Mashino, Tadahiko



Faculty of Pharmacy 医薬品化学講座 (Mita)


Professor Emeritus

E-mail Address

E-mail address

Career 【 Display / hide

  • 1983.10

    Assistant professor, Tokyo University, Faculty of Pharmaceutical Sciense

  • 1997.01

    Associate professor, Kyoritsu University of Pharmacy

  • 2002.04

    Pprofessor, Kyoritsu University of Pharmacy

  • 2008.04

    Keio University. Faculty of Pharmacy

Academic Background 【 Display / hide

  • 1979.03

    The University of Tokyo, Faculty of Pharmaceutical Science, Devision of Pharmaceutical Science

    University, Graduated

  • 1983.09

    The University of Tokyo, Graduate School, Division of Pharmaceutical Sciences, Division of Pharmaceutical Sciences

    Graduate School, Withdrawal before completion, Doctoral course

Academic Degrees 【 Display / hide

  • Ph.D, The University of Tokyo, Dissertation, 1985.07


Research Areas 【 Display / hide

  • Chemical pharmacy (Chemical Pharmaceutical Science)

  • Drug development chemistry (Drug Development Chemistry)

Research Keywords 【 Display / hide

  • Cytochrome P450

  • Fullerene Derivatives

  • Antioxidant

  • Drug Metabolism

Research Themes 【 Display / hide

  • 抗酸化物質の開発, 


  • 医薬品を目指したフラーレン誘導体の合成と評価, 


  • 2. 薬物・環境物質の新規代謝物検索とその生理活性の検討, 



Books 【 Display / hide

  • フラーレン誘導体・内包技術の最前線.

    Ohe T, Mashino T., シーエムシー出版, 東京, 2014.04

    Scope: 237-247

  • Fullerene Nanowhiskers. Preparation and characterization of fullerene derivatives and their nanowhiskers.

    Nakamura S, Miyazawa K, Mashino T., Pan Stanford Publishing, Singapore, 2011.09

    Scope: 53-62

  • 各ナノ粒子・微粒子の毒性評価・安全性試験の動向 フラーレン.

    増野匡彦, 中村成夫., 東京/技術情報協会, 2007.10

    Scope: 383-396

  • ナノカーボンハンドブック(遠藤守信,飯島澄男監修) フラーレンの抗菌薬、抗ウイルス薬等医薬への応用.

    中村成夫, 増野匡彦, 他180名., 東京/エヌ・ティー・エス, 2007.07

    Scope: 668-673

  • フラーレンの医薬への応用.

    増野匡彦., /医学書院, 2006.12

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Papers 【 Display / hide

  • Fullerene derivatives as dual inhibitors of HIV-1 reverse transcriptase and protease

    Yasuno T., Ohe T., Kataoka H., Hashimoto K., Ishikawa Y., Furukawa K., Tateishi Y., Kobayashi T., Takahashi K., Nakamura S., Mashino T.

    Bioorganic and Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters)  31 2021.01

    ISSN  0960894X

     View Summary

    © 2020 Elsevier Ltd In the present study, we newly synthesized three types of novel fullerene derivatives: pyridinium-type derivatives trans-3a and 4a-5b, piperidinium-type derivative 9, and proline-type derivatives 10a-12. Among the assessed compounds, 5a, 10e, 10f, 10i, 11a-d, and 12 were found to inhibit both HIV reverse transcriptase and HIV protease (HIV-PR), with IC50 values in the low micromolar range being observed. Regarding HIV-PR inhibition activity, proline-type derivatives 11a-11d and 12, bearing an alkyl chain between the hydroxylmethylcarbonyl (HMC) moiety and pyrrolidine ring, were more potent than other derivatives. This result might indicate that connecting HMC moieties with proline-type fullerene derivatives through properly sized alkyl chain leads to improved HIV-PR inhibitory activity.

  • Development of Novel Diclofenac Analogs Designed to Avoid Metabolic Activation and Hepatocyte Toxicity

    Tateishi Y., Ohe T., Ogawa M., Takahashi K., Nakamura S., Mashino T.

    ACS Omega (ACS Omega)  5 ( 50 ) 32608 - 32616 2020.12

     View Summary

    © Diclofenac (DCF) is widely used as a nonsteroidal anti-inflammatory drug; however, it is associated with severe liver injury. This adverse reaction is thought to be related to the reactive quinone imine (QI) and acyl glucuronide (AG) metabolites of DCF, but it remains controversial which reactive metabolites mainly contribute to DCF-induced toxicity. In this study, we synthesized five types of DCF analogs that were designed to mitigate the formation of reactive QI and/or AG metabolites and evaluated their metabolic stability, cyclooxygenase (COX) inhibitory activity, and toxicity to cryopreserved human hepatocytes. Compounds with fluorine at the 5- A nd 4-positions of aromatic rings exhibited modest and high metabolic stability to oxidation by cytochrome P450, respectively, but induced cytotoxicity comparable to DCF. Replacing the carboxylic group of DCF with its bioisosteres was effective in terms of stability to oxidative metabolism and glucuronidation; however, sulfonic acid and sulfonamide groups were not preferable for COX inhibition, and tetrazole-containing analogs induced strong cytotoxicity. On the other hand, compounds that have fluorine at the benzylic position were resistant to glucuronidation and showed little toxicity to hepatocytes. In addition, among these compounds, those with hydrogen at the 4-position (2a and 2c) selectively inhibited the COX-2 enzyme. Throughout these data, it was suggested that compounds 2a and 2c might be novel safer and more efficacious drug candidates instead of DCF.

  • Synthesis and evaluation of nevirapine analogs to study the metabolic activation of nevirapine

    Tateishi Y., Ohe T., Yasuda D., Takahashi K., Nakamura S., Kazuki Y., Mashino T.

    Drug Metabolism and Pharmacokinetics (Drug Metabolism and Pharmacokinetics)  35 ( 2 ) 238 - 243 2020.04

    ISSN  13474367

     View Summary

    © 2020 The Japanese Society for the Study of Xenobiotics Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury.

  • Inhibitors of the protein–protein interaction between phosphorylated p62 and Keap1 attenuate chemoresistance in a human hepatocellular carcinoma cell line

    Yasuda D., Ohe T., Takahashi K., Imamura R., Kojima H., Okabe T., Ichimura Y., Komatsu M., Yamamoto M., Nagano T., Mashino T.

    Free Radical Research (Free Radical Research)   2020

    ISSN  10715762

     View Summary

    © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Resistance to anticancer agents has been an obstacle to developing therapeutics and reducing medical costs. Whereas sorafenib is used for the treatment of human hepatocellular carcinoma (HCC), resistance limits its efficacy. p62, a multifunctional protein, is overexpressed in several HCC cell lines, such as Huh-1 cells. Phosphorylated p62 (p-p62) inhibits the protein–protein interaction (PPI) between Keap1 and Nrf2, resulting in the Nrf2 overactivation that causes drug resistance. We have found a unique Nrf2 inactivator, named K67, that inhibited the PPI between Keap1 and p-p62 and attenuated sorafenib resistance in Huh-1 cells. Herein, we designed and synthesised novel K67 derivatives by modification of the substituent at the 4-position of the two benzenesulfonyl groups of K67. Although these new derivatives inhibited the Keap1-p-p62 PPI to a level comparable to or weaker than that of K67, the isopropoxy derivative enhanced the sensitivity of Huh-1 cells to sorafenib to a greater extent than K67 without any influence on the viability of Huh-7 cells, which is a non-resistant HCC cell line. The isopropoxy derivative also increased the sensitivity of Huh-1 cells to regorafenib, which suggests that this derivative has the potential to be used as an agent to overcome chemoresistance based on Nrf2 inactivation.

  • N-Acetyl cysteine prevents activities of STAT3 inhibitors, Stattic and BP-1-102 independently of its antioxidant properties

    Uchihara Y., Ohe T., Mashino T., Kidokoro T., Tago K., Tamura H., Funakoshi-Tago M.

    Pharmacological Reports (Pharmacological Reports)  71 ( 6 ) 1067 - 1078 2019.12

    ISSN  17341140

     View Summary

    © 2019 Institute of Pharmacology, Polish Academy of Sciences Background: Inhibitors for signal transducer and activator of transcription 3 (STAT3), Stattic, BP-1-102, and LLL12 significantly induce apoptosis in transformed Ba/F3 cells expressing an oncogenic fusion protein, nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) that induces the activation of STAT3. We found that the antioxidant reagent, N-acetyl cysteine (NAC) prevented the abilities of Stattic and BP-1-102, but not LLL12 to induce apoptosis in transformed cells expressing NPM-ALK, providing a novel problem in use of STAT3 inhibitors. We herein investigated the mechanisms how NAC prevented the effects of Sttatic and BP-1-102. Methods: Ba/F3 cells expressing NPM-ALK and SUDHL-1 cells were treated with antioxidants such as NAC, Trolox or edaravone in combination with STAT3 inhibitors. Phosphorylation of STAT3, cell proliferation rate, cell viability, cell cycle, internucleosomal DNA fragmentation and the intracellular accumulation of reactive oxygen species (ROS) was investigated. The binding of STAT3 inhibitors and NAC was analyzed by LC–MS. Results: NAC but not Trolox and edaravone diminished the abilities of Stattic and BP-1-102 to induce apoptosis in cells expressing NPM-ALK. The ROS levels in cells expressing NPM-ALK were not markedly affected by the treatments with Stattic and BP-1-102 in combination with NAC, suggesting that NAC inhibited the activity of Stattic and BP-1-102 independent of its antioxidant activity. LC–MS analysis revealed that NAC directly bound to Stattic and BP-1-102. Furthermore, these NAC adducts exhibited no cytotoxicity, and failed to affect the activity of STAT3. Conclusions: NAC antagonizes the activities of Stattic and BP-1-102, which inhibit STAT3 activation by interacting with cysteine residues in STAT3.

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

Reviews, Commentaries, etc. 【 Display / hide

  • アカデミアにおける Hit-to-Lead の実践 ~Keap1-Nrf2 タンパク間相互作用阻害剤の創製~


    薬学雑誌 138 ( 8 ) 1059 - 1065 2018.08

    Introduction and explanation (scientific journal), Joint Work

  • ヒトや野生生物における医薬品、環境化学物質の安全性評価の精度向上にむけて -代謝的活性化、種差、エピジェネティクスの観点から 肝毒性を示す医薬品の代謝活性化機構の解析とそれに基づいた創薬戦略

    大江知之, 高橋恭子, 中村成夫, 増野匡彦

    薬学雑誌 137 ( 3 ) 249 - 255 2017.03

    Introduction and explanation (scientific journal), Joint Work

Presentations 【 Display / hide

  • HIVプロテアーゼ/逆転写酵素、HCV NS5B を標的とするピリジニウム型C60誘導体の創製

    小林透威, 高橋恭子, 中村成夫, 大江知之, 増野匡彦

    第64回日本薬学会関東支部大会, 2020.09, Oral Presentation(general)

  • トラッピング剤を用いた反応性アシルグルクロニドの新規検出法

    柴﨑 智香子, 高橋 恭子, 中村成夫, 大江 知之, 増野 匡彦

    日本薬学会第140年会 (京都), 2020.03, Oral Presentation(general)

  • 薬学共用試験CBTの結果解析―2019―

    石川さと子, 伊藤智夫, 中村明弘, 増野匡彦, 石塚忠男, 松野純男, 前田定秋, 小澤孝一郎, 出口芳春,三田智文, 飯島史朗, 宮崎智, 矢ノ下良平, 奥直人.

    日本薬学会第140年会(京都), 2020.03, Poster (general)

  • 代謝活性化回避を指向した新規ジクロフェナク類縁体の合成と評価

    立石泰寛, 大江知之, 小川真依, 安田大輔, 高橋恭子, 中村成夫, 増野匡彦

    日本薬学会第140 年会 (京都), 2020.03, Oral Presentation(general)

  • HIV/HCV共感染治療薬を志向した 多標的型ピリジニウム型C60誘導体の創製

    小林透威, 高橋恭子, 中村成夫, 大江知之, 増野匡彦

    日本薬学会第140年会 (京都), 2020.03, Oral Presentation(general)

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

  • 成功確率の高いリード創出を支援する高機能ADMET評価基盤の構築


    日本医療研究開発機構, 創薬等ライフサイエンス研究支援基盤事業, 増野匡彦, Research grant, Principal Investigator

  • 神経細胞死保護作用を有するテトラロン型新規パーキンソン病治療薬の創製


    日本医療研究開発機構, 橋渡し研究戦略的推進プログラム シーズ A, 増野 匡彦, Research grant, Principal Investigator

Intellectual Property Rights, etc. 【 Display / hide

  • パーキンソン病治療薬

    Application No.: 特願2019-014281  2019.01 

    Patent, Joint, National application

  • 潰瘍性大腸炎の予防または治療剤と新規フラーレン誘導体

    Application No.: PCT/JP2014/053950  2014.02 

    Announcement No.: WO2014/129513  2014.08 

    Patent, Joint, PCT international application

  • 潰瘍性大腸炎の予防または治療剤と新規フラーレン誘導体

    Application No.: 特願2013-030455  2013.02 

    Patent, Joint, National application

  • Anti-Hepatitis C Virus Agents and Anti-HIV Agents.

    Application No.: 444404719087.1  2004.03 

    Registration No.: 1607091  2009.05

    Patent, Joint, PCT international application

  • フラーレンウィスカー及びフラーレンウィスカーの製造方法

    Application No.: 2003-110087  2003.04 

    Registration No.: 4322540  2009.06

    Patent, Joint, National application

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Courses Taught 【 Display / hide











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Courses Previously Taught 【 Display / hide


    Keio University, 2015, Spring Semester, Major subject, Lecture, Within own faculty, 1h, 220people


    Keio University, 2015, Autumn Semester, Major subject, Laboratory work/practical work/exercise, Lecturer outside of Keio, 220people


    Keio University, 2015, Autumn Semester, Major subject, Laboratory work/practical work/exercise, Lecturer outside of Keio, 65people


    Keio University, 2015, Autumn Semester, Major subject, Lecture, Within own faculty, 1h, 220people


    Keio University, 2015, Spring Semester, Lecture, Within own faculty, 1h, 40people

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Educational Activities and Special Notes 【 Display / hide

  • 薬学教育の改善・充実に関する調査研究委員会


    , Special Affairs

  • 薬学教育モデル・コアカリキュラム改訂案に関する全国説明会


    , Lecture at Education Method and Practice

  • 薬学生のための実習実験安全ガイド


    , Development of Textbook and Teaching Material

  • 薬学教育モデル・コアカリキュラム改訂に向けて


    , Lecture at Education Method and Practice

  • 薬学共用試験センターCBT実施委員会委員長


    , Special Affairs

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