Higashibayashi, Shuhei



Faculty of Pharmacy, Department of Pharmaceutical Sciences 有機薬化学講座 (Shiba-Kyoritsu)


Associate Professor

Licenses and Qualifications 【 Display / hide

  • 甲種危険物取扱者, 2004.08


Research Areas 【 Display / hide

  • Organic chemistry


Papers 【 Display / hide

  • Synthesis of indirubins by aldol condensation of isatins with indoxyl anion generated in situ by lipase-catalyzed deacetylation of indoxyl acetate

    Sugai T., Hanaya K., Higashibayashi S.

    Heterocycles 100   129 - 136 2020

    Research paper (scientific journal), Joint Work, Accepted

  • Synthesis of 5-Hydroxy-3′,4′,7-trimethoxyflavone and Related Compounds and Elucidation of Their Reversal Effects on BCRP/ABCG2-Mediated Anticancer Drug Resistance

    Tsunekawa R., Katayama K., Hanaya K., Higashibayashi S., Sugimoto Y., Sugai T.

    ChemBioChem (ChemBioChem)  20 ( 2 ) 210 - 220 2019.01

    ISSN  14394227

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    © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3′,4′,7-Trimethoxyflavone (TMF) has been reported to show a potent reversal effect on drug resistance mediated by breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2). In this study, we designed and synthesized five derivatives with either a hydroxy group or a fluorine atom at C-5 and several kinds of capping moiety at the C-7 hydroxy group, on the same 3′,4′-dimethoxy-substituted flavone skeleton. We subsequently evaluated the efficacies of these compounds against BCRP-expressing human leukaemia K562/BCRP cells. Reversal of drug resistance was expressed as the concentration of compound causing a twofold reduction in drug sensitivity (RI 50 ). Of the synthesized compounds, the reversal effect of 5-hydroxy-3′,4′,7-trimethoxyflavone (HTMF, RI 50 7.2 nm) towards 7-ethyl-10-hydroxycamptothecin (SN-38) was stronger than that of TMF (RI 50 18 nm). Fluoro-substituted 5-fluoro-3′,4′,7-trimethoxyflavone (FTMF, RI 50 25 nm) and monoglycosylated 7-(β-glucosyloxy)-5-hydroxy-3′,4′-dimethoxyflavone (GOHDMF, 91 nm) also exhibited reversal effects, whereas the di- and triglycoside derivatives did not. TMF, HTMF and FTMF at 0.01–10 μm upregulated the K562/BCRP cellular accumulation of Hoechst 33342 nuclear staining dye. In addition, western blotting revealed that treatment of K562/BCRP cells with 0.1 μm TMF, HTMF or FTMT suppressed the expression of BCRP. HTMF showed the strongest inhibition of BCRP-mediated efflux and suppression of BCRP expression of the three effective synthesized flavones.

  • Site-selective synthesis of acacetin and genkwanin through lipase-catalyzed deacetylation of apigenin 5,7-diacetate and subsequent methylation

    Fujita R., Mandal S., Hanaya K., Shoji M., Higashibayashi S., Sugai T.

    Heterocycles (Heterocycles)  99 ( 1 ) 638 - 648 2019

    ISSN  03855414

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    © 2019 The Japan Institute of Heterocyclic Chemistry. Candida antarctica lipase B-catalyzed deacetylation proceeded with high site-selectivity on the C-4′ acetyl group in apigenin triacetate to give apigenin 5,7-diacetate. Methylation of the liberated hydroxy group with the combination of trimethyloxonium tetrafluoroborate (Meerwein reagent) and 1,8-bis(dimethylamino)naphthalene (proton sponge) in CH2Cl2 proceeded in a quantitative manner to give the product methylated at the C-4′ hydroxy group (acacetin 5,7-diacetate). Even with the same precursor, a different methylation product at the C-7 hydroxy group (genkwanin 4′,5-diacetate) was obtained in 86% yield by applying iodomethane and Cs2CO3 in dimethyl sulfoxide (DMSO). The methylated products were deprotected to form acacetin and genkwanin. We inferred that the latter unexpected methylation was ascribable to the intermolecular migration of an acetyl group from C-7 to C-4′. DFT calculations indicated that the C-7 phenoxide ion was 12.6 kJ/mol more stable than the initially formed C-4′ phenoxide ion.

  • Lipase-catalyzed site-selective deacetylation of sterically hindered naphthohydroquinone diacetate and its application to the synthesis of a heterocyclic natural product

    Hashimoto R., Sakakura A., Hanaya K., Higashibayashi S., Sugai T.

    Heterocycles (Heterocycles)  99 ( 1 ) 625 - 632 2019

    ISSN  03855414

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    © 2019 The Japan Institute of Heterocyclic Chemistry. Lipase-catalyzed site-selective deacetylation of 2,5-dimethylnaphthalene-l,4-diol diacetate was examined. With Candida antarctica lipase B, the suppressing effect of a methyl substituent at the peri-position of the a-naphthyl ester over that at the ortho-position was significant. This site-selectivity was in contrast to that of chemical hydrolysis reported to date. From the resulting monoacetate, mansonone F, a physiologically active heterocyclic orthoquinone, was synthesized in 38% yield in as few as three steps.

  • Chemoenzymatic synthesis of hydroxytyrosol monoesters and their suppression effect on nitric oxide production stimulated by lipopolysaccharides

    Sakakura A., Pauze M., Namiki A., Funakoshi-Tago M., Tamura H., Hanaya K., Higashibayashi S., Sugai T.

    Bioscience, Biotechnology and Biochemistry (Bioscience, Biotechnology and Biochemistry)  83 ( 2 ) 185 - 191 2019

    ISSN  09168451

     View Summary

    © 2018 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Fatty acid monoesters of hydroxytyrosol [2-(3,4-dihydroxyphenyl)ethanol] were synthesized in two steps from tyrosol (4-hydroxyphenylethanol) by successive Candida antarctica lipase B-catalyzed chemoselective acylation on the primary aliphatic hydroxy group over phenolic hydroxy group in tyrosol, and 2-iodoxybenzoic acid (IBX)-mediated hydroxylation adjacent to the remaining free phenolic hydroxy group. Examination of their suppression effects on nitric oxide production stimulated by lipopolysaccharides in RAW264.7 cells showed that hydroxytyrosol butyrate exhibited the highest inhibition (IC 50 7.0 μM) among the tested compounds.

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Papers, etc., Registered in KOARA 【 Display / hide

Presentations 【 Display / hide

  • 第四級炭素を有するセスキテルペン類の骨格合成を志向した脱水素的O-ベンジル化-ルイス酸触媒[1,3]-転位シーケンスによるCsp3-Csp3結合形成

    藤谷万, 花屋賢悟, 須貝威, 東林修平

    第78回有機合成化学協会関東支部シンポジウム (新潟) , 2019.11, Oral Presentation(general)

  • Acid-responsieve helical heterocycles with embedded hydrazine

    Higashibayashi S.

    The 4th Joint Conference Keio & Kaohsiung Medical University (Kaohsiung Medical University) , 2019.09, Oral Presentation(guest/special)

  • Development of oxidative C-C bond formation between phenols and alkenes

    Deguchi H., Hanaya K., Sugai T., Higashibayashi S.

    The 4th Joint Conference Keio & Kaohsiung Medical University (Kaohsiung Medical University) , 2019.09, Oral Presentation(general)

  • 三次元ヘテロπ電子系分子の創製


    分子研シンポジウム2019 (分子科学研究所) , 2019.06, Oral Presentation(guest/special), 分子科学研究所

  • 3-カルバモイル-2,4-ジニトロフェニルピリジニウムのDiels-Alder反応に関する計算化学的考察

    中原正貴, 花屋賢悟, 須貝威, 東林修平

    第115回有機合成化学シンポジウム (仙台) , 2019.06, Poster (general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • ジグザグ型ヘテロカーボンナノベルトの合成


    MEXT,JSPS, Grant-in-Aid for Scientific Research, 東林 修平, Grant-in-Aid for Challenging Research (Exploratory) , Principal Investigator

Awards 【 Display / hide

  • 有機合成化学奨励賞

    2012, おわん型π共役分子バッキーボウルの合成

  • 日本化学会第90春季年会「若い世代の特別講演会」

    2010, C3対称バッキーボウルの液相合成法の開発

  • 日本化学会第87春季年会優秀講演賞

    2007, キラルバッキーボウルの合成研究

  • 天然物化学談話会奨励賞

    2005, 非環状天然有機化合物の立体配置決定法Universal NMR Databaseの開発


Courses Taught 【 Display / hide











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Memberships in Academic Societies 【 Display / hide

  • 日本薬学会

  • 日本化学会

  • 有機合成化学協会

  • 基礎有機化学会