 46 ) 9726 - 9734 2013.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0040-4020

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<p>New firefly luciferin analogs of the 4,4′-substituted biphenyl-type were synthesized. One analog with a 4′-dimethylamino group possessed bioluminescence activity, emitting near-infrared biological window light at 675 nm suitable for deep-site bioimaging of living animals. The chemiluminescence light-emission maximum of the corresponding methyl ester of the bioluminescence active analog was 500 nm, implying that biphenyl and thiazolinone rings in the light emitter might be placed in a coplanar conformation at the polar luciferase active site. © 2013 Elsevier Ltd. All rights reserved.</p>

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Development of simple firefly luciferin analogs emitting blue, green, red, and near-infrared biological window light

Iwano Satoshi, Obata Rika, Miura Chihiro, Kiyama Masahiro, Hama Kazutoshi, Nakamura Mitsuhiro, Amano Yoshiharu, Kojima Satoshi, Hirano Takashi, Maki Shojiro, Niwa Haruki

Tetrahedron (Elsevier Ltd.)  69 ( 19 ) 3847 - 3856 2013.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0040-4020

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<p>Simple firefly luciferin analogs emitting blue, green, and red light were developed. The longest emission maximum was observed at 675 nm, which belongs to the NIR biological window (650-900 nm), useful for deep site bioimaging of living animals. The analogs showed a slow rise of emission intensity compared with the rapid emission of natural luciferin. The light emission of the adenylated analogs was strongly enhanced compared with those of analogs themselves.© 2013 Elsevier Ltd. All rights reserved.</p>

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A new NF-κB inhibitor based on the amino-epoxyquinol core of DHMEQ

Saitoh Tsuyoshi, Shimada Chika, Takeiri Masatoshi, Shiino Mitsuhiro, Ohba Shigeru, Obata Rika, Ishikawa Yuichi, Umezawa Kazuo, Nishiyama Shigeru

Bioorganic and Medicinal Chemistry Letters 20 ( 19 ) 5638 - 5642 2010.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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<p>The amino-epoxyquinols 6a and 6b were synthesized as soluble derivatives of an NF-κB inhibitor DHMEQ (1). In spite of the opposite configuration from 1, 6b rather than 6a affected the deactivation of NF-κB, based on NO secretion and MALDI-TOF MS analysis. It was indicated that 6b inhibited the activation by different manner from that of 1. © 2010 Elsevier Ltd. All rights reserved.</p>

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Synthesis of Epoxyquinols via Anodic Oxidation and Evaluation of NF-κB Inhibitory Activity.

Takeshi Saitoh, Eriko Suzuki, Arisa Takasugi, Rika Obata, Yuichi Ishikawa, Kazuo Umezawa, Shigeru Nishiyama

ECS Meeting Abstract, 217th ECS Meeting (The Electrochemical Society)  MA2010-01 2010.04

Research paper (international conference proceedings), Joint Work

Structural basis for inverting the enantioselectivity of arylmalonate decarboxylase revealed by the structural analysis of the Gly74Cys/Cysl88Ser mutant in the liganded form

Obata Rika, Nakasako Masayoshi

Biochemistry (American Chemical Society)  49 ( 9 ) 1963 - 1969 2010.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0006-2960

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<p>Arylmalonate decarboxylase catalyzes the enantioselective decarboxylation of α-aryl-α-methylmalonate to produce optically pure α-arylpropionate. The enzyme is comprised of two α/β domains and contains an active site situated between the two domains. The site is formed by Tyr48, Gly74-Thr75-Ser76, Tyr126, and Cys188-Gly189-Gly190 residues. Since it has been observed that the Gly74Cys/Cys188Ser mutation inverts the enantioselectivity of the enzyme, we determined the crystal structure of the Gly74Cys/ Cys188Ser mutant in the liganded form at a resolution of 1.45 Å to understand the structural basis for this inversion. The overall structure of the enzyme overlapped well with that of the benzylphosphonate-associated wild-type enzyme, and the mutations had little effect on the structure of the active site. A ligand molecule bound to the active site in an unusual semiplanar conformation resembling the planar enediolate reaction intermediate could be assigned as phenyl acetate. The inversion in enantioselectivity by the paired mutation is explained by the mirror symmetry between Cys74 in the mutant and Cys188 of the wild type with respect to the carbon atom in the ligand to be protonated. Comparison of the wild-type and Gly74Cys mutant crystal structures suggested that ligand binding induces a positional shift of the Cys188-Gly189-Gly190 region toward the Gly74-Thr75 pair which provides two oxyanion holes necessary to stabilize the negatively charged enediolate reaction intermediate. The ligand binding also simultaneously induces the formation of a hydrophobic cluster over the active site cleft. Thus, AMDase is proposed to have "open" and "closed" conformations of the active site that are regulated by ligand binding. These results may provide an effective strategy for the rational design to invert the enantioselectivity of enzymes. © 2010 American Chemical Society.</p>

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Efficient synthesis of (±)-parasitenone, a novel inhibitor of NF-κB.

Saitoh Tsuyoshi, Suzuki Eriko, Takasugi Arisa, Obata Rika, Ishikawa Yuichi, Umezawa Kazuo, Nishiyama Shigeru

Bioorganic and Medicinal Chemistry Letters 19 ( 18 ) 5383 - 5386 2009.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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<p>Dehydroxymethylepoxyquinomicin (DHMEQ, 1) is a novel nuclear factor-κB (NF-κB) inhibitor that inhibits DNA binding of NF-κB components including p65. To inspect its biological activity of 1, we synthesized parasitenone (3), possessing the common epoxycyclohexenone moiety of 1. Assessment of the inhibitory activity against NF-κB indicated that the epoxycyclohexenone moiety is the most essential element for the NF-κB inhibitory activity and the salicylic acid moiety may contribute the binding efficiency and specificity. © 2009 Elsevier Ltd. All rights reserved.</p>

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Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone, an inhibitor of NF-κB.

Ishikawa Yuichi, Tachibana Miyuki, Matsui Chino, Obata Rika, Umezawa Kazuo, Nishiyama Shigeru

Bioorganic and Medicinal Chemistry Letters (Elsevier B.V.)  19 ( 6 ) 1726 - 1728 2009.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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<p>Synthesis of 9-methylstreptimidone analogs and their inhibitory activities against NF-κB (nuclear factor-κB) are reported. Among several active derivatives synthesized in this study, 8 with a relatively simple structure, exhibited inhibitory activity against LPS-induced NO production comparable to that of 9-methylstreptimidone. © 2009 Elsevier Ltd. All rights reserved.</p>

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Crystallization and preliminary X-ray diffraction experiments of arylmalonate decarboxylase from Alcaligenes bronchisepticus

Nakasako Masayoshi, Obata Rika, Okubo Ryosuke, Nakayama Shyuichi, Miyamoto Kenji, Ohta Hiromichi

Acta Crystallographica Section F: Structural Biology and Crystallization Communications (International Union of Crystallography)  64 ( 7 ) 610 - 613 2008.05

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1744-3091

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<p>Arylmalonate decarboxylase catalyses the enantioselective decarboxylation of α-aryl-α-methylmalonates to produce optically pure α-arylpropionates. The enzyme was crystallized with ammonium sulfate under alkaline pH conditions with the aim of understanding the mechanism of the enantioselective reaction. X-ray diffraction data collected to a resolution of 3.0 Å at cryogenic temperature showed that the crystals belonged to the orthorhombic space group P212121, with unit-cell parameters a = 83.13, b = 99.62, c = 139.64 Å. This suggested that the asymmetric unit would contain between four and six molecules. Small-angle X-ray scattering revealed that the enzyme exists as a monomer in solution. Thus, the assembly of molecules in the asymmetric unit was likely to have been induced during the crystallization process. © International Union of Crystallography 2008.</p>

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Synthesis of pinguisane-type sesquiterpenoids acutifolone A, pinguisenol, and bisacutifolones by a Diels-Alder dimerization reaction

Shiina Junichi, Oikawa Masataka, Nakamura Kensuke, Obata Rika, Nishiyama Shigeru

European Journal of Organic Chemistry (Wiley-VCH Verlag GmbH & Co. KGaA)   ( 31 ) 5190 - 5197 2007.08

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1434-193X

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<p>The total synthesis of pinguisane-type sesquiterpenoids, acutifolone A (1) and pinguisenol (2), has been achieved by using the Mukaiyama aldol reaction as the key step. The intermolecular Diels-Alder reaction of these monomelic natural products successfully led to stereoselective dimerization, leading to bisacutifolones A (3) and B (4). Theoretical calculations revealed that the dimerization reaction proceeded through the most stable transition state. © Wiley-VCH Verlag GmbH &amp; Co. KGaA, 2007.</p>

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Bacillus subtilis epoxide hydrolase-catalyzed preparation of enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether and its application to expeditious synthesis of (R)-bicalutamide

Fujino Aya, Asano Masayoshi, Yamaguchi Hitomi, Shirasaka Naoki, Sakoda Akiko, Ikunaka Masaya, Obata Rika, Nishiyama Shigeru, Sugai Takeshi

Tetrahedron Letters 48 ( 6 ) 979 - 983 2007.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0040-4039

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<p>Expeditious synthesis of (R)-bicalutamide (1), a synthetic antiandrogen, from enantiopure 2-methylpropane-1,2,3-triol monobenzyl ether (4) was achieved. An engineered Bacillus subtilis epoxide hydrolase worked enantioselectively on the racemic epoxide (7) to provide the above starting material in highly enantiomerically enriched state. © 2006 Elsevier Ltd. All rights reserved.</p>

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Screening, substrate specificity and stereoselectivity of yeast strains, which reduce sterically hindered isopropyl ketones

Hiraoka Chihiro, Matsuda Masaaki, Suzuki Yuya, Fujieda Shigeo, Tomita Mina, Fuhshuku Ken ichi, Obata Rika, Nishiyama Shigeru, Sugai Takeshi

Tetrahedron Asymmetry 17 ( 24 ) 3358 - 3367 2006.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0957-4166

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<p>Towards the synthesis of sterically hindered optically active secondary alcohol 2, yeast strains (Candida floricola IAM 13115 and Trichosporon cutaneum IAM 12206) with si-face hydride attack on isopropyl phenylsulfonylmethyl ketone 1 were developed by screening. Strains with complementary re-facial selectivity (Pichia angusta IAM 12895 and Pichia minuta IAM 12215) were also found. Based on the substrate specificity studies of these four strains, microbial reduction was applied to the synthesis of (3S,5S)-2,6-dimethyl-3,5-heptanediol 12a. © 2007 Elsevier Ltd. All rights reserved.</p>

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Oxidative cyclization of isodityrosine tripeptides: Optimized condition and application of electrochemically generated thallium(III) ion

Tanabe Takamasa, Obata Rika, Nishiyama Shigeru

Heterocycles (Japan Institute of Heterocyclic Chemistry)  69 ( 1 ) 113 - 118 2006.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0385-5414

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<p>Thallium(III) trinitrate oxidation of the tripeptide, which was a synthetic precursor of the 17-membered isodityrosine natural product, eurypamide, was investigated to give the desired cyclized compound in 96% yield at best. In addition, the thallium(III) species generated by electrochemical oxidation of thallium(I) successfully produced the target compounds. © 2006 The Japan Institute of Heterocyclic Chemistry.</p>

Synthesis of chiloscyphones and the biological activities of their synthetic intermediates against methicillin-resistant Staphylococcus aureus (MRSA)

Shiina Junichi, Obata Rika, Tomoda Hiroshi, Nishiyama Shigeru

European Journal of Organic Chemistry  ( 10 ) 2362 - 2370 2006.05

Research paper (scientific journal), Joint Work,  ISSN  1434-193X

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<p>The total syntheses of chiloscyphone (1) and isochiloscyphone (2) have been achieved. Furthermore, the synthetic intermediate 5 shows biological activity against methicillin-resistant Staphyrococcus aureus, and compounds 5, 17, and 18, display imipenem-type activity. The tricyclic lactone framework, which includes an α,β-unsaturated ketone moiety, might play a crucial role in the anti-MRSA activity. © Wiley-VCH Verlag GmbH &amp; Co. KGaA, 2006.</p>

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Synthesis and biological assessment of hemiacetal spiro derivatives towards development of efficient chemotherapeutic agent

Ogamino Takahisa, Ohnishi Sayo, Ishikawa Yuichi, Sugai Takeshi, Obata Rika, Nishiyama Shigeru

Science and Technology of Advanced Materials 7 ( 2 ) 175 - 183 2006.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1468-6996

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<p>We have developed an efficient construction of spiro derivatives by anodic oxidation of the corresponding phenols, which enabled synthesis of spiroisoxazoline natural products as well as heliannuols, carrying chroman and benzooxepin structures. In addition to nucleophilic attack of hydroxyl or amino groups to the cation generated electrochemerically, it might be of interest to use a carbonyl oxygen as a nucleophilic center, which would provide hemiacetal-type spiro compounds. Gymnastatin A 1 was isolated from the strain of Gymnescella dankaliensis separated from the sponge Halichondria japonica, together with other gymnastatins. This marine natural product consists of the spiro structure between the dienone part including two chlorine atoms, and the tetrahydrofuran ring with a hemiacetal moiety, along with the fatty acid part having an asymmetric carbon center attached with the amino group. As part of our extensive electrochemical investigation of halogenated tyrosine derivatives, synthesis of the acetal-spiro derivatives and its application to gymnastatin A 1 was undertaken to develop further efficient and green sustainable methodology. In these investigations, construction of spiro compounds having hemiacetal moiety, and synthesis of gymnastatin A 1 was achieved successfully. In addition to the synthesis, biological assessment of synthetic samples was examined. Among them, 3, 5, 14, and 15 showed a wide range of inhibitory activity against Gram-positive, -negative bacteria, fungus, and Mycobacterium. © 2006 Elsevier Ltd. All rights reserved.</p>

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An expeditious chemo-enzymatic synthesis of dihydronorcapsaicin β-d-glucopyranoside

Sultana Israt, Shimamoto Miwa, Obata Rika, Nishiyama Shigeru, Sugai Takeshi

Science and Technology of Advanced Materials 7 ( 2 ) 197 - 201 2006.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  1468-6996

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<p>A seven-step and scalable synthesis of dihydronorcapsaicin β-d-glucopyranoside, non-pungent and adrenal secretion enhancement activity (diet effect), was accomplished from vanillin. A simple and inexpensive glucosyl donor, acetobromoglucose, was reacted with phenolic hydroxyl group of α-iodovanillin nitrile under basic conditions. Another key step was the lipase-catalyzed coupling reaction of primary amine, which was resulted from the reduction of the glucosylated product, with methyl nonanoate. © 2006.</p>

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Chemo-enzymatic approach towards the capsaicin glucoside

Sultana, Israt, Shimamoto, Miwa, Obata, Rika, Nishiyama, Shigeru, Sugai, Takeshi

Abstracts of Papers, 231st ACS National Meeting, Atlanta, GA, United States, March 26-30, 2006 (AMERICAN CHEMICAL SOCIETY)   2006.03

Research paper (conference, symposium, etc.), Joint Work

Asymmetric synthesis of aerothionin, a marine dimeric spiroisoxazoline natural product, employing optically active spiroisoxazoline derivative

Ogamino Takahisa, Obata Rika, Nishiyama Shigeru

Tetrahedron Letters 47 ( 5 ) 727 - 731 2006.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0040-4039

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<p>Successful first synthesis of optically pure (+)- and (-)-aerothionins (1) from the racemic spiroisoxazoline derivative 8 has been accomplished. The absolute configuration of natural (+)-1 was determined by comparison of (+)- and (-)-8 with related derivatives. © 2005 Elsevier Ltd. All rights reserved.</p>

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Total synthesis, structural revision and biological evaluation of calafianin, a marine spiroisoxazoline from the sponge, Aplysina gerardogreeni.

T. Ogamino, R. Obata, H. Tomoda, and S. Nishiyama

Bulletin of the Chemical Society of Japan (Chemical Society of Japan)  79 ( 1 ) 134 - 139 2006.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0009-2673

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The reported structure of the natural calafianin (I) and its isomer in the epoxide region II were successfully synthesized through the cis- and trans-spiroisoxazoline compds., which were produced by electrochem. oxidn. of the hydroxyimino-phenol deriv. III, followed by Zn[BH4]2 redn. Comparison of the spectroscopic data of the synthetic (±)-I and (±)-II resulted in structural revision of the natural calafianin to II, possessing the trans-relationship between an epoxide and an oxygen of the isoxazoline. In addn., a significant difference of antimicrobial activity between I and II is discussed.

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Solid-Phae Synthesis and Biological Activities of Biphenyl Ether-Containing Cyclic Oligopeptides

Nazuhiko Nakamura, Rika Obata, and Shigeru Nishiyama

Peptide Science 2005: T. Wakamiya (Ed.) (The Japanese Peptide Society)  42nd   127 - 130 2005.12

Research paper (conference, symposium, etc.), Joint Work,  ISSN  1344-7661

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A symposium report. Halogenated cyclic isodityrosine-class tripeptides were synthesized as analogs of eurypamide B, a marine natural product. The cyclic peptides were synthesized using thallium(III) oxidn. as a key reaction to construct the biaryl ether linkage in good yield. In addn., manipulation of trityl resin-supported tripeptide as a substrate of oxidn. enabled a solid-phase synthesis of the peptides. Upon combination with imipenem, some of the resultant eurypamide-analogs showed anti-MRSA activity.

Efficient route to (S)-azetidine-2-carboxylic acid

Futamura Yasuhiko, Kurokawa Masayuki, Obata Rika, Nishiyama Shigeru, Sugai Takeshi

Bioscience, Biotechnology and Biochemistry 69 ( 10 ) 1892 - 1897 2005.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0916-8451

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<p>A new and efficient route to (S)-azetidine-2-carboxylic acid (&gt;99.9% ee) in five steps and total yield of 48% via malonic ester intermediates was established. As the key step, efficient four-membered ring formation (99%) was achieved from dimethyl (S)-(1′-methyl)benzylaminomalonate by treating with 1,2-dibromoethane (1.5 eq) and cesium carbonate (2 eq) in DMF. Krapcho dealkoxycarbonylation of dimethyl (1′S)-1-(1′-methyl) benzylazetidine-2,2-dicarboxylate, the product of this cyclization procedure, proceeded with preferential formation (2.7:1, 78% total yield) of the desired (2S,1′S)-monoester, with the help of a chiral auxiliary which was introduced on the nitrogen atom. The undesired (2R,1′S)-isomer could be converted to that with proper stereochemistry, by a deprotonation and subsequent reprotonation step. Finally, lipase-catalyzed preferential hydrolysis of the (2S,1′S)-monoester and subsequent deprotection provided enantiomerically pure (S)-azetidine-2-carboxylic acid in a 91% yield from the mixture of (2S,1′S)- and (2R,1′S)-isomers.</p>

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Discovery of halogenated eurypamide B analogues as inhibitors of lipid droplet accumulation in macrophages

Obata Rika, Ohshiro Taichi, Tomoda Hiroshi, Nishiyama Shigeru

Bioorganic and Medicinal Chemistry Letters 15 ( 19 ) 4189 - 4191 2005.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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<p>Halogenated cyclic isodityrosine-tripeptides were synthesized as analogues of a marine natural product, eurypamide B. Although the original eurypamides showed no inhibitory activity, the new analogues were found to inhibit lipid droplet accumulation in macrophages with a low micromolar IC₅₀ value. © 2005 Elsevier Ltd. All rights reserved.</p>

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Purification of Shiga-like toxin 1 by pigeon egg white glycoproteins immobilized on Sepharose gels

Tomoda Hiroshi, Arai Masayoshi, Koyama Nobuhiro, Matsui Hidenori, Omura Satoshi, Obata Rika, Lee Yuan C.

Analytical Biochemistry 311 ( 1 ) 50 - 56 2002.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0003-2697

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<p>The galabiose structure Galα1-4Gal is rarely found in natural glycoproteins, but is abundantly present in pigeon egg white proteins as Galα(1-4)Galβ(1-4)GlcNAc termini. Pigeon ovalbumin, ovomucoid, or the whole egg white were immobilized on periodate-oxidized Sepharose CL-6B gels by reductive amination. These gels were found to bind Shiga-like toxin type 1 (SLT-1) specifically and efficiently. SLT-1 was eluted from the gel beads with 0.5 M melibiose, which was more efficient and milder than elution with 4.5 M MgCl₂. SLT-1 was purified to homogeneity from the crude extract of Escherichia coli SLT100 expressing SLT-1 by a single affinity chromatographic step in 83-88% yield. The capacity of the gel was estimated to be ca. 1 mg toxin/ml gel. Interestingly, SLT-2 was not bound by these affinity gels containing Galα1-4Galβ1-4GlcNAc termini. Since SLT-2 has been shown to bind to Galα1-4Galβ1-4Glc-terminating compounds, our results suggest that Glc in globotriose moiety is important for binding SLT-2, and replacing the Glc with GlcNAc in this triose renders it ineffective for binding SLT-2. © 2002 Elsevier Science (USA). All rights reserved.</p>

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Reversal of multidrug resistance by 7-O-Benzoylpyripyropene A in multidrug-resistant tumor cells.

Rho M. C., Hayashi M., Fukami A., Obata R., Sunazuka T., Tomoda H., Komiyama K., Omura S.

Journal of Antibiotics 53 ( 10 ) 1201 - 1206 2000.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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<p>7-O-Benzoylpyripyropene A (7-O-BzP), a semi-synthetic analog of pyripyropene, was investigated for its reversing effect on multidrug-resistant (MDR) tumor cells. 7-O-BzP (6.25 μg/ml) completely reversed resistance against vincristine and adriamycin in vincristine-resistant KB cells (VJ-300) and adriamycin-resistant P388 cells (P388/ADR), respectively. 7-O-BzP alone had no effect on the growth of drug sensitive and drug-resistant cells. 7-O-BzP (6.25 μg/ml) significantly enhanced accumulation of [³H]vincristine in VJ-300 cells and completely inhibited the binding of [³H]azidopine to the P-glycoprotein in VJ-300 cells and P388/ADR cells. The result suggests that 7-O-BzP effectively reverses P-glycoprotein-related MDR by interacting directly with P-glycoprotein in drug resistant VJ-300 and P388/ADR cells.</p>

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Synthetic conversion of ACAT inhibitor to acetylcholinesterase inhibitor

Obata Rika, Sunazuka Toshiaki, Otoguro Kazuhiko, Tomoda Hiroshi, Harigaya Yoshihiro, Omura Satoshi

Bioorganic and Medicinal Chemistry Letters 10 ( 12 ) 1315 - 1316 2000.06

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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<p>Natural product acyl-CoA:cholesterol acyltrasferase (ACAT) inhibitor pyripyropene A was synthetically converted to acetylcholinesterase (AChE) inhibitor via heterolitic cleavage of the 2-pyrone ring, followed by γ-acylation/cyclization with several aroyl chlorides. The 4-pyridyl analogue selectively showed AChE inhibitory activity (IC₅₀ = 7.9 μM) and no ACAT inhibitory activity IC₅₀ = &gt; 1000 μM. (C) 2000 Elsevier Science Ltd. All rights reserved.</p>

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Structure-activity relationships study of pyripyropenes: reversal of cancer cell multidrug resistance.

Obata Rika, Sunazuka Toshiaki, Harigaya Yoshihiro, Hayashi Masahiko, Rho Mun Chual, Tomoda Hiroshi, Omura Satoshi

Journal of Antibiotics 53 ( 4 ) 422 - 425 2000.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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This article describes the potential in reversing multidrug resistance by pyripyropene derivs. in drug-resistant cells. Sixten structurally representative derivs. of pyripyropene were tested for the enhancement of sensitivity of adriamycin or vincristine in antitumor agent resistant P388 cells by previously reported methods.

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ラット白血球遊走に対する14員環マクロライド系化合物の影響

OBATA RIKA

Japanese Journal of Antibiotics 53 ( Suppl A ) 85 - 88 2000

Research paper (scientific journal), Joint Work, Accepted

Effects of erythromycin and its derivatives on interleukin-8 release by human bronchial epithelial cell line BEAS-2B cells

Sunazuka T., Takizawa H., Desaki M., Suzuki K., Obata R., Otoguro K., Omura S.

Journal of Antibiotics 52 ( 1 ) 71 - 74 1999.01

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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The authors report here the suppressive effect on IL-8 release, the antimicrobial activity and the gastrointestinal motor-stimulating activity of erythromycin-A, clarithromycin and erythromycin derivs. and describe the structure-activity relationships. The results suggest that 14-membered macrolides such as erythromycin had specifically suppressive effect on the release of cytokines such as IL-8 from bronchial epithelial cells. There are no relation among the suppressive effects on IL-8 release and min inhibitory concns. and the gastrointestinal motor-stimulating activities. One compd. is interesting because this compd. showed a moderate suppressive effect on IL-8. release but had no antimicrobial and gastrointestinal motor-stimulating activities. The possible development of erythromycin derivs. as new type anti-inflammatory agents is discussed.

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New analogs of the pyripyropene family of ACAT inhibitors via α-pyrone fragmentation and γ-acylation/cyclization

Obata Rika, Sunazuka Toshiaki, Tian Zhiming, Tomoda Hiroshi, Harigaya Yoshihiro, Omura Satoshi, Smith Amos B. III

Chemistry Letters (Chemical Society of Japan)   ( 9 ) 935 - 936 1997.09

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0366-7022

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<p>The pyridine moiety of pyripyropene A was replaced with other aromatic and heteroaromatic substituents via α-pyrone degradation followed by dienolate γ-acylation and in situ cyclization.</p>

Chemical modification and structure-activity relationships of pyripyropenes. 3. Synthetic conversion of pyridine-pyrone moiety

Obata Rika, Sunazuka Toshiaki, Tian Zhiming, Tomoda Hiroshi, Harigaya Yoshihiro, Omura Satoshi

Journal of Antibiotics 50 ( 3 ) 229 - 236 1997.03

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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<p>Structure-activity relationships of the pyridine-pyrone moiety in pyripyropene A (1), a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor of fungal origin, were studied. Several kinds of aromatic or hetero ring substituents for the pyridine moiety were synthesized using unique degradation reaction, following by γ-acylation. All the six synthesized analogs decreased the inhibitory activity with 20 to 200 times larger IC₅₀ values than that of 1. Furthermore, the pyridine-pyrone substituent also dramatically decrease the inhibitory activity. Thus, the pyridine-pyrone moiety is important for eliciting potent ACAT inhibition.</p>

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Chemical modification and structure-activity relationships of pyripyropenes. 1. Modification at the four hydroxyl groups

Obata Rika, Sunazuka Toshiaki, Li Zhuorong, Tian Zhiming, Harigaya Yoshihiro, Tabata Noriko, Tomoda Hiroshi, Omura Satoshi

Journal of Antibiotics 49 ( 11 ) 1133 - 1148 1996.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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<p>Four hydroxyl groups of pyripyropenes have been modified and evaluated for their ability to inhibit microsomal acyl-CoA: cholesterol acyltransferase (ACAT) activity in vitro and to lower cholesterol absorption in vivo in a cholesterol-fed hamster. 7-O-n-Valeryl derivative (8c) improved the in vitro ACAT inhibitory activity (IC₅₀ = 13 nM) about 7 times better than pyripyropene A. Introduction of methanesulfonyl group at 11-hydroxyl group (17a) increased both in vitro activity(IC₅₀ = 19 nM) and in vivo efficacy (ED₅₀ = 10 mg/kg).</p>

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Chemical modification and structure-activity relationships of pyripyropenes. 2. 1,11-cyclic analogs

Obata Rika, Sunazuka Toshiaki, Kato Yumiko, Tomoda Hiroshi, Harigaya Yoshihiro, Omura Satoshi

Journal of Antibiotics 49 ( 11 ) 1149 - 1156 1996.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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<p>A series of 1,11-cyclic analogs of pyripyropene A were prepared. Replacement of the 1,11-acyl groups of pyripyropenes with 1,11-cyclic acetals effectively improved in vitro acyl CoA:cholesterol acyltransferase (ACAT) inhibitory activity. Especially noteworthy is benzylidene acetal analog 35, the most potent inhibitor (IC₅₀ = 5.6 nM) among the derivatives prepared so far, which showed 16 times more potent inhibitory activity than pyripyropene A.</p>

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Biosynthesis of pyripyropene A

Tomoda H., Tabata N., Nakata Y., Nishida H., Kaneko T., Obata R., Sunazuka T., Omura S.

Journal of Organic Chemistry 61 ( 3 ) 882 - 886 1996.02

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-3263

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<p>The biosynthetic origin of pyripyropene A (1) was studied by feeding sodium [1-¹³C]-, [2-¹³C]-, and [1,2-¹³C₂]acetates, D,L-[2-¹³C]mevalonolactone, and [carboxy-¹⁴C]nicotinic acid to the producing organism Aspergillus fumigatus FO-1289-2501. ¹³C NMR and degradation experiments of ¹³C- and ¹⁴C-labeled 1 established that 1 is derived from three mevalonates, five acetates, and one nicotinic acid. The biosynthetic scheme for 1 proposes that (1) a pyridino-α-pyrone moiety is produced via condensation of a primer nicotinic acid with two acetates in a 'head-to-tail' fashion, (2) an all-trans farnesyl pyrophosphate is produced via the mevalonate pathway, (3) the two parts are linked and cyclized to form the core skeleton, and (4) then three acetyl residues from acetates are introduced into the skeleton to yield 1. This is the first demonstration that an intact nicotinic acid works as an acyl primer unit for oligoketide formation in fungal secondary metabolites.</p>

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Total synthesis of (+)-pyripyropene A. A potent, orally bioavailable inhibitor of acyl-CoA

Nagamitsu Tohru, Sunazuka Toshiaki, Obata Rika, Tomoda Hiroshi, Tanaka Haruo, Harigaya Yoshihiro, Omura Satoshi, Smith Amos B.

Journal of Organic Chemistry 60 ( 25 ) 8126 - 8127 1995.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0022-3263

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The first total synthesis of pyripyropene A (I), a potent, orally active inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), has been achieved via a flexible, concise and efficient route (16 steps, 9.3% yield). In the key transformation, O-acylation of hydroxy α-pyrone II with acid chloride III in trifluoroacetic acid led to 1,3-acyl migration and internal 1,4-addn., generating pentacyclic ketone IV with the requisite anti BC ring junction.

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Chemical modification and structure-activity relationships of pyripyropenes; potent, bioavailable inhibitor of acyl-CoA

Obata Rika, Sunazuka Toshiaki, Tomoda Hiroshi, Harigaya Yoshihiro, Omura Satoshi

Bioorganic and Medicinal Chemistry Letters 5 ( 22 ) 2683 - 2688 1995.11

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0960-894X

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<p>Modification and structure-activity relationships of ACAT inhibitor pyripyropene were examined. PR-109 (7g) showed the most potent (IC₅₀ = 6 nM) inhibitory activity. PR-86 (2e) also had strong inhibitory activity (IC₅₀ = 19 nM) and its in vivo activity improved 10 times better (ED₅₀ = 10 mg/kg) than that of pyripyropene A. © 1995.</p>

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The first total synthesis of (+)-pyripyropene A; potent, bioavailable inhibitor of acyl-CoA: cholesterol acyltransferase.

Toshiaki Sunazuka, Tohru Nagamitsu, Haruo Tanaka, Toshihiro Harigaya, Rika Obata, Hiroshi Tomoda, Satoshi Omura

Tennen Yuki Kagobutsu Toronkai Koen Yoshishu (Nippon Kagakkai)  37th   1 - 6 1995.09

Research paper (conference, symposium, etc.), Joint Work, Accepted

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A symposium reporting on the total synthesis of (+)-pyripyropene A with 6 refs.

Structure-activity relationships of lactacystin, the first non-protein neurotrophic factor.

Nagamitsu T., Sunazuka T., Stump H., Obata R., Arima S., Matsuzaki K., Tanaka H., Omura S.

Journal of Antibiotics 48 ( 7 ) 747 - 748 1995.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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Some derivs. of lactacystin were prepd. and evaluated for neurotrophic activity and cytotoxicity. Structure-activity relationships are discussed. The most interesting compd. is the descarboxylactacystin.

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Structure-activity relationships of pyripyropenes fungal Acyl-CoA

Obata R., Sunazuka T., Zhuorong L., Tomoda H., Omura S.

Journal of Antibiotics 48 ( 7 ) 749 - 750 1995.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0021-8820

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Fifteen derivs. of pyripyropene A I (R = acyl groups) were prepd. and tested as inhibitors of acyl-CoA cholesterol acyltransferase. Among the derivs., the one with the n-valeryl group was the most potent.

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Relative and absolute stereochemistry of pyripyropene A, A potent, bioavailable inhibitor of Acyl-CoA

Tomoda Hiroshi, Nishida Hiroyuki, Kim Young Kook, Obata Rika, Sunazuka Toshiaki, Omura Satoshi, Bordner Jon, Guadliana Mark, Dormer Peter G., Smith Amos B.

Journal of the American Chemical Society 116 ( 26 ) 12097 - 12098 1994.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0002-7863

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The complete relative stereochem. of pyripyropene A has been elucidated via NOE difference studies and X-ray crystallog.; the abs. configuration was then assigned via the Kakisawa-Kashman modification of Mosher's NMR method. The biosynthetically related pyripyropenes B-D presumably share the same relative and abs. stereochem.

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Relative and absolute stereochemistry of the melanogenesis inhibitors OH-3984 K1 and K2. Partial synthesis from albocycline

Sunazuka Toshiaki, Obata Rika, Zhuorong Li, Takamatsu Satoshi, Komiyama Kanki, Omura Satoshi, Smith Amos B.

Tetrahedron Letters 35 ( 17 ) 2635 - 2636 1994.04

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0040-4039

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<p>The transformation of the macrolide antibiotic albocycline (3) to the recently isolated melanin synthesis inhibitors OH-3984 K1 (1 and K2 (2) has established the relative and absolute configurations of 1 (4R, 7R, 12S) and 2 (4R, 7R, 12S, 13R). © 1994.</p>

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Pyripyropenes, novel inhibitors of acyl-CoA:cholesterol acyltransferase produced by Aspergillus fumigatus. II. Structure elucidation of pyripyropenes A, B, C and D.

Kim Y. K., Tomoda H., Nishida H., Sunazuka T., Obata R., Omura S.

Journal of Antibiotics 47 ( 2 ) 154 - 162 1994.02

Research paper (scientific journal), Accepted,  ISSN  0021-8820

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<p>The structures of pyripyropenes A, B, C and D, novel acyl-CoA :cholesterol acyltransferase (ACAT) inhibitors, were determined mainly by spectroscopic studies including various NMR measurements. Pyripyropenes have a common structure which consists of pyridine, α-pyrone and sesquiterpene moieties. One of the three O-acetyl residues in the sesquiterpene moiety of pyripyropene A is replaced with an O-propionyl residue in pyripyropenes B, C and D.</p>

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Electrochemical oxidation of anti-tumor agent, etoposide.

Rika Obata, Takeshi Ohnuma

Chemical & Pharmaceutical Bulletin (Chemical Society of Japan)  41 ( 10 ) 1846 - 1847 1993.10

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0009-2363

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As part of a search for new potent derivs., electrochem. oxidn. of etoposide was carried out under controlled potential (500 mV) to yield 1,2-dehydroetoposide I, dehydroxy-podophyllotoxin II (R2 = H) and tetradehydroetoposide II (R2 = OR). Compds. I-III showed no cytotoxicity against B16-melanoma.

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Preparation and antitumor activity of 2"-O-, 3"-O- and 2",3"-di-O-substituted derivatives of etoposide.

Takeshi Ohnuma, Rika Obata, Yuji Nishiyama, Tetsuro Yamasaki, Hideo Kamei, Takayuki Naito, Toshikazu Oki

Chemical & Pharmaceutical Bulletin (Chemical Society of Japan)  40 ( 7 ) 1783 - 1788 1992.07

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0009-2363

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The 2"-O-, 3"-O- and 2",3"-di-O-substituted derivs. I (R1, R2 = Ac, Bz, CHO, SO2Me, SO2C6H4Me-4, PO3Na2, SO3Na) of etoposide were prepd. by nucleophilic substitution of 4'-O-benzyloxycarbonyletoposide followed by deprotection. Controlled reaction (a limited amt. of reagents and low temp.) was required for prepg. the mono-O-substituted derivs. In terms of ED125 values, doses which show 125% of T/C against P388 leukemia in mice, both the 2"-O-acetate (ED125=0.18 mg/kg) and 3"-O-acetate (0.23 mg/kg) were nearly as active as etoposide (0.19 mg/kg), while the 2",3"-di-O-acetate (1.9 mg/kg) was somewhat less potent. In the replacement with other substituents, antitumor activity of the 2"-O-substituted derivs. was affected much more than that of the 3"-O-substituted derivs. In the 2",3"-di-O-substituted derivs., the activity was decreased additively by the substituents.

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