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医薬分子化学研究室

研究テーマ

・医療への応用を志向した光機能分子の開発

・エピジェネティクス、エピトランスクリプトームを制御、解析する分子の開発

・生体防御、抗がん及び抗老化作用を有する化合物の創薬研究

医薬分子化学研究室では、様々な機能を持った分子を開発しています。生物学および医療の現場では、薬のもととなる生理機能を制御する分子だけでなく、光の照射によって蛍光を発する分子、化学反応が起こる分子など、様々な機能を持った分子が用いられています。当研究室では、副作用が少ない治療法の構築や、疾患の診断などにも利用できる、こうした分子を開発しています。また、生体防御を司るKeap1-Nrf2系に着目し、そのシステムを利用した創薬や、機能解析に応用可能な多機能型蛍光プローブの開発等も行なっています。
 

キーワード

創薬化学、光機能分子、蛍光物質、光分解性保護基、エピジェネティクス、エピトランスクリプトーム、Keap1-Nrf2、抗がん剤、抗老化薬、オートファジー
 

配属学生

大学院生 0名
学部学生 6年次生：13名、5年次生：16名、4年次生：14名

所属教員

研究内容

（1）医療への応用を志向した光機能分子の開発

光を用いる手法は、生体の非侵襲的な制御、解析を可能とするため、疾患の治療、診断において広く利用されています。当研究室では、こうした手法に用いる蛍光物質、光分解性保護基などの光機能分子の開発を行っています。例えば、疾患組織近傍などの特定の環境選択的に治療薬を光放出する分子システムや、疾患診断を可能とする蛍光物質です。分子構造を論理的にデザインするだけでなく、植物などに由来する天然物を基に開発する研究も行っています。
OFF-ON-OFF型の機能制御により特定のpH領域で機能する光分解性保護基
開発した光分解性保護基を基にした選択的疾患治療システム

（2）エピジェネティクス、エピトランスクリプトームを制御、解析する分子の開発

DNA、RNA内の核酸、DNAと複合体を形成するヒストン蛋白質では、メチル化などの化学修飾反応が起こります。塩基配列の変化を伴わずに遺伝子の活性化などを制御する、こうした修飾を解析する学問領域は、エピジェネティクス、エピトランスクリプトームと呼ばれており、修飾を制御する酵素群は新たな創薬標的として注目されています。我々は、疾患治療薬となりえるこうした酵素に対する阻害剤および、生理機能を解析するための有機化学反応の開発を行っています。

（3）生体防御と老化を制御する低・中分子化合物創薬

近年、老化は加齢に伴う自然現象だけではなく、疾病の一種とする考えが広まってきました。我々は老化や加齢性疾患 (がん、パーキンソン病、アルツハイマー病など)の新規治療標的として、生体防御を担うKeap1-Nrf2 系が有望であると考え、その制御を可能とする低〜中分子化合物を創成しています。これまでに、がん細胞の抗がん剤に対する感受性を増強するユニークな作用を持った分子を合成しています。
また、独自に創製したKeap1結合分子を活用し、選択的オートファジーを検出する蛍光プローブの設計・合成にも取り組んでいます。
参考: Keap1-Nrf2系について
https://www.chem-station.com/blog/2021/01/nrf2.html

代表的論文

2026年

  1. Komeda K, Toyoshima K, Yasuda D, Ishida H, Kojima K, Osawa M, Hirano T, Ohe T, Tago K, Funakoshi-Tago M: KMN003 activates Nrf2 via disruption of the Keap1-Nrf2 interaction and p38-dependent transcriptional regulation. Cell. Signal. 137, 112194, 2026

2025年

  1. Yasuda D, Toyoshima K, Kojima K, Ishida H, Kaitoh K, Imamura R, Kanamitsu K, Kojima H, Funakoshi-Tago M, Osawa M, Ohe T, Hirano T: Development of Keap1-Nrf2 Protein-protein Interaction Inhibitor Activating Intracellular Nrf2 Based on the Naphthalene-2-acetamide Scaffold, and its Anti-inflammatory Effects. ChemMedChem. 20, e202500474, 2025
  2. Asano H, Kawaguchi T, Kato C, Morimoto S, Yano M, Minaguchi M, Yasuda D, Fukushima K, Okano H: Ropinirole Functions Through a Dopamine Receptor D2-Independent Mechanism to Ameliorate Amyotrophic Lateral Sclerosis Phenotypes in TARDBP-Mutant iPSC-Derived Motor Neurons. J. Neurochem. 169, e70183, 2025
  3. Hirano T, Yasuda D, Yamada T, Kagechika H, Development of fluorescent estrogen receptor ligands with pH sensor functionality. Chem. Pharm. Bull. 73, 412, 2025

2023年

  1. Kikuchi T, Anami D, Morikawa S, Nakagawa Y, Li W, Yamada T, Hirano T: Secoergostane- and ergostane-type steroids from Pleurotus cornucopiae var. citrinopileatus Phytochemistry 206,113552, 2023
  2. Katagishi D, Yasuda D, Takahashi K, Nakamura S, Mashino T, Ohe T: Fullerene derivatives as inhibitors of SARS-Cov-2 main protease, Bioorg. Med. Chem. Lett, 80, 129121, 2023
  3. Kanehara R, Tanaka K, Yamada T, Koshino H, Hashimoto M: Termination of the chirality confusion of peribysins Bull.Chem.Soc.Jpn. 96, 318, 2023
  4. 山田　剛司, 菊地　崇: 抗がん剤, 特許第7334927号

2022年

  1. Usami Y, Mizobuchi Y, Ijuin M, Yamada T, Morita M, Mizuki K, Yoneyama H, Harusawa S: Synthesis of 6-halo-substituted pericosine A and an evaluation of their antitumor and antiglycosidase activities Mar. Drugs 20, 438, 2022
  2. Yasuda D, Yoshida I, Imamura R, Katagishi D, Takahashi K, Kojima H, Okabe T, Ichimura Y, Komatsu M, Mashino T, Ohe T: Development of p62-Keap1 Protein-Protein Interaction Inhibitors as Doxorubicin-Sensitizers Against Non-Small Cell Lung Cancer. Results Chem. 4, 100609,2022
  3. 平野智也、横尾英知、影近弘之、蛍光性天然物を基にした新規蛍光物質の創製、有機合成化学協会誌、80, 922, 202

2021年

  1. Kato D, Shiraishi T, Kagechika H, Hirano T: 6-Arylcoumarin as a Scaffold of Photofunctional Molecules with OFF–ON–OFF Type Regulation. J. Org. Chem., 86, 2264, 2021. (Selected as “Supplementary Journal Cover”)
  2. Takayanagi S, Watanabe K, Maruyama T, Ogawa M, Morishita K, Soga M, Hatta T, Natsume T, Hirano T, Kagechika H, Hattori K, Naguro I, Ichijo H: ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes. Sci. Rep., 11, 22009, 2021
  3. Asano A, Nakagawa C, Miyajima M, Yasui K, Minoura K, Yamada T, Doi M: Effect of the powerful plasticity of the tert-butyl side chain on the conformational equilibrium of ascidiacyclamides J. Pep. Sci. 27, e3363, 2021

2020年

  1. Yamada T, Kogure H, Kataoka M, Kikuchi T, Hirano T, Nehira T, Nishii T: Halosmysin A, a novel 14-membered macrodiolide isolated from the marine-algae-derived fungus Halosphaeriaceae sp. Mar. Drugs, 18, 320/1–320/9, 2020
  2. Kikuchi T, Akiyama K, Koike H, In Y, Yamada T, Tanaka R: Carapanins A-C: new limonoids from andiroba (Carapa guianensis) fruit oil. Org. Biomol. Chem., 18, 9268–9274, 2020
  3. Asano A, Minoura K, Kojima Y, Yoshii T, Yamada T, Doi M. NMR-​based quantitative studies of the conformational equilibrium between their square and folded forms of ascidiacyclamide and its analogues. RSC Adv., 10, 33317–33326, 2020
  4. Kikuchi T, Mori M, In Y, Zhang J, Yamada T, Hirano T: leurocorols A and B: rearranged steroids from the fruiting bodies of Pleurotus cornucopiae. Org. Chem. Front., 7, 2022–2028, 2020
  5. Asano A, Yamada T, Doi M.Incorporation of β-​amino acids into ascidiacyclamides: Effects on conformation, cytotoxicity and interaction with copper (II) ion. J. Pep. Sci., 25, e3225/1–e3225/10, 2020
  6. 平野智也、新たな構造・機能を持った光機能分子の開発、ファルマシア、56(12), 1112-1116, 2020

2019年

  1. H. Yokoo, H. Kagechika, A. Ohsaki, T. Hirano, A Polarity‐Sensitive Fluorescent Amino Acid and its Incorporation into Peptides for the Ratiometric Detection of Biomolecular Interactions, ChemPlusChem, 84, 1716-1719, 2019. (Featured in ChemistryViews Magazine, 15 December 2019, “Fluorescent Peptides Help to Detect Biomolecular Interactions”.)
  2. Yamada T, Tanaka R, Nehira T, Nishii T, Kikuchi T. Altercrasins A-E, decalin derivatives, from a sea-urchin-derived Alternaria sp.: isolation and structural analysis including stereochemistry. Mar. Drugs, 17, 218/1–218/10, 2019
  3. Inoue K, Tanaka K, Yamada T, Koshino H, Hashimoto M. Isolation of peribysins O, P, and Q from Periconia macrospinosa KT3863 and configurational reinvestigation of peribysin E diacetate from Periconia byssoides OUPS-N133. J. Nat. Pro., 82, 911–918, 2019
  4. Yamada T, Fujii A, Kikuchi T. New Diterpenes with a Fused 6-5-6-6 Ring System Isolated from the Marine Sponge-Derived Fungus Trichoderma harzianum. Mar. Drugs, 17, 480/1–10, 2019
  5. 平野智也、植物由来の天然物を基にした蛍光物質の創製、アグリバイオ、3(2), 61-65, 2019.

2018年

  1. Hirano T, Fujiwara T, Niwa H, Hirano M, Ohira K, Okazaki Y, Sato S, Umehara T, Maemoto Y, Ito A, Yoshida M, Kagechika H, Development of novel inhibitors for histone methyltransferase SET7/9 based on cyproheptadine. ChemMedChem, 13, 1530-1540 (2018) (Selected as “Cover Features”).
  2. Yokoo Y, Ohsaki A, Kagechika H, Hirano T, Unique properties of 1,5-naphthyridin-2(1H)-one derivatives as environmental-polarity-sensitive fluorescent dyes. Eur. J. Org. Chem. 679-687, 2018 (Selected as “Outstanding Organics”).
  3. Urushibara K, Masu H, Mori H, Azumaya I, Hirano T, Kagechika H, Tanatani A, Synthesis and Conformational Analysis of Alternately N‑Alkylated Aromatic Amide Oligomers. J. Org. Chem. 83, 14338-14349, 2018.
  4. Tojo Y, Urushibara K, Yamamoto S, Mori H, Masu H, Kudo M, Hirano T, Azumaya I, Kagechika H, Tanatani A, Conformational Properties of Aromatic Oligoamides Bearing Pyrrole Rings. J. Org. Chem. 83, 4606-4617, 2018.
  5. Sasayama A, Akita K, Ohya H, Kikuchi T, In Y, Fujitake M, Yamada T, Tanaka R: Guianofruits A and B from the fruit oil of andiroba (Carapa guianensis, Meliaceae) and their effects on LPS-activated NO Production. Chem.Select, 3:6056-6060, 2018
  6. Kikuchi T, Kitaura K, Katsumoto A, Zhang J, Yamada T, Tanaka R: Three bisabolane-type sesquiterpenes from edible mushroom Pleurotus eryngii. Fitoterapia, 129:108-113, 2018
  7. Yamada T, Matsyda M, Seki M, Hirose M, Kikuchi T: Sterepinic acids A-C, new carboxylic acids produced by a marine alga-derived fungus. Molecules, 23:1336/1-1336/10, 2108
  8. Inoue T, Ohmori S, Ohya H, Kikuchi T, Yamada T, Tanaka R: Carapanosins D-F from the seeds of andiroba (Carapa guianensis, Meliaceae) and their effects on LPS-activated NO production. Molecules, 23:1778/1-1778/9, 2108
  9. Zhang J, Zhu W-F, Zhu W-Y, Yang P-P, Xu J, Manosroi J, Kikuchi T, Abe M, Akihisa T, Feng F: Melanogenesis-inhibitory and cytotoxic activities of chemical constituents from the leaves of Sauropus androgynus L. MERR. (Euphorbiaceae). Chem. Biodivers., 15: e1700486, 2018
  10. Zhang J, Akihisa T, Kurita M, Kikuchi T, Zhu W-F, Ye F, Dong Z-H, Liu W-Y, Feng F, Xu J: Melanogenesis-inhibitory and cytotoxic activities of triterpene glycoside constituents from the bark of Albizia procera. J. Nat. Prod., 81: 2612-2620, 2018
  11. Miao D., Zhang T-Q, Xu J, Ma C-Y, Liu, W-Y, Kikuchi T, Akihisa T, Abe M, Feng F, Zhang J: Three new cardiac glycosides obtained from the roots of Streblus asper Lour. and their cytotoxic and melanogenesis-inhibitory activities. RSC Adv., 8: 19570-19579, 2018
  12. Morikawa T, Nagatomo A, Kitagawa K, Muraoka O, Kikuchi T, Yamada T, Tanaka R, Ninomiya K: Collagen synthesis-promoting effects of andiroba oil and its limonoid constituents in normal human dermal fibroblasts. J. Oleo Sci., 67: 1271-1277, 2018
  13. Yamada T, Kajimoto J, Kikuchi T, Tanaka R: Elucidation of the relationship between CD Cotton effects and the absolute configuration of sixteen stereoisomers of spiroheterocyclic-lactams. Mar. Drugs 16: 223/1–223/12, 2018
  14. Hirano T, Mori S, Kagechika H, Development of functional molecules for regulating and elucidating histone methyltransferase. Chemical Record, 18, 1745-1759, 2018.

2017年

  1. Mori S, Hirano T, Takaguchi A, Fujiwara T, Okazaki Y, Kagechika H, Selective reagent for detection of N-ε-monomethylation of peptide lysine residue via SNAr reaction. Eur. J. Org. Chem. 3606-3611, 2017.
  2. Endo Y, Kasahara T, Harada K, Kubo M, Etoh T, Ishibashi M, Ishiyama A, Iwatsuki M, Otoguro K, Omura S, Akisue G, Hirano T, Kagechika H, Fukuyama Y, Ohsaki A, Sucupiranins A−L, Furanocassane Diterpenoids from the Seeds of Bowdichia virgilioides. J. Nat. Prod. 80, 3120−3127, 2017.
  3. Yamada T, Suzue M, Arai T, Kikuchi T, Tanaka R: Trichodermanins C–E, new diterpenes with a fused 6-5-6-6 ring system produced by a marine sponge-derived fungus. Mar. Drugs, 15:169/1-169/7, 2017
  4. Yamada T, Kimura H, Arimitsu T, Kajimoto T, Kikuchi T, Tanaka R: Absolute configuration of eight cephalimysins isolated from the marine-derived Aspergillus fumigatus. ChemistrySelect, 2: 10936 -10940, 2017
  5. Asano A, Numata S, Yamada T, Minoura K, Doi M: Conformational properties of ascydiacyclamide analogues with cyclic α-amino acids instead of oxazoline residues. Bioorg. Med. Chem., 25: 6554-6562, 2017
  6. Higuchi K, Tani Y, Kikuchi T, In Y, Yamada T, Muraoka O, Tanaka N, Tanaka R: Guianolactones A and B, two rearranged pentacyclic limonoids from the seeds of Carapa guianensis. Chem.-Asian J., 12: 3000-3004, 2017
  7. Kikuchi T, Horii Y, Maekawa Y, Masumoto Y, In Y, Tomoo K, Sato H, Yamano A, Yamada T, Tanaka R: Pleurocins A and B: unusual 11(9→7)-abeo-ergostanes and eringiacetal B: A 13,14-seco-13,14-epoxyergostane from fruiting bodies of Pleurotus eryngii and their inhibitory effects on nitric oxide production. J. Org. Chem., 82: 10611-10616, 2017
  8. Kikuchi T, Ueno Y, Hamada Y, Furukawa C, Fujimoto T, Yamada T, Tanaka R: Five new limonoids from peels of satsuma orange (Citrus reticulata). Molecules, 22: 907/1-907/10, 2017
  9. Higuchi K, Miyake T, Ohmori S, Tani Y, Minoura K, Kikuchi T, Yamada T, Tanaka R: Carapanosins A-C from seeds of andiroba (Carapa guianensis, Meliaceae) and their effects on LPS-activated NO production. Molecules, 22: 502/1-502/9, 2017
  10. Kikuchi T, Motoyashiki N, Yamada T, Shibatani K, Ninomiya K, Morikawa T, Tanaka R: Ergostane-type sterols from king trumpet mushroom (Pleurotus eryngii) and their inhibitory effects on aromatase. Int. J. Mol. Sci., 18: 2479/1-2479/10, 2017
  11. 平野智也、森修一、影近弘之「ヒストンメチル化酵素を標的とする創薬およびケミカルバイオロジー研究」MedChemNews, 27(4), 208-212, 2017.

2016年

  1. Hirano T, Noji Y, Shiraishi T, Ishigami-Yuasa M, Kagechika H, Development of an ‘OFF-ON-OFF’ fluorescent pH sensor suitable for the study of intracellular pH. Tetrahedron 72, 4925-4930, 2016.
  2. Yokoo H, Ohsaki A, Kagechika H, Hirano T, Structural development of canthin-5,6-dione moiety as a fluorescent dye and its application to novel fluorescent sensors. Tetrahedron 72, 5872-5879, 2016.
  3. Fujiwara T, Ohira K, Urushibara K, Ito A, Yoshida M, Kanai M, Tanatani A, Kagechika H, Hirano T, Steric structure-activity relationship of cyproheptadine derivatives as inhibitors of histone methyltransferase SET7/9. Bioorg. Med. Chem. 24, 4318-4323, 2016.
  4. Takemoto Y, Ito A, Niwa H, Okamura M, Fujiwara T, Hirano T, Handa N, Umehara T, Sonoda T, Ogawa K, Tariq M, Nishino N, Dan S, Kagechika H, Yamori T, Yokoyama S, Yoshida M, Identification of cyproheptadine as an inhibitor of SET domain containing lysine methyltransferase 7/9 (Set7/9) that regulates estrogen-dependent transcription, J. Med. Chem. 59, 3650-3660, 2016.
  5. Kinoshita M, Negishi M, Sakai H, Hirano T, Mori S, Fujii S, Kagechika H, Tanatani A, Development of 6-Arylcoumarins as Nonsteroidal Progesterone Antagonists. Structure-activity Relationships and Fluorescence Properties. Bioorg. Med. Chem. 24, 5602-5610, 2016.
  6. Yamada T, Ohshima M, Yuasa K, Kikuchi T, Tanaka R: Assignment of the CD cotton effect to the chiral center in pseurotins, and the stereochemical revision of pseurotin A2. Mar. Drugs, 14:e74, 2016
  7. Suzue M, Kikuchi T, Tanaka R, Yamada T: Tandyukisins E and F, novel cytotoxic decalin derivatives isolated from a marine sponge-derived fungus. Tetrahedron Lett., 57:5070-5073, 2016
  8. Ninomiya K, Miyazawa S, Ozeki K, Matsuo N, Muraoka O, Kikuchi T, Yamada T, Tanaka R, Morikawa T: Hepatoprotective limonoids from andiroba (Carapa guianensis). Int. J. Mol. Sci., 17:e591, 2016
  9. Kikuchi T, Tanaka A, Uriuda M, Yamada T, Tanaka R: Three Novel Triterpenoids from Taraxacum officinale roots. Molecules, 21:e1121, 2016
  10. Kikuchi T, Maekawa Y, Tomio A, Masumoto Y, Yamamoto T, In Y, Yamada T, Tanaka R: Six new ergostane-type steroids from king trumpet mushroom (Pleurotus eryngii) and their inhibitory effects on nitric oxide production. Steroids, 115:9-17, 2016
  11. Asano A, Minoura K, Yamada T, Doi M: Conformational transformation of ascidiacyclamide analogs induced by incorporating enantiomers of phenylalanine, 1-naphthylalanine or 2-naphthylalanine. J. Pept. Sci., 22:156-165, 2016
  12. Baba S., Ueno Y., Kikuchi T., Tanaka R., Fujimori K.: A Limonoid kihadanin B from immature Citrus unshiu peels suppresses adipogenesis through repression of the Akt-FOXO1-PPARγ axis in adipocytes. J. Agric. Food Chem., 64:9607-9615, 2016
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