菊地　晴久 （キクチ　ハルヒサ）

Kikuchi, Haruhisa

写真a

所属（所属キャンパス）

薬学部 薬学科 天然医薬資源学講座 （芝共立）

職名

教授

外部リンク
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経歴 【 表示 ／ 非表示 】

  • 1998年05月
    -
    1999年03月

    東北大学, 薬学部, 助手

  • 1999年04月
    -
    2007年03月

    東北大学, 大学院薬学研究科, 助手

  • 2007年04月
    -
    2009年03月

    東北大学, 大学院薬学研究科, 助教

  • 2009年04月
    -
    2021年03月

    東北大学, 大学院薬学研究科, 准教授

  • 2021年04月
    -
    継続中

    慶應義塾大学, 薬学部, 教授

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研究分野 【 表示 ／ 非表示 】

  • ライフサイエンス / 環境、天然医薬資源学 （天然物化学）

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著書 【 表示 ／ 非表示 】

  • 細胞性粘菌：研究の新展開〜モデル生物，創薬資源，バイオ〜

    菊地晴久, 久保原禅, アイピーシー出版, 2012年

    担当範囲: 第１０章 創薬資源としての細胞性粘菌

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論文 【 表示 ／ 非表示 】

  • Kinetics of the Inhibition of CYP3A4 and CYP2C19 Activity by Jabara Juice and Identification of the Responsible Inhibitory Components

    Kana Koinuma, Kenji Noto, Tokio Morita, Yoshinori Uekusa, Haruhisa Kikuchi, Miyuki Shimoji, Hiroyuki Seki, Hiroshi Yamazaki, F. Peter Guengerich, Katsunori Nakamura, Koujirou Yamamoto, Ayuko Imaoka, Takeshi Akiyoshi, Hisakazu Ohtani

    Journal of Pharmaceutical Sciences （Elsevier BV）  2024年10月

    査読有り,  ISSN  0022-3549

    　概要を見る

    Some citrus fruits are known to cause clinically significant drug interactions by inhibiting intestinal cytochrome P450 (CYP) enzymes. This in vitro study aimed to investigate the kinetics of the inhibition of CYP3A4 and CYP2C19 by the juice of jabara, a Japanese citrus fruit that does not contain furanocoumarins such as 6′,7′-dihydroxybergamottin, and to identify the inhibitory compound(s). CYP3A4 and CYP2C19 activity levels were determined in vitro using recombinant CYP preparations and their respective substrates. The ethyl acetate extract (EAE) of jabara juice was separated to isolate and identify the compound(s) that inhibited CYP3A4. Then, the time-dependent kinetics of the inhibition of CYP3A4 and CYP2C19 by the EAE and its inhibitory compound(s) were analyzed. The EAE of jabara juice was found to inhibit CYP3A4 in a time-dependent manner. Two flavonoids, 3,3′,4′,5,6,7,8-heptamethoxyflavone (HpMF) and 3,3′,4′,5,6,7-hexamethoxyflavone (HxMF), were identified as the responsible compounds. HpMF and HxMF inhibited CYP3A4 activity in a concentration- and time-dependent manner, with inhibition constants (KI) of 10.0 and 7.90 µM and maximal inactivation rate constants (kinact,max) of 0.00856 and 0.0134 min−1, respectively. The EAE did not inhibit CYP2C19, even when preincubation was employed. These findings imply that jabara juice may cause food-drug interactions via time-dependent inhibition of intestinal CYP3A4.

  • A longer-chain acylated derivative of Dictyostelium differentiation-inducing factor-1 enhances the antimalarial activity against Plasmodium parasites

    Naoko Yoshida, Haruhisa Kikuchi, Makoto Hirai, Betty Balikagala, Denis A. Anywar, Hikari Taka, Naoko Kaga, Yoshiki Miura, Naoyuki Fukuda, Emmanuel I. Odongo-Aginya, Yuzuru Kubohara, Toshihiro Mita

    Biochemical Pharmacology （Elsevier BV）  225   116243 - 116243 2024年07月

    査読有り,  ISSN  0006-2952

    　概要を見る

    The spread of malarial parasites resistant to first-line treatments such as artemisinin combination therapies is a global health concern. Differentiation-inducing factor 1 (DIF-1) is a chlorinated alkylphenone (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one) originally found in the cellular slime mould Dictyostelium discoideum. We previously showed that some derivatives of DIF-1, particularly DIF-1(+2) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) octan-1-one), exert potent antimalarial activities. In this study, we synthesised DIF-1(+3) (1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) nonan-1-one). We then evaluated the effects of DIF-1(+3) in vitro on Plasmodium falciparum and in vivo over 7 days (50–100 mg/kg/day) in a mouse model of Plasmodium berghei. DIF-1(+3) exhibited a half-maximal inhibitory concentration of approximately 20–30 % of DIF-1(+2) in three laboratory strains with a selectivity index > 263, including in strains resistant to chloroquine and artemisinin. Parasite growth and multiplication were almost completely suppressed by treatment with 100 mg/kg DIF-1(+3). The survival time of infected mice was significantly increased (P = 0.006) with no apparent adverse effects. In summary, addition of an acyl group to DIF-1(+2) to prepare DIF-1(+3) substantially enhanced antimalarial activity, even in drug-resistant malaria, indicating the potential of applying DIF-1(+3) for malaria treatment.

  • Synthesis of a Library of Terpenoid Alkaloid–Like Compounds Containing Medium-Sized Rings via Reconstruction of the Humulene Skeleton

    Nishimura T., Shiga K., Sekiya M., Sugawara A., Yonezawa T., Kikuchi H.

    Chemistry - A European Journal 30 （ 48 ） e202402082 2024年06月

    ISSN  09476539

    　概要を見る

    The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized a terpenoid alkaloid-like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11-membered monocyclic, oxabicyclic, and medium-sized aza ring-containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C−O bond formation via Lewis acid-mediated epoxide-opening transannulation, and a ring-reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three-dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid-like compound library for drug discovery and the accessibility to structure-activity relationship studies were validated by performing an assay for osteoclast-specific tartrate-resistant acid phosphatase activity, resulting in the identification of a seed compound for bone-resorptive diseases such as osteoporosis.

  • Isolation and Structure Determination of New Pyrones from Dictyostelium spp. Cellular Slime Molds Coincubated with Pseudomonas spp.

    Nishimura T., Murotani T., Sasaki H., Uekusa Y., Eguchi H., Ishigaki H., Takahashi K., Kubohara Y., Kikuchi H.

    Molecules （MDPI AG）  29 （ 9 ） 2143 - 2143 2024年05月

    　概要を見る

    Cellular slime molds are excellent model organisms in the field of cell and developmental biology because of their simple developmental patterns. During our studies on the identification of bioactive molecules from secondary metabolites of cellular slime molds toward the development of novel pharmaceuticals, we revealed the structural diversity of secondary metabolites. Cellular slime molds grow by feeding on bacteria, such as Klebsiella aerogenes and Escherichia coli, without using medium components. Although changing the feeding bacteria is expected to affect dramatically the secondary metabolite production, the effect of the feeding bacteria on the production of secondary metabolites is not known. Herein, we report the isolation and structure elucidation of clavapyrone (1) from Dictyostelium clavatum, intermedipyrone (2) from D. magnum, and magnumiol (3) from D. intermedium. These compounds are not obtained from usual cultural conditions with Klebsiella aerogenes but obtained from coincubated conditions with Pseudomonas spp. The results demonstrate the diversity of the secondary metabolites of cellular slime molds and suggest that widening the range of feeding bacteria for cellular slime molds would increase their application potential in drug discovery.

  • Anti-trypanosomal Lignans Isolated from Salvadoran Peperomia pseudopereskiifolia

    Castillo U.G., Uekusa Y., Nishimura T., Kiuchi F., Martínez M.L., Menjívar J., Nakajima-Shimada J., Núñez M.J., Kikuchi H.

    Journal of Natural Products （American Chemical Society (ACS)）  87 （ 4 ） 1067 - 1074 2024年04月

    ISSN  0163-3864

    　概要を見る

    A search for anti-trypanosomal natural compounds from plants collected in El Salvador, a country particularly endemic for Chagas disease, resulted in the isolation of five lignan-type compounds (1-5) from Peperomia pseudopereskiifolia. The lignan derivatives 1, 2, and 4 are new. Their absolute configuration was determined by chemical derivatization. Compounds 1, 5, 6, and 8 exhibited anti-trypanosomal activity against the amastigote form of T. cruzi comparable to that of the existing drug benznidazole.

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KOARA（リポジトリ）収録論文等 【 表示 ／ 非表示 】

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  • ケミカルバイオロジーの冒険（6）生体を制御するための化学 天然物関連の生物活性分子開発

    叶 直樹, 菊地晴久, 高岡洋輔

    現代化学  （ 642 ） 45 - 52 2024年09月

  • New Development of Disaster-Related and Tropical Infectious Diseases Control

    Gaowa Bai, Toshiro Niki, Haruhisa Kikuchi, Ayako Sumi, Nobuyuki Kobayashi, Takahiro Haruyama, Jing Zhang, Haorile Chagan-Yasutan, Toshio Hattori

    Reports — Medical Cases, Images, and Videos （MDPI AG）  3 （ 1 ） 5 - 5 2020年03月

    その他, 共著

    　概要を見る

    As described in Japanese essay (Hojoki), written around 1200, various disasters such as big fires, earthquakes, and famines have occurred in Japan. Asian countries have been suffering from the disasters; furthermore, natural disasters are increasing due to global warming. Because tropical-infectious diseases are often disaster-related infectious diseases (DRIDs), the strategies against the former kind of disease could be applicable to DRIDs. Meteorological analysis of the occurrence of DRIDs using a method of time series analysis is important. In situations of disasters, it is desirable if you can identify the pathogen and identify disease severity simultaneously. A dipstick DNA chromatography assay termed as Single-Tag Hybridization—Printed Array Strip (STH—PAS) system was developed based on the DNA sequences of various mosquito-borne diseases. The plasma levels of matricellular proteins including galectin-9 (Gal-9) and osteopontin (OPN) were found to reflect the disease severities in the dengue virus and other DIRDs. Because both proteins have been reported to be immune-check molecules, their inhibition might enhance the immune system against pathogens. We found that brefelamide derivatives could inhibit OPN and other inflammatory molecules synthesis. Very recently, different derivatives were found to inhibit PD-L1 transcription. Applications of these agents should be considered as multi-step strategies against DRIDs.

  • 多様性拡大抽出物を利用した天然化合物様ライブラリーの創出

    菊地晴久, 大島吉輝

    MedChem News 24 （ 2 ） 45 - 51 2014年

    記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）, 共著

  • 未利用微生物・細胞性粘菌から得られた新規生物活性物質（総説）

    菊地晴久

    薬学雑誌 （PHARMACEUTICAL SOC JAPAN）  127 （ 9 ） 1431 - 1439 2007年

    書評論文，書評，文献紹介等, 単著,  ISSN  0031-6903

    　概要を見る

    Cellular slime molds are thought to be excellent model organisms for the study of cell and developmental biology because of their simple pattern of development. However, there have been few reports on secondary metabolites of them. We have focused on the utility of cellular slime molds as novel resources for natural product chemistry, and have studied the diversity of secondary metabolites produced by them as well as their physiological and pharmacological activities. We have recently isolated many novel compounds from the fruiting bodies of various species of Dictyostelium cellular slime molds. Total syntheses and biological evaluation of these compounds have been carried out. It was shown that dictyopyrones and dictyomedins may regulate Dictyostelium development. Amino sugar derivatives such as furanodictines and dictyoglucosamines induced neuronal differentiation of rat PC-12 cells. In addition, brefelarnide inhibited the cellular proliferation of 1321N1 human astrocytorna cells. These results show that cellular slime molds are promising sources in natural product chemistry.

  • 細胞性粘菌の生活環を制御する物質−単細胞から多細胞への移行をコントロールするα-ピロノイド

    大島吉輝, 菊地晴久, 前田靖男

    化学と生物 40 （ 2 ） 76 - 77 2002年

    記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）, 共著,  ISSN  0453-073X

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研究発表 【 表示 ／ 非表示 】

  • Development of Natural Product-Like Compound Library Based on Diversity-Enhanced Extracts

    KIKUCHI Haruhisa

    The 5th Japan-Taiwan Joint Symposium for Pharmaceutical Sciences, 

    2019年08月
    , 

    シンポジウム・ワークショップ パネル（指名）

  • 創薬シーズを指向した天然物を越える構造多様化合物群の創出

    菊地 晴久

    BINDS: ケミカルシーズ・リード探索ユニットジョイントシンポジウム 2019 IN 仙台, 

    2019年05月
    , 

    シンポジウム・ワークショップ パネル（指名）

  • Development of Natural Product-Like Compound Library Based on Diversity-Enhanced Extracts

    KIKUCHI Haruhisa

    The 2nd International Symposium on Chemical Communication, 

    2018年05月
    , 

    口頭発表（招待・特別）

  • Diversity enhanced extract: a new approach for increasing chemical diversity of natural product-like compounds

    KIKUCHI Haruhisa

    Tohoku University’s Chemistry Summer School, 

    2016年08月
    , 

    口頭発表（基調）

  • 多様性拡大抽出物を活用した天然化合物類縁体ライブラリーの創出

    菊地晴久

    日本薬学会第136年会 シンポジウム MONOTORIの新戦略, 

    2016年03月
    , 

    シンポジウム・ワークショップ パネル（指名）

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競争的研究費の研究課題 【 表示 ／ 非表示 】

  • 天然化合物を越える多様性を有した生物活性指向型化合物ライブラリーの構築

    2019年04月
    -
    2022年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 菊地 晴久, 基盤研究(B), 補助金,  研究代表者

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受賞 【 表示 ／ 非表示 】

  • 日本生薬学会学術貢献賞

    2022年, 日本生薬学会

  • 第９回インテリジェント・コスモス奨励賞

    2010年

  • 第46回天然有機化合物討論会奨励賞

    2004年

    受賞区分： 国内学会・会議・シンポジウム等の賞

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担当授業科目 【 表示 ／ 非表示 】

  • 漢方概論

    2024年度

  • 英語演習（薬科学科）

    2024年度

  • 早期体験学習（薬科学科）

    2024年度

  • 創薬科学特論

    2024年度

  • 化学系薬学特論Ⅱ

    2024年度

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