高橋 恭子 (タカハシ キョウコ)

Takahashi, Kyoko

写真a

所属(所属キャンパス)

薬学部 薬科学科 医薬品化学講座 (芝共立)

職名

専任講師

メールアドレス

メールアドレス

外部リンク

学歴 【 表示 / 非表示

  • 1986年03月

    共立薬科大学, 薬学部

    大学, 卒業

学位 【 表示 / 非表示

  • 博士(薬学), 共立薬科大学, 論文, 2007年12月

 

研究分野 【 表示 / 非表示

  • 化学系薬学

  • 創薬化学

研究テーマ 【 表示 / 非表示

  • パーキンソン病治療薬の創製, 

    2012年
    -
    継続中

  • 抗酸化活性化合物の合成とデザイン, 

    2002年04月
    -
    継続中

 

著書 【 表示 / 非表示

  • Interprofessional Education at the Keio University Faculty of Pharmacy, in: Advanced Initiatives in Interprofessional Education in Japan" (ed. by Watanabe H, Koizumi M)."

    Ehara Y, Abe Y, Fujimoto K, Fukushima N, Iijima S, Ishikawa S, Kishimoto K, Mochizuki M, Takahashi K, Yokota E, Kobayashi S., Springer, Tokyo, Berlin, Heidelberg, New York, 2010年02月

    担当範囲: pp57-63

論文 【 表示 / 非表示

  • 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年04月

    ISSN  13474367

     概要を見る

    © 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年

    ISSN  10715762

     概要を見る

    © 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.

  • Synthesis and antitumor activity of novel pyridinium fullerene derivatives

    Yasuno T., Ohe T., Ikeda H., Takahashi K., Nakamura S., Mashino T.

    International Journal of Nanomedicine (International Journal of Nanomedicine)  14   6325 - 6337 2019年

    ISSN  11769114

     概要を見る

    © 2019 Yasuno et al. Purpose: We have previously reported that some cationic fullerene derivatives exhibited anticancer activity, and they are expected to be a potential lead compound for an anti-drug resistant cancer agent. However, they are bis-adducts and a mixture of multiple regioisomers, which cannot be readily separated due to the variability of substituent positions on the fullerene cage. To overcome this issue, we evaluated the antiproliferative activities of a set of mono-adduct derivatives and examined their structure-activity relationship. In addition, the in vivo antitumor activity of selected derivatives was also examined. Methods: Nineteen pyridinium fullerene derivatives were newly designed and synthesized in this study. Their antiproliferative activities were evaluated using several cancer cell lines including drug-resistant cells. Furthermore, in vivo antitumor activity of several derivatives was investigated in mouse xenograft model of human lung cancer. Results: The derivatives inhibited the proliferation of cancer cell lines, including cisplatin-resistant cells and doxorubicin-resistant cells. It was also shown that compound 10 (10 μM), 13 (10 μM) and cis-14 (10 μM) induced the intracellular oxidative stress. In addition, compound 13 (20 mg/kg) and cis-14 (15 mg/kg) significantly exhibited antitumor activity in mouse xenograft model of human lung cancer. Conclusion: We synthesized a novel set of mono-adduct fullerene derivatives functionalized with pyridinium groups and found that most of them show potent antiproliferative activities against cancer cell lines and some of them show significant antitumor activities in vivo. We propose that these fullerene derivatives serve as the lead compounds for a novel type of antitumor agents.

  • Synthesis of novel benzbromarone derivatives designed to avoid metabolic activation

    Ohe T., Umezawa R., Kitagawara Y., Yasuda D., Takahashi K., Nakamura S., Abe A., Sekine S., Ito K., Okunushi K., Morio H., Furihata T., Anzai N., Mashino T.

    Bioorganic and Medicinal Chemistry Letters (Bioorganic and Medicinal Chemistry Letters)  28 ( 23-24 ) 3708 - 3711 2018年12月

    ISSN  0960894X

     概要を見る

    © 2018 Elsevier Ltd We synthesized six novel BBR derivatives that were designed to avoid metabolic activation via ipso-substitution and evaluated for their degree of toxicity and hURAT1 inhibition. It was found that all of the derivatives demonstrate lower cytotoxicity in mouse hepatocytes and lower levels of metabolic activation than BBR, while maintaining their inhibitory activity toward the uric acid transporter. We propose that these derivatives could serve as effective uricosuric agents that have much better safety profiles than BBR.

  • A 5-hydroxyoxindole derivative attenuates LPS-induced inflammatory responses by activating the p38-Nrf2 signaling axis

    Niino T., Tago K., Yasuda D., Takahashi K., Mashino T., Tamura H., Funakoshi-Tago M.

    Biochemical Pharmacology (Biochemical Pharmacology)  155   182 - 197 2018年09月

    ISSN  0006-2952

     概要を見る

    © 2018 Elsevier Inc. 5-Hydroxyoxindole is a urinary metabolite of indole that exhibits antioxidant activity. In the present study, we found that a 5-hydroxyoxindole derivative (5-HI) significantly inhibited LPS-induced inflammatory effects in the murine macrophage cell line, RAW264.7. 5-HI induced the expression of the transcription factor, Nrf2, which is typically ubiquitinated by Keap1, an adaptor component of the ubiquitin E3 ligase complex, resulting in its proteasomal degradation. By utilizing Keap1−/− MEFs reconstituted with Keap1 mutants harboring substitutions in their major cysteine residues, we clarified the importance of Cys151 in Keap1 as a sensor for 5-HI in the induction of Nrf2 expression. Furthermore, 5-HI induced the activation of the MKK3/6-p38 pathway, which is required for the transcriptional activation of Nrf2. The knockdown of Nrf2 enhanced the LPS-induced expression of inflammatory mediators, including iNOS, NO, and CCL2, and effectively repressed the inhibitory effects of 5-HI on their expression. Although 5-HI and antioxidant N-acetyl cysteine (NAC) both reduced LPS-induced ROS generation, the treatment with NAC did not affect the LPS-induced expression of inflammatory mediators, suggesting that the anti-inflammatory activity of 5-HI mediated by Nrf2 is independent of redox control. Furthermore, when injected into mice with 5-HI, the expression of Nrf2 was significantly increased, and the LPS-induced mRNA expression of CXCL1, CCL2, TNFα and IL-6 were remarkably inhibited in the kidneys, liver, and lungs, and the production of these cytokines in serum was effectively reduced. Collectively, these results suggest that 5-HI has potential in the treatment of inflammatory diseases through the activation of Nrf2.

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研究発表 【 表示 / 非表示

  • フッ素導入により反応性代謝物の生成を回避した改良型Diclofenac類縁体の創製

    ○小川 真依、山田晶子、安田大輔、高橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, ポスター(一般), 日本薬学会第139年会

  • ハード及びソフトな反応性代謝物を捕捉する新規蛍光標識トラッピング剤の創製

    ○柴崎智香子、髙橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, 口頭(一般), 日本薬学会第139年会

  • オキシカム構造を模倣したスルホン類の抗パーキンソン病効果

    ○小町元輝、鈴木啓太、高橋恭子、中村成夫、大江知之、大久保知子、春名柚佳、田﨑嘉一、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, 口頭(一般), 日本薬学会第139年会

  • ハードな反応性代謝物を捕捉する新規蛍光標識化トラッピング剤の創製

    ○長邑花、柴崎智香子、髙橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, ポスター(一般), 日本薬学会第139年会

  • HIVプロテアーゼおよび逆転写酵素阻害活性を有する新規多標的型C60誘導体の創製:基質遷移状態模倣型イソスターとC60コアを結ぶリンカーの長さの検討

    ○古川 慶吾、髙橋恭子、中村成夫、大江知之、増野匡彦

    日本薬学会第139年会 (千葉) , 2019年03月, ポスター(一般), 日本薬学会第139年会

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担当授業科目 【 表示 / 非表示

  • 課題研究(医薬品化学)

    2020年度

  • 演習(医薬品化学)

    2020年度

  • 卒業研究1(薬学科)

    2020年度

  • 高度研究機器特別演習

    2020年度

  • 英語演習(薬学科)

    2020年度

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