Hanaya, Kengo

写真a

Affiliation

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

Position

Assistant Professor/Senior Assistant Professor
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Academic Degrees 【 Display / hide 】

  • 博士（薬学）, Tokyo University of Science, Coursework, 2012.03

    Design and Synthesis of Biomedical Tools and Metalloprotease Inhibitors Based on Chemical Properties of 8-Quinolinol and Their Sulfonates

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Papers 【 Display / hide 】

  • Development of a sensitive LC–MS/MS method for quantification of linezolid and its primary metabolites in human serum

    Souza E., Felton J., Crass R., Hanaya K., Pai M.

    Journal of Pharmaceutical and Biomedical Analysis （Journal of Pharmaceutical and Biomedical Analysis)  178 2020.01

    ISSN  07317085

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    © 2019 Elsevier B.V. Linezolid (LZD) is a widely used antimicrobial that is active against a broad range of disease-causing bacteria. Myelosuppression is major treatment-limiting toxicity of LZD that occurs more frequently in patients with renal insufficiency. Quantification of LZD and its two primary metabolites (PNU-142300 and PNU-142586), which undergo significant renal elimination, may support design of improved dosing strategies to mitigate the risk of myelosuppression. In this study, we established the first liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the simultaneous quantification of LZD and its main metabolites in human serum. Proteins in serum samples were precipitated with acetonitrile containing a deuterated internal standard. Chromatographic separation of analytes was performed with Waters X-bridge column (C18, 150 × 4.6 mm, 3.5 μm) at 25 °C and subjected to mass analysis using positive electro-spray ionization. The mobile phase A was water with 0.1% formic acid, and mobile phase B was acetonitrile with 0.1% formic acid at a flow rate of 0.6 mL/min, within a 15 min run time. Standard curves were linear and correlation coefficients (r2) were ≥0.99 for concentration ranges of 0.1–50 μg/mL for LZD and PNU-142300, and 0.1–25 μg/mL for PNU-142586. The inter- and intra-assay precisions were <15% for all analytes in quality control samples, and the accuracies ranged from 97 to 112%. Extraction recoveries ranged from 78 to 103% for all analytes, and there was no significant matrix effect. Samples from 10 patients (5 with renal impairment) were assayed. Mean (SD) LZD, PNU-142300 and PNU-142586 trough concentrations were 19.4(6.8), 11.6(6.8), 25.7(16.4) μg/mL, respectively, in patients with renal impairment. These values were 2.5-, 5.8-, and 6.8-fold higher for LZD, PNU-142300 and PNU-142586, respectively compared to patients without renal impairment. The method was effectively applied in the determination of LZD and its main metabolites in human serum.

  • Nickel(II)-promoted amide N-H arylation of pyroglutamate-histidine with arylboronic acid reagents

    Hanaya K., Miller M., Ball Z.

    Organic Letters （Organic Letters)  21 （ 7 ） 2445 - 2448 2019.04

    ISSN  15237060

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    © 2019 American Chemical Society. Small and simple bioorthogonal reactive handles that can be readily encoded by natural processes are important for bioconjugation. A rapid nickel-promoted N-H arylation of pyroglutamate-histidine sequences with 2-nitroarylboronic acids proceeds under mild aqueous conditions. Chemoselective activation of a lactam amide N-H within a peptide or protein provides a new approach to selective conjugation in polyamide structures.

  • 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.

  • Syntheses of Englerin A, a Potent Renal Cancer Inhibitor

    Hagihara S., Hanaya K., Sugai T., Shoji M.

    Asian Journal of Organic Chemistry （Asian Journal of Organic Chemistry)  8 （ 1 ） 48 - 62 2019.01

    ISSN  21935807

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    © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Mankind has been searching for anticancer drugs from nature and artificial compounds. Since the discovery of englerin A, a guaiane sesquiterpene possessing the characteristic tricyclic 5–6-5 fused ring framework with contiguous seven stereogenic centers and isolated from Phyllanthus engleri, many synthetic groups have enthusiastically launched and accomplished its the chemical synthesis. All the synthetic groups focused on how to efficiently construct the tricyclic framework containing oxygen bridge with various approaches. In this review, the total and formal syntheses of englerin A reported to date are summarized.

  • 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.

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

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Presentations 【 Display / hide 】

  • ボロン酸を活用した生体高分子の化学修飾

    花屋賢悟

    ２０１９年度若手研究者のためのセミナー, 2019.08, Public discourse, seminar, tutorial, course, lecture and others

  • Nickel(II)-mediated arylation of biopolymers with arylboronic acid

    Kengo Hanaya, Mary K. Miller, Jun Ohata, Alicia E. Mangubat-Medina, Zachary T. Ball

    ISABC 2019 — 15th International Symposium on Applied Bioinorganic Chemistry, 2019.06, Oral Presentation(general)

  • ニッケル触媒を用いたシステイン選択的アリール化反応

    花屋 賢悟, 大畠 潤, Mary K. MILLER, Alicia E. MANGUBAT-MEDINA, Zachary T. BALL

    日本薬学会　第139年会, 2019.03, Oral Presentation(general)

  • Selective chemical protein modification with nickel(II) and arylboronic acid

    Kengo Hanaya, Jun Ohata, Mary K. Miller, Alicia E. Mangubat-Medina, Zachary T. Ball

    日本化学会　第99春季年会, 2019.03, Oral Presentation(general)

  • Development of enzyme-activatable sulfonate-based prodrugs for active targeting therapy

    SASAKI Akio, SHOJI Mitsuru, SUGAI Takeshi, HANAYA Kengo

    ICC05-AEM2016, 2016.09, Poster (general)

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

  • ボロン酸を用いるクロスカップリング反応を基盤としたタンパク質化学修飾法の開発

    2019.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 花屋　賢悟, Grant-in-Aid for Early-Career Scientists , Principal Investigator

  • スルホン酸エステルを母核とした刺激応答性リンカーの開発とプロドラッグへの応用

    2016.04
    -
    2019.03

    JAPAN SOCIETY FOR THE PROMOTION OF SCIENCE, Grant-in-Aid for Scientific Research, KENGO HANAYA, Research grant

  • 刺激応答性リンカーの創製に向けたアミノスルホン酸エステルの分子内環化反応の開発

    2016.04
    -
    2017.03

    THE JAPAN SCIENCE SOCIETY, SASAKAWA SCIENTIFIC RESEARCH GRANT, KENGO HANAYA, Research grant, Principal Investigator

  • 酵素触媒を活用した不斉誘導体化試薬の創製 （超高感度化と効率的供給法の開発）

    2015.04
    -
    2016.03

    日本私立学校振興・共済事業団, The Science Research Promotion Fund, Kengo Hanaya, Principal Investigator

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Courses Taught 【 Display / hide 】

  • STUDY OF MAJOR FIELD: (ORGANIC AND BIOCATALYTIC CHEMISTRY)

    2020

  • SEMINAR: (ORGANIC AND BIOCATALYTIC CHEMISTRY)

    2020

  • RESEARCH FOR BACHELOR'S THESIS 1

    2020

  • RESEARCH APPARATUS LABORATORY COURSE

    2020

  • PHARMACEUTICAL-ENGLISH SEMINAR

    2020

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