Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Go Hirai Last modified date:2021.10.26

Professor / Department of Chemo-Pharmaceutical Sciences / Faculty of Pharmaceutical Sciences

1. Yosei Nagaoka, Prakash Parvatkar, Go Hirai, Junko Ohkanda, Design, synthesis, and functional evaluation of triazine-based bivalent agents that simultaneously target the active site and hot spot of phosphatase Cdc25B., Bioorganic & medicinal chemistry letters, 10.1016/j.bmcl.2021.128265, 48, 128265-128265, 2021.09, Cdc25B phosphatase catalyzes the dephosphorylation and activation of cyclin-dependent kinases 2 (CDK2/CycA) and their overexpression has been reported in cancers. Although Cdc25B has received much attention as a drug target, its flat and featureless surface makes it challenging to develop new agents targeting this protein. In this study, we investigated the rational design of a series of bivalent triazine-based derivatives with the aim of simultaneously targeting the active site and the remote hotspot critical for the interaction with CDK2/CycA. Compounds 1e and 10, containing aromatic residues, were shown to inhibit Cdc25B activity selectively over Cdc25A at low micromolar concentration..
2. Daiki Takeda, Makoto Yoritate, Hiroki Yasutomi, Suzuka Chiba, Takahiro Moriyama, Atsushi Yokoo, Kazuteru Usui, Go Hirai, β-Glycosyl Trifluoroborates as Precursors for Direct α-C-Glycosylation: Synthesis of 2-Deoxy-α-C-glycosides, Organic Letters, 10.1021/acs.orglett.1c00402, 2021.03.
3. Go Hirai, Marie Kato, Hiroyuki Koshino, Eri Nishizawa, Kana Oonuma, Eisuke Ota, Toru Watanabe, Daisuke Hashizume, Yuki Tamura, Mitsuaki Okada, Taeko Miyagi, Mikiko Sodeoka, Ganglioside GM3 Analogues Containing Monofluoromethylene-Linked Sialoside: Synthesis, Stereochemical Effects, Conformational Behavior, and Biological Activities, JACS Au, 10.1021/jacsau.0c00058, 2021.02, Glycoconjugates are an important class of biomolecules that regulate numerous biological events in cells. However, these complex, medium-size molecules are metabolically unstable, which hampers detailed investigations of their functions as well as their potential application as pharmaceuticals. Here we report sialidase-resistant analogues of ganglioside GM3 containing a monofluoromethylene linkage instead of the native O-sialoside linkage. Stereoselective synthesis of CHF-linked disaccharides and kinetically controlled Au(I)-catalyzed glycosylation efficiently furnished both stereoisomers of CHF-linked as well as CF2- and CH2-linked GM3 analogues. Like native GM3, the C-linked GM3 analogues inhibited the autophosphorylation of epidermal growth factor (EGF) receptor induced by EGF in vitro. Assay of the proliferation-enhancing activity toward Had-1 cells together with NMR-based conformational analysis showed that the (S)-CHF-linked GM3 analogue with exo-gauche conformation is the most potent of the synthesized compounds. Our findings suggest that exo-anomeric conformation is important for the biological functions of GM3..
4. Kazuhiro Shiozaki, Keiya Uezono, Go Hirai, Akinobu Honda, Masaya Minoda, Ryuta Wakata, Identification of novel fish sialidase genes responsible for KDN-cleaving activity, Glycoconjugate Journal, 10.1007/s10719-020-09948-6, 37, 6, 745-753, 2020.12.
5. Yu Hidaka, Noriaki Kiya, Makoto Yoritate, Kazuteru Usui, Go Hirai, Synthesis of CH2-linked alpha-galactosylceramide and its glucose analogues through glycosyl radical-mediated direct C-glycosylation, Chemical Communications, 10.1039/d0cc00785d, 56, 34, 4712-4715, 2020.04, We describe a new synthetic approach for C-linked glycolipid analogues, in which the cleavable O-glycosidic linkage is replaced by a carbon unit. Direct C-glycosylation of a conformationally constrained and stable C1-sp3 hybridized xanthate carbohydrate with carefully designed sphingosine units afforded the CH2-linked analogue of antitumor-active KRN7000 and its glucose congener..
6. Ryoma Shiraishi, Tomoyo Kaneko, Kazuteru Usui, Tatsuya Naganuma, Naoko Iizuka, Kosuke Morishita, Shigeki Kobayashi, Yasufumi Fuchi, Yuta Matsuoka, Go Hirai, Ken Ichi Yamada, Satoru Karasawa, Effects of Substituents on the Properties of Metal-Free MRI Contrast Agents, ACS Omega, 10.1021/acsomega.9b03003, 4, 24, 20715-20723, 2019.12, Materials possessing electron spin can shorten the T1 relaxation times in magnetic resonance imaging (MRI). For example, gadolinium (Gd) complexes with seven f-orbital electrons are widely used as contrast agents in clinical applications. However, Gd has severe potential side effects, and thus metal-free alternatives are needed. Toward this end, we synthesized seven NO radicals consisting of a dioxa-azaspiro[4.5]decane framework having various substituents, DAD-X (X = methyl, ethyl, n-propyl, c-propyl, vinyl, phenyl, and 2-pyridyl), that functioned as metal-free MRI contrast agents. The relationship between (i) water-proton relaxivity and log※P and (ii) reactivity for ascorbic acid and the spin density of the NO oxygen atom were established, which provided a basis for the rational design of practical metal-free contrast agents..
7. M. Elsbaey, Bai Jie, Chiaki Tanaka, Hikaru Kato, Sachiko Tsukamoto, Kazuteru Usui, Go Hirai, Tomofumi Miyamoto, Nuciferols A and B
Novel sesquineolignans from Cocos nucifera, Tetrahedron Letters, 10.1016/j.tetlet.2019.150948, 60, 33, 2019.08, Two novel epimers, named nuciferols A (1) and B (2), possessing a unique 6.9′, 9.6′, 7′.8″-cyclosesquineolignan skeleton, were isolated from the ethyl acetate fraction of the endocarp of Cocos nucifera. Their planar structure was elucidated by 1D-, 2D-NMR, HRESIMS and their absolute configuration was determined by ECD. Nuciferols A and B showed radical scavenging activity using DPPH assay, and only nuciferol B showed neuroprotective effects against t-BHP induced cell death in N2a cells..
8. Shota Matsumoto, Yasufumi Fuchi, Kazuteru Usui, Go Hirai, Satoru Karasawa, Development of Turn-On Probes for Acids Triggered by Aromaticity Enhancement Using Tricyclic Amidine Derivatives, Journal of Organic Chemistry, 10.1021/acs.joc.9b00023, 84, 11, 6612-6622, 2019.06, Two fluorophores consisting of tricyclic amidine derivatives (DHIm and DHPy) were prepared as selective turn-on probes for acids, which were triggered by an aromaticity enhancement. Both amidine derivatives were expanded rings prepared by condensed reactions between the corresponding dibromoalkanes and an aminonaphthyridine analogue. In X-ray analyses, DHIm, in which the dihydroimidazole ring was condensed into aminonaphthyridine, showed high planarity, compared to DHPy, with condensed dihydropyrimidine. The fluorescence properties of DHIm exhibited a higher quantum yield than DHPy due to the difference in planarity. Under acidic conditions, such as in the presence of H+ and M(II), protonations and complexations occurred, exhibiting a higher quantum yield than the neutral DHX (X = Im or Py). The nucleus-independent chemical shift values from the density functional theory calculations suggested that the protonations and complexations caused an enhancement of the aromaticity within the frameworks. These aromaticity changes led to intense fluorescence, and DHX behaved as a selective turn-on probe for acids and metal ions. Interestingly, this fluorescence turn-on system triggered by the aromaticity-based enhancement is not a typical system, such as the photoinduced electron transfer, aggregation-induced enhanced emission, and twisted intramolecular charge transfer systems, but is classified as a novel turn-on system..
9. Yusaku Nomura, Frédéric Thuaud, Daisuke Sekine, Akihiro Ito, Satoko Maeda, Hiroyuki Koshino, Daisuke Hashizume, Atsuya Muranaka, Thomas Cruchter, Masanobu Uchiyama, Satoshi Ichikawa, Akira Matsuda, Minoru Yoshida, Go Hirai, Mikiko Sodeoka, Synthesis of All Stereoisomers of Monomeric Spectomycin A1/A2 and Evaluation of Their Protein SUMOylation-Inhibitory Activity, Chemistry - A European Journal, 10.1002/chem.201901093, 25, 35, 8387-8392, 2019.06, A synthetic methodology to access all possible stereoisomers of spectomycin A1 (SMA1) and A2 (SMA2) has been established through late-stage diversification. The key reaction for the construction of all four diastereomers is an intramolecular cyclization based on the umpolung of π-allyl palladium species with bis(pinacolato)diborane (B2(pin)2). Silyl group assisted direct benzylic oxidation of each isomer enabled construction of the fragile β-hydroxytetralone skeleton to provide the SMAs. The relative and absolute stereochemistry of SMA2 was also determined, and the absolute stereochemistry of SMA1 was extrapolated based on the optical rotation of SMA2. The axial chirality of SMAs is discussed based on circular dichroism spectra and DFT calculations, and it is concluded that the M isomer is predominant in solution. Biochemical assessment of all isomers in vitro revealed that the C9 hydroxyl group and dimeric structure were both important for protein SUMOylation-inhibitory activity..
10. Yulu Jiang, Shan Lu, Go Hirai, Taira Kato, Hiroyasu Onaka, Hideaki Kakeya, Enhancement of saccharothriolide production and discovery of a new metabolite, saccharothriolide C
, by combined-culture of Saccharothrix sp. and Tsukamurella pulmonis, Tetrahedron Letters, 10.1016/j.tetlet.2019.03.034, 60, 15, 1072-1074, 2019.04, A combined-culture method was applied to saccharothriolide-producing strain Saccharothrix sp. A1506 with the mycolic acid-containing bacterium (MACB) Tsukamurella pulmonis TP-B0596. The combined-culture not only enhanced saccharothriolide production, but also produced saccharothriolide C
, a new C-2 epimer of saccharothriolide C, thereby indicating its potential for increasing the chemical diversity of microbial metabolites..
11. Yu Mikame, Kazuko Yoshida, Daisuke Hashizume, Go Hirai, Kazuo Nagasawa, Hiroyuki Osada, Mikiko Sodeoka, Synthesis of All Stereoisomers of RK460 and Evaluation of Their Activity and Selectivity as Abscisic Acid Receptor Antagonists, Chemistry - A European Journal, 10.1002/chem.201806056, 25, 14, 3496-3500, 2019.03, The PYR/PYL/RCAR protein families have recently emerged as receptors of the phytohormone abscisic acid (ABA, 1), which regulates plant responses to environmental stress. These families have multiple members with different physiological actions, and so selective agonists or antagonists are needed both as tools to elucidate functional differences and as lead compounds for agrochemicals. We previously identified RK460 (rac-3 a) as a PYR1-selective antagonist, and showed that it possesses five stereocenters on a 6,5-cis-bicyclo skeleton. Here, we synthesized all the stereoisomers of RK460 and evaluated their activity towards a panel of receptors. Relative stereochemistry as well as absolute stereochemistry was important for selective action..
12. Noriaki Kiya, Yu Hidaka, Kazuteru Usui, Go Hirai, Synthesis of CH2-Linked α(1,6)-Disaccharide Analogues by α-Selective Radical Coupling C-Glycosylation, Organic Letters, 10.1021/acs.orglett.9b00133, 21, 6, 1588-1592, 2019.03, C-Linked carbohydrate structure, in which the cleavable O-glycosidic linkage is replaced by a carbon unit, is a useful tool for functional analyses of glycoconjugates. We describe a synthetic method for α-CH2-linked disaccharide structures, such as Glc(1,6)-Glc, by stereoselective radical-coupling C-glycosylation between a conformationally constrained and stable C1-sp3 hybridized xanthate donor and a carefully designed acceptor..
13. Kazuma Shimoda, Takahiro Mitsuoka, Kenta Ueda, Hiroshi Suemune, Go Hirai, Mariko Aso, Synthesis of dendritic bisphosphonates as bone targeting ligands, Tetrahedron Letters, 10.1016/j.tetlet.2018.11.028, 59, 51, 4528-4531, 2018.12, A dendritic bisphosphonate carrying three bisphosphonate (BP) units in close proximity was designed as a ligand to conjugate large therapeutic molecules for their bone selective delivery. The Bu
P-catalyzed conjugate addition of nitromethane to vinylidene bisphosphonate was effective to construct a quaternary carbon center carrying BP units. Owing to multivalent interactions, the dendritic bisphosphonate showed considerable affinity for the bone mineral hydroxyapatite even in the presence of a competitor, demonstrating potential as a bone targeting ligand..
14. Kosuke Morishita, Shoji Ueki, Yasufumi Fuchi, Shuhei Murayama, Tomoyo Kaneko, Nozomi Narita, Shigeki Kobayashi, Go Hirai, Ichio Aoki, Satoru Karasawa, Self-Assembled Biradical Ureabenzene Nanoparticles for Magnetic Resonance Imaging, ACS Applied Nano Materials, 10.1021/acsanm.8b01774, 1, 12, 6967-6975, 2018.12, As part of a series of investigations related to the construction of metal-free magnetic resonance imaging (MRI) contrast agents as alternatives to gadolinium agents, water-soluble biradicals, denoted as 1-AMP and 2-HEG, were prepared, in which two stable radicals were introduced to a ureabenzene framework. We found that 1-AMP possessed an amphiphilic side chain that consisted of an alkyl group and a hexaethylene glycol (HEG) chain, whereas 2-HEG possessed only an HEG chain. Accordingly, the biradicals showed self-assembly behavior due to multiple intermolecular interactions through which nanoparticles were formed in a water solution. Magnetic interaction took place in both biradicals, and the estimated interaction strength was J = 5.4 mT. Through MRI measurement, the water proton relaxivities, r1, were estimated to be 0.12 and 0.41 mM-1 s-1 for 1-AMP and 2-HEG, respectively; in other words, the r1 value for 2-HEG was approximately twice as high as that of monoradical-based contrast agents. ©.
15. Kazuteru Usui, Kosuke Yamamoto, Yuhei Ueno, Kazunobu Igawa, Ryusuke Hagihara, Toshinobu Masuda, Akio Ojida, Satoru Karasawa, Katsuhiko Tomooka, Go Hirai, Hiroshi Suemune, Internal-Edge-Substituted Coumarin-Fused [6]Helicenes
Asymmetric Synthesis, Structural Features, and Control of Self-Assembly, Chemistry - A European Journal, 10.1002/chem.201803270, 24, 55, 14617-14621, 2018.10, π-Conjugated helicenes containing heteroatoms have attracted significant attention due to their diverse chemical and electronic structures, as well as tunable physical properties. It was rationally anticipated that the self-assembly of coumarin-fused helicenes would be controlled by the effects of a substituent on the internal edge of the helix. Here, this work reports the efficient syntheses of coumarin-fused helicenes 1 a,b (R=Ph, Me), and the enantioselective synthesis of 1 a (R=Ph) by chiral AuI-catalyzed hydroarylation. The helical structure of 1 was unambiguously determined by X-ray crystallography. Of particular note, the enantiomerically pure crystal of 1 a adopted a one-dimensional columnar structure based on π–π stacking interactions, as expected. Furthermore, a significant difference between the fluorescence quantum yields of the enantiomerically pure form and racemate of 1 a was observed..
16. Eisuke Ota, Kazuteru Usui, Kana Oonuma, Hiroyuki Koshino, Shigeru Nishiyama, Go Hirai, Mikiko Sodeoka, Thienyl-Substituted α-Ketoamide
A Less Hydrophobic Reactive Group for Photo-Affinity Labeling, ACS Chemical Biology, 10.1021/acschembio.7b00988, 13, 4, 876-880, 2018.02, Photoaffinity labeling (PAL) is an important tool in chemical biology research, but application of α-ketoamides for PAL has been hampered by their photoinstability. Here, we show that 2-thienyl-substituted α-ketoamide is a superior photoreactive group for PAL. Studies with a series of synthetic mannose-conjugated α-ketoamides revealed that 2-thienyl substitution of α-ketoamide decreased the electrophilicity of the keto group and reduced the rate of photodegradation. Mannose-conjugated thienyl α-ketoamide showed greater concanavalin A labeling efficiency than other alkyl or phenyl-substituted α-ketoamides. In comparison with representative conventional photoreactive groups, 2-thienyl ketoamide showed reduced labeling of nontarget proteins, probably owing to its lower hydrophobicity..
17. Kosuke Morishita, Yuna Okamoto, Shuhei Murayama, Kazuteru Usui, Eriko Ohashi, Go Hirai, Ichio Aoki, Satoru Karasawa, Water-Proton Relaxivities of Radical Nanoparticles Self-Assembled via Hydration or Dehydration Processes, Langmuir, 10.1021/acs.langmuir.7b01126, 33, 31, 7810-7817, 2017.08, Nanoparticles capable of accumulating in tumor tissues are promising materials for tumor imaging and therapy. In this study, two radical nanoparticles (RNPs), denoted as 1 and 2, composed of self-assembled ureabenzene derivatives possessing one or two amphiphilic side chains were demonstrated to be candidates for metal-free functional magnetic resonance imaging (MRI) contrast agents (CAs). Because of the self-assembly behavior of 1 and 2 in a saline solution, spherical RNPs of sizes ∼50-90 and ∼30-100 nm were detected. In a highly concentrated solution, RNP 1 showed considerably small water-proton relaxivity values (r1 and r2), whereas RNP 2 showed an r1 value that was around 5 times larger than that of RNP 1. These distinct r1 values might be caused by differences in the self-assembly behavior by a hydration or dehydration process. In vivo studies with RNP 2 demonstrated a slightly enhanced T1-weighted image in mice, suggesting that the RNPs can potentially be used as metal-free functional MRI CAs for T1-weighted imaging..
18. Morita Masaki, Shuntaro Kojima, Megumi Ohkubo, Hiroyuki Koshino, Daisuke Hashizume, Go Hirai, Keiji Maruoka, Mikiko Sodeoka, Synthesis of the Right-Side Structure of Type B Physalins, ISRAEL JOURNAL OF CHEMISTRY, 10.1002/ijch.201600110, 57, 309-318, 2017.04.
19. Yusuke Kimuro, Kazuteru Usui, Satoru Karasawa, Go Hirai, Mariko Aso, 7-Hydroxy-3-methyleneisoindolin-1-one as a New ESIPT-Fluorescent Probe to Monitor Aqueous Environments, Chemical and Pharmaceutical Bulletin, 10.1248/cpb.c17-00306, 65, 8, 796-800, 2017.04, A 7-hydroxy derivative of 3-methyleneisoindolin-1-one 1 was synthesized and its properties as a new fluorophore undergoing excited-state intramolecular proton transfer (ESIPT) were investigated. In alcohols and dimethylsulfoxide, 1 exhibited dual emission at ca. 380 and 525-540 nm when excited at ca. 336 nm, which agreed well with the density functional theory (DFT) and time-dependent (TD)-DFT-calculated emission predictions of 1 and its ESIPT tautomer. In aqueous solutions at near neutral pH, 1 exhibited a broad emission band at ca. 497 nm, presumably caused by the overlap of emissions from 1 and the excited state phenolate species of 1. In binary mixtures of H2O and EtOH, the wavelength and intensity of fluorescence maxima were dependent on the dielectric constant of the solvent, suggesting that 1 could be applied as a fluorescent probe to monitor aqueous environments..
20. Qianqian Wang, Yuta Kuramoto, Yozo Okazaki, Eisuke Ota, Masaki Morita, Go Hirai, Kazuki Saito, Mikiko Sodeoka, Synthesis of polyunsaturated fatty acid-containing glucuronosyl-diacylglycerol through direct glycosylation, Tetrahedron Letters, 10.1016/j.tetlet.2017.06.034, 58, 30, 2915-2918, 2017.01, We describe a total synthesis of a polyunsaturated fatty acid (PUFA)-containing glucuronosyldiacylglycerol (GlcADG), which is a surrogate glycolipid whose synthesis is remarkably upregulated in plant membranes under phosphorus-depleted conditions. Glycosylation between the glucuronide donor bearing 3,4-dimethoxybenzyl (DMPM) protecting groups and di-acylglycerol acceptor proceeded smoothly in the presence of gold(I) catalyst to provide the protected α-isomer of GlcADG as the major product..
21. Atsushi Fukushima, Michimi Nakamura, Hideyuki Suzuki, Mami Yamazaki, Eva Knoch, Tetsuya Mori, Naoyuki Umemoto, Masaki Morita, Go Hirai, Mikiko Sodeoka, Kazuki Saito, Comparative Characterization of the Leaf Tissue of Physalis alkekengi and Physalis peruviana Using RNA-seq and Metabolite Profiling, FRONTIERS IN PLANT SCIENCE, 10.3389/fpls.2016.01883, 7, 1883, 2016.12.
22. Takayuki Ohyoshi, Yuki Tamura, Ichiro Hayakawa, Go Hirai, Yamato Miyazawa, Shota Funakubo, Mikiko Sodeoka, Hideo Kigoshi, Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation, ORGANIC & BIOMOLECULAR CHEMISTRY, 10.1039/c6ob02268e, 14, 11426-11437, 2016.11, We have established an efficient synthetic methodology for the 13-oxyingenol natural derivative (13-oxyingenol-13-dodecanoate-20-hexanoate), featuring a ring-closing olefin metathesis reaction for the "direct" construction of a highly strained inside-outside framework and a Mislow-Evans-type [2,3]-sigmatropic rearrangement for the stereoselective introduction of the hydroxy group at C5. We also synthesized artificial analogs of 13-oxyingenol and ingenol by using our synthetic strategy. In vitro activation assays of protein kinase C (PKC) α and δ revealed that the dodecanoyl group at O13 on 13-oxyingenol analogs had a significant role in PKCδ activation. The PKCα- or PKCδ-activating 13-oxyingenol and ingenol analogs induced both distinct morphological changes and increases of CD11b expression in HL-60 cells, which would be typical signs of HL-60 cell differentiation to macrophage-like cells, as expected by previous reports. Intriguingly, however, similar differentiation phenotypes were observed with the use of 13-oxyingenol natural derivatives and 13-oxyingenol-13-dodecanoate showing a remarkably less potent PKCα or PKCδ activation ability, which the PKC inhibitor Gö6983 diminished. This indicated the involvement of other PKC isozymes or related kinase activities. 13-Oxyingenol analogs, which induced HL-60 cell differentiation, also induced HL-60 cell death, similar to the action of a phorbol ester, a strong PKC activator..
23. Kosuke Yamamoto, Takashi Shimizu, Kazunobu Igawa, Katsuhiko Tomooka, Go Hirai, Hiroshi Suemune, Kazuteru Usui, Rational Design and Synthesis of [5] Helicene-Derived Phosphine Ligands and Their Application in Pd-Catalyzed Asymmetric Reactions, SCIENTIFIC REPORTS, 10.1038/srep36211, 6, 36211, 2016.11.
24. Yuya Hikone, Go Hirai, Masaki Mishima, Kohsuke Inomata, Teppei Ikeya, Souichiro Arai, Masahiro Shirakawa, Mikiko Sodeoka, Yutaka Ito, A new carbamidemethyl-linked lanthanoid chelating tag for PCS NMR spectroscopy of proteins in living HeLa cells, JOURNAL OF BIOMOLECULAR NMR, 10.1007/s10858-016-0059-4, 66, 99-110, 2016.10.
25. Xiaoying Sun, Go Hirai, Masashi Ueki, Hiroshi Hirota, Qianqian Wang, Yayoi Hongo, Takemichi Nakamura, Yuki Hitora, Hidekazu Takahashi, Mikiko Sodeoka, Hiroyuki Osada, Makiko Hamamoto, Minoru Yoshida, Yoko Yashiroda, Identification of novel secreted fatty acids that regulate nitrogen catabolite repression in fission yeast, Scientific Reports, 10.1038/srep20856, 6, 20856, 2016.02.
26. Eisuke Ota, Yu Mikame, Go Hirai, Shigeru Nishiyama, Mikiko Sodeoka, Photochemical and Additive-Free Coupling Reaction of α-Cumyl α-Keto Esters via Intermolecular C–H Bond Activation, SYNLETT, 10.1055/s-0035-1561098, 27, 1128-1132, 2016.01.
27. Eisuke Ota, Yu Mikame, Go Hirai, Hiroyuki Koshino, Shigeru Nishiyama, Mikiko Sodeoka, Photo-induced formation of cyclopropanols from α-ketoamides via γ-C-H bond activation, Tetrahedron Lett., 10.1016/j.tetlet.2015.09.038, 56, 5991-5994, 2015.09.
28. Go Hirai, Eri Nishizawa, Daiki Kakumoto, Masaki Morita, Mitsuaki Okada, Daisuke Hashizume, Sayoko Nagashima, Mikiko Sodeoka, Reactions of Carbonyl Compounds with Phosphorus Ylide Generated from Tribromofluoromethane and Tris(dimethylamino)phosphine, Chem. Lett., 44, 1389-1391, 2015.07.
29. Go Hirai, Mikiko Sodeoka, Focused library with a core structure extracted from natural products and modified
Application to phosphatase inhibitors and several biochemical findings, Accounts of Chemical Research, 10.1021/acs.accounts.5b00048, 48, 5, 1464-1473, 2015.05, ConspectusSynthesis of a focused library is an important strategy to create novel modulators of specific classes of proteins. Compounds in a focused library are composed of a common core structure and different diversity structures. In this Account, we describe our design and synthesis of libraries focused on selective inhibitors of protein phosphatases (PPases). We considered that core structures having structural and electronic features similar to those of PPase substrates, phosphate esters, would be a reasonable choice. Therefore, we extracted core structures from natural products already identified as PPase inhibitors. Since many PPases share similar active-site structures, such phosphate-mimicking core structures should interact with many enzymes in the same family, and therefore the choice of diversity structures is pivotal both to increase the binding affinity and to achieve specificity for individual enzymes.Here we present case studies of application of focused libraries to obtain PPase inhibitors, covering the overall process from selection of core structures to identification and evaluation of candidates in the focused libraries. To synthesize a library focused on protein serine-threonine phosphatases (PPs), we chose norcantharidin as a core structure, because norcantharidin dicarboxylate shows a broad inhibition profile toward several PPs. From the resulting focused library, we identified a highly selective PP2B inhibitor, NCA-01. On the other hand, to find inhibitors of dual-specificity protein phosphatases (DSPs), we chose 3-acyltetronic acid extracted from natural product RK-682 as a core structure, because its structure resembles the transition state in the dephosphorylation reaction of DSPs. However, a highly selective inhibitor was not found in the resulting focused library. Furthermore, an inherent drawback of compounds having the highly acidic 3-acyltetronic acid as a core structure is very weak potency in cellulo, probably due to poor cell membrane permeability. Therefore, we next modified the core structure from acidic to neutral by transformation to the enamine derivative and constructed a second-generation focused library (RE derivatives). The resulting compounds showed dramatically improved cell membrane permeability and inhibitory selectivity and included VHR (vaccinia VH1-related)-selective RE12 and CDC25A/B (cell division cycle 25A/B)-selective RE44. These inhibitors act on target enzymes in cellulo and do not generate reactive oxygen species, which is a potential problem with quinoid-type inhibitors of CDC25s. The cellular activity of RE12 was further improved by replacement of the side chain to afford RE176, which showed more potent antiproliferative activity than RE12 against HeLa cells.The dramatic change of inhibitory selectivity obtained by core structure modification from 3-acyltetronic acid to its enamine derivative was associated with a change in the mode of action. Namely, RE derivatives were found to be noncompetitive inhibitors with respect to a small-molecular substrate of CDC25A/B, whereas RK-682 was a competitive inhibitor of VHR. We identified the binding site of RE derivatives on the CDC25A as a pocket adjacent to the active site; this appears to be a promising target site for development of further novel inhibitors of CDC25s..
30. Shan Lu, Shinichi Nishimura, Go Hirai, Masashi Ito, Teppei Kawahara, Miho Izumikawa, Mikiko Sodeoka, Kazuo Shin-ya, Toshio Tsuchida and Hideaki Kakeya, Saccharothriolides A-C, novel phenyl-substituted 10-membered macrolides from a rare actinomycete Saccharothrix sp., Chem. Commun., 51, 8047-8077, 2015.04.
31. Go Hirai, Mimicking/Extracting structure and functions of natural products
Synthetic approaches that address unexplored needs in chemical biology, Chemical Record, 10.1002/tcr.201402074, 15, 2, 445-456, 2015.04, Natural products are often attractive and challenging targets for synthetic chemists, and many have interesting biological activities. However, synthetic chemists need to be more than simply suppliers of compounds to biologists. Therefore, we have been seeking ways to actively apply organic synthetic methods to chemical biology studies of natural products and their activities. In this personal review, I would like to introduce our work on the development of new biologically active compounds inspired by, or extracted from, the structures of natural products, focusing on enhancement of functional activity and specificity and overcoming various drawbacks of the parent natural products. The synthesis and development of natural product analogues that mimic the essential character or activity, or that isolate a particular activity, of the parent molecules is described. Biological experiments to characterize some of the new compounds and establish their modes of action are also described..
32. Go Hirai, Eisuke Ota, Motonari Sakai, Shigeru Nishiyama, Mikiko Sodeoka, C-Sialosides
Synthesis and biological activities, Trends in Glycoscience and Glycotechnology, 10.4052/tigg.1313.1, 27, 154, 47-60, 2015.01, This mini-review focuses on the synthesis and biological activities of sialic acid (SA) derivatives with a C-glycosidic linkage in place of the standard O-glycosidic bond at the C-2 position. We summarize reported synthetic methodologies for monoand di-saccharides in separate sections. Then, we introduce our strategy for the construction of C-sialoside linkages utilizing Ireland-Claisen rearrangement reaction and its application to the synthesis of a ganglioside GM4 analogue. Although C-sialosides are expected to be useful as sialidase-resistant analogues of sialoglycoconjugates (sialoGCs), their biological activities have not yet been investigated in detail. Herein we briefly discuss the potential applications of C-sialosides..
33. Go Hirai, Eri Nishizawa, Daiki Kakumoto, Masaki Morita, Mitsuaki Okada, Daisuke Hashizume, Sayoko Nagashima, Mikiko Sodeoka, Reactions of carbonyl compounds with phosphorus ylide generated from tribromofluoromethane and tris(dimethylamino)phosphine, Chemistry Letters, 10.1246/cl.150523, 44, 10, 1389-1391, 2015.01, The reactions of fluorinated ylide, generated from tris(dimethylamino) phosphine and tribromofluoromethane, with simple aldehydes and reactive ketones gave the expected Wittig reaction products. However, a ketone having a galactose skeleton afforded an acid fluoride, probably through an unprecedented CoreyChaykovski- type epoxide formation reaction, followed by spontaneous Meinwald rearrangement..
34. Frédéric Thuaud, Shuntaro Kojima, Go Hirai, Kana Oonuma, Ayako Tsuchiya, Takako Uchida, Teruhisa Tsuchimoto, Mikiko Sodeoka, RE12 derivatives displaying Vaccinia H1-related phosphatase (VHR) inhibition in the presence of detergent and their anti-proliferative activity against HeLa cells, Bioorg. Med. Chem., 22, 2771-2782, 2014.05.
35. Katsunori Tanaka, Yuka Nakamoto, Eric R. O. Siwu, Ambara R. Pradipta, Koji Morimoto, Takeshi Fujiwara, Suguru Yoshida, Takamitsu Hosoya, Yuki Tamura, Go Hirai, Mikiko Sodeoka and Koichi Fukase, Development of bis-unsaturated ester aldehydes as amino-glue probes: sequential double azaelectrocyclization as a promising strategy for bioconjugation, Org. Biomol. Chem., 11, 7326-7333, 2013.09.
36. Masaaki Ozawa, Masaki Morita, Go Hirai, Satoru Tamura, Masao Kawai, Ayako Tsuchiya, Kana Oonuma, Keiji Maruoka, and Mikiko Sodeoka, Contribution of Cage-Shaped Structure of Physalins to Their Mode of Action in Inhibition of NF-kB Action, ACS Med. Chem. Lett. , 10.1021/ml400144e, 4, 730-735, 2013.06.
37. Takahiro Suzuki, Yuria Miyajima, Kaname Suzuki, Kanako Iwakiri, Masaki Koshimizu, Go Hirai, Mikiko Sodeoka, and Susumu Kobayashi, Unexpected Diels–Alder/Carbonyl-ene Cascade toward the Biomimetic Synthesis of Chloropupukeananin, Org, Lett., 15, 1748-1751, 2013.03.
38. Ayako Tsuchiya, Miwako Asanuma, Go Hirai, Kana Oonuma, Muhammad Muddassar, Eri Nishizawa, Yusuke Koyama, Yuko Otani, Kam Y. J. Zhang, and Mikiko Sodeoka, CDC25A-inhibitory RE Derivatives Bind to Pocket Adjacent to the Catalytic Site, Mol. BioSyst., 10.1039/C3MB00003F, 9, 1026-1034, 2013.02.
39. Masaki Morita, Go Hirai, Meguni Ohkubo Hiroyuki koshino, Daisuke Hashizume, Keiji Maruoka, and Mikiko Sodeoka, Kinetically Controlled One-Pot Formation of DEFGH-Rings of Type B Physalins through Domino-Type Transformations, Org, Lett., 14, 3434-3437, 2012.06.
40. Ayako Tsuchiya, Go Hirai, Yusuke Koyama, Kana Oonuma, Yuko Otani, Hiroyuki Osada, and Mikiko Sodeoka, Dual-specificity Protein Phosphatase CDC25A/B Inhibitor Identified from a Focused Library with Non-electrophilic Enamine Core Structure, ACS Med. Chem. Lett. , 10.1021/ml2002778, 3, 264-298, 2012.02.
41. Marie Kato, Go Hirai, Mikiko Sodeoka, Studies on the Selectivity between Glycosylation and Intermolecular Aglycone Transfer of Thioglucoside in Synthesis of Lactose Derivatives, Chem. Lett., 40, 877-879, 2011.07.
42. Go Hirai, Megumi Ohkubo, Yuki Tamura, Mikiko Sodeoka, Design and Synthesis of Protein Kinase Cα activators based on 'out of pocket' interaction, Bioorg. Med. Chem. Lett., 21, 3587-3590, 2011.06.
43. Go Hirai, Ayako Tsuchiya, Yusuke Koyama, Yuko Otani, Kana Oonuma, Kosuke Dodo, Siro Simizu, Hiroyuki Osada, and Mikiko Sodeoka, Development of a Vaccinia H1-Related (VHR) Phosphatase Inhibitor with NonAcidic Phosphate-Mimicking Core Structure, ChemMedChem, 10.1002/cmdc.201100107, 6, 617-622, 2011.03.
44. Go Hirai, Yosuke Ogoshi, Megumi Ohkubo, Yuki Tamura, Toru Watanabe, Tadashi Shimizu, Mikiko Sodeoka, Asymmetric synthesis of isobenzofuranone derivatives and their unique character as protein kinase Cα (PKCα) activators, Tetrahedron Lett., 50, 3609-3612, 2009.07.
45. Megumi Ohkubo, Go Hirai, Mikiko Sodeoka, Synthesis of the DFGH ring system of Type B Physalins: Highly Oxygenated, Cage-Shaped Molecules, Angew. Chem. Int. Ed., 10.1002/anie.200900634, 48, 3862-3866, 2009.04.
46. Mikiko Sodeoka, Go Hirai, Toru Watanabe, Taeko Miyagi, A strategy for constructing C-sialosides based on Ireland-Claisen rearrangement and its application for synthesis of CF2-linked ganglioside GM4 analog, Pure and Applied Chemistry, 10.1351/PAC-CON-08-09-14, 81, 2, 205-215, 2009.03, Sialidase-resistant ganglioside analogs having similar biological activities to natural gangliosides are expected to be important probes for clarifying the biological functions of gangliosides. Focusing on difluoromethylene-linked (CF2-linked) and methylene-linked (CH 2-linked) α(2,3)sialylgalactose as a core structure of sialidase-resistant ganglioside mimics, we have developed novel, stereocontrolled, and efficient methodologies to synthesize C-sialosides based on Ireland - Claisen rearrangement. These methods were employed to synthesize CF2-linked GM4. The CF2-linked GM4 inhibited human sialidases NEU2 and NEU4 with IC50 values of 754 and 930 μM, respectively, and strongly inhibited human lymphocyte proliferation in the same concentration range as natural GM4..
47. Isao Fukuda, Akihiro Ito, Go Hirai, Shinichi Nishimura, Hisashi Kawasaki, Hisato Saitoh, Ken-ichi Kimura, Mikiko Sodeoka, Minoru Yoshida, Ginkgolic Acid Inhibits Protein SUMOylation by Blocking Formation of the E1-SUMO Intermediate, Chemistry & Biology, 10.1016/j.chembiol.2009.01.009, 16, 133-140, 2009.02.
48. Keiko Hata, Koichi Koseki, Kazunori Yamaguchi, Setsuko Moriya, Yasuo Suzuki, Sangchai Yingsakmongkon, Go Hirai, Mikiko Sodeoka, Mark Von Itzstein, Taeko Miyagi, Limited inhibitory effects of oseltamivir and zanamivir on human sialidases, Antimicrobial Agents and Chemotherapy, 10.1128/AAC.00344-08, 52, 10, 3484-3491, 2008.10, Oseltamivir (Tamiflu) and zanamivir (Relenza), two extensively used clinically effective anti-influenza drugs, are viral sialidase (also known as neuraminidase) inhibitors that prevent the release of progeny virions and thereby limit the spread of infection. Recently mortalities and neuropsychiatric events have been reported with the use of oseltamivir, especially in pediatric cases in Japan, suggesting that these drugs might also inhibit endogenous enzymes involved in sialic acid metabolism, including sialidase, sialyltransferase, and CMP-synthase, in addition to their inhibitory effects on the viral sialidase. The possible inhibition could account for some of the rare side effects of oseltamivir. However, there has been little direct evidence in regard to the sensitivities of animal sialidases to these drugs. Here, we examined whether these inhibitors might indeed affect the activities of human sialidases, which differ in primary structures and enzyme properties but possess tertiary structures similar to those of the viral enzymes. Using recombinant enzymes corresponding to the four human sialidases identified so far, we found that oseltamivir carboxylate scarcely affected the activities of any of the sialidases, even at 1 mM, while zanamivir significantly inhibited the human sialidases NEU3 and NEU2 in the micromolar range (Ki, 3.7 ± 0.48 and 12.9 ± 0.07 μM, respectively), providing a contrast to the low nanomolar concentrations at which these drugs block the activity of the viral sialidases..
49. Keiko Hata, Koichi Koseki, Kazunori Yamaguchi, Setsuko Moriya, Yasuo Suzuki, Sangchai Yingsakmongkon, Go Hirai, Mikiko Sodeoka, Mark von Itzstein, and Taeko Miyagi, Limited Inhibitory Effects of Oseltamivir and Zanamivir on Human Sialidases, Antimicrob. Agents Chemother., 52, 3484-3491, 2008.09.
50. Naoki Sugano, Yuuki. Koizumi, Go Hirai, Hiroki Oguri, Shoji Kobayashi, Shuji Yamashita, Masahiro Hirama, Enatioselective Synthesis of the Fully Functionalized ABC Ring of Zoanthenol, Chem. Asian J., 3, 1549-1557, 2008.09.
51. Toru Watanabe, Go Hirai, Marie Kato, Daisuke Hashizume, Taeko Miyagi, and Mikiko Sodeoka, Synthesis of CH2-Linked α(2,3)Sialylgalactose Analogue: On the Stereoselectivity of the Key Ireland-Claisen Rearrangement, Org. Lett., 10.1021/ol801519j, 10, 4167-4170, 2008.09.
52. Naoki Sugano, Yuuki Koizumi, Go Hirai, Hiroki Oguri, Shoji Kobayashi, Shuji Yamashita, Masahiro Hirama, Enantioselective synthesis of the fully functionalized ABC ring of zoanthenol, Chemistry - An Asian Journal, 10.1002/asia.200800079, 3, 8-9, 1549-1557, 2008.09, Zoanthenol, isolated from Zoanthus sp., possesses an extremely complex architecture including contiguous quaternary carbons. An enantioselective synthesis of the fully functionalized ABC-ring of zoanthenol has been achieved and is described herein. The key features of the synthesis are the enzymatic kinetic optical resolution and the Mizoroki-Heck/Simmons-Smith reaction strategy used to construct the congested asymmetric quaternary carbons..
53. Go Hirai, Toru Watanabe, Kazunori Yamaguchi, Taeko Miyagi, and Mikiko Sodeoka, Stereocontrolled and Convergent Entry to CF2-Sialosides: Synthesis of CF2-Linked Ganglioside GM4, J. Am. Chem. Soc., 10.1021/ja075738w, 129, 15420-15421, 2007.11.
54. Go Hirai, Tadashi Shimizu, Toru Watanabe, Yosuke Ogoshi, Megumi Ohkubo, and Mikiko Sodeoka, Importance of interaction between C1 domain and lipids in protein kinase Cα activation: Hydrophobic side chain direction in isobenzofuranone ligands controls enzyme activation level., ChemMedChem, 2, 1006-1009, 2007.06.
55. Go Hirai, Chemical modification of bio-molecules to change their functionalities, Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry, 10.5059/yukigoseikyokaishi.64.1306, 64, 12, 1306-1307, 2006.12, Some strategies to modify a certain amino acid residue of a native protein in a chemo-selective fashion have been developed. In this review, the modifications of proteins, which can change their functionalities, such as solubility or retargeting of adenoviral gene transfer, are discussed..
56. Go Hirai, Tadashi Shimizu, Mikiko Sodeoka, Development of novel C1 domain ligands of protein kinase C to clarify the precise structure and activation mechanism, Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry, 64, 5, 515-527, 2006.05, Protein kinase C (PKC) is a family of enzymes which play important roles in intracellular signal transduction. We designed a series of novel PKC ligands having an isobenzofuranone (IB) template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol) with PKC. Since interaction of the hydrophobic alkyl chain of the IB derivatives with lipid membrane is expected to be critical for the PKC activation, we were interested in the synthesis of the IB derivatives having the hydrophobic alkyl chain at various positions of the benzene ring. Effects of these synthetic ligands on the PKCa phosphorylation activity were examined. Surprisingly, 4-substitued derivative showed no activation of PKCα even at high concentration at which significant binding to PKCα was observed. These results suggest that position of the hydrophobic chain is critical for the PKC activation..
57. Keisuke Ishida, Go Hirai, Koji Murakami, Takayuki Teruya, Siro Simizu, Mikiko Sodeoka, and Hiroyuki Osada, Structure-based Design of a Selective Heparanase Inhibitor as an Antimetastatic Agent., Mol. Cancer Therapeutics, 3, 1069-1077, 2004.09.
58. Yoshiyasu Baba, Yosuke Ogoshi, Go Hirai, Takeshi Yanagisawa, Kumiko Nagamatsu, Satoshi Mayumi, Yuichi Hashimoto, and Mikiko Sodeoka, Design, Synthesis, and Structure-Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C., Bioorg. Med. Chem. Lett., 14, 2963-2967, 2004.06.
59. Yoshiyasu Baba, Satoshi Mayumi, Go Hirai, Hidekazu Kawasaki, Yosuke Ogoshi, Takeshi Yanagisawa, Yuichi Hashimoto, and Mikiko Sodeoka, Evaluation of Series of Isobenzofuranone Dimers as PKCa Ligands: Implication for the Distance between the Two Ligand Binding Sites., Bioorg. Med. Chem. Lett., 14, 2696-2972, 2004.06.
60. Go Hirai, Hiroki Oguri, Masahiko Hayashi, Koji Koyama, Yuuki Koizumi, Sameh M. Moharram, Masahiro Hirama*, Synthesis and preliminary biological evaluation of truncated zoanthenol analogues, Bioorganic and Medicinal Chemistry Letters, 14, 2647-2651, 2004.05.
61. Go Hirai, Yuuki Koizumi, Sameh M. Moharram, Hiroki Oguri, Masahiro Hirama, Construction of Quaternary Carbon Center of Zoanthenol by Intramolecular Mizoroki-Heck Reaction of Enone, Org. Lett., 4, 1627-1630, 2002.04.
62. Go Hirai, Hiroki Oguri, Sameh M. Moharram, Koji Koyama, Masahiro Hirama, Convergent Synthesis of ABC-ring Moiety of Zoanthenol: Intramolecular Mizoroki-Heck Reaction, Tetrahedron Lett., 42, 5789-5787, 2001.08.
63. S. M. Moharram, Go Hirai, K. Koyama, H. Oguri, M. Hirama, Erratum
Enantio-face control by molecular sieves in the asymmetric Diels-Alder reaction (Tetrahedron Letters (2000) 41 (6669) PII: S0040403900011163), Tetrahedron Letters, 10.1016/S0040-4039(00)01451-9, 41, 43, 2000.10.
64. Sameh M. Moharram, Go Hirai, Koji Koyama, Hiroki Oguri, Masahiro Hirama, Enatio-face Control by Molecular Sieves in the Asymmetric Diels-Alder Reaction, Tetrahedron Lett., 41, 6669-6673, 2000.08.
65. Go Hirai, Hiroki Oguri, Masahiro Hirama, Synthetic Study of Zoanthamine Alkaloids: The C-ring Model Possessing Three Consecutive Quaternary Carbons, Chemistry Letters, 10.1246/cl.1999.141, 28, 2, 141-142, 1999.02.