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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機能性分子の開発

・天然からの新規生理活性物質の探索及びそれらをシーズとした機能性分子の開発

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。加えて、海洋生物から分離した真菌の産生する生理活性物質の探索及びこれら菌類の共培養による新たな天然物探索のアプローチに取り組んでおり、新たに見出された化合物について培養がん細胞を用いた生理活性試験を行っています。また、高槻市淀川流域のヨシからアルツハイマー型認知症予防効果を示す物質を探索しています。
 

キーワード

創薬化学、蛍光センサー、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、海洋天然物、細胞増殖阻害、真菌、共培養、ヨシ、アルツハイマー型認知症予防効果
 

配属学生

大学院生 0名
学部学生 6年次生：11名、5年次生：18名、4年次生：13名

所属教員

研究内容

疾患診断、治療に有用な光機能性分子の開発

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新たな光機能性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。

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。

高槻市淀川流域のヨシを天然物の探索対象とする研究

その成分にアルツハイマー型認知症の予防効果を見出すことを目的とし、種々のカラムクロマトグラフィー及びHPLCを用いて分離・精製を行っています。現在、活性を示す幹皮のメタノールエキスの水溶性画分について検討を行い、これまで新規物質を含む数種の化合物を単離しています。


Phragmites australis
　　　　
アルツハイマー型認知症の病理学的所見でみられるtauタンパク質によるPHF形成
 
 

微生物コミュニケーションを利用した天然化合物探索の新しいアプローチ

当研究室の保有する海洋菌類をランダムに共培養を行い、単独培養(A及びB)及び共培養(A+B)の代謝物の組成をLC/MSを用いて比較分析することにより新たな代謝物を探索しています。現在、具体的には海藻由来真菌Halosphaeriaceae sp.とムラサキウニ由来真菌Alternaria sp.の共培養で産生された代謝物の分離精製が進められ、すでに数種の新規化合物が得られています。

代表的論文

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

2015年

  1. Shiraishi T, Kagechika H, Hirano T, 6-Arylcoumarins: versatile scaffolds for fluorescent sensors, New. J. Chem. 39, 8389-8396, 2015.
  2. Inoue K, Urushibara K, Kanai M, Yura K, Fujii S, Ishigami-Yuasa M, Hashimoto Y, Mori S, Kawachi E, Matsumura M, Hirano T, Kagechika H, Tanatani A, Design and synthesis of 4-benzyl-1-(2H)-phthalazinone derivatives as novel androgen receptor antagonists. Eur. J. Med. Chem. 102, 310-319, 2015.
  3. Yamada T, Umebayashi Y, Kawashima M, Sugiura Y, Kikuchi T, Tanaka R: Determination of the chemical structures of tandyukisins B-D, isolated from a marine sponge-derived fungus. Mar. Drugs, 13:3231-3240, 2015
  4. Yamada T, Kikuchi T, Tanaka R: Altercrasin A, a novel decalin derivative with spirotetramic acid, produced by a sea urchin-derived Alternaria sp. Tetrahedron Lett., 56:1229-1232, 2015
  5. Sakamoto A, Tanaka Y, Yamada T, Kikuchi T, Muraoka O, Ninomiya K, Morikawa T, Tanaka R: Andirolides W-Y from the flower oil of andiroba (Carapa guianensis, Meliaceae). Fitoterapia, 100:81-87, 2015
  6. Miyake T, Ishimoto S, Ishimatsu N, Higuchi K, Minoura K, Kikuchi T, Yamada T, Muraoka O, Tanaka R: Carapanolides T-X from Carapa guianensis (andiroba) seeds. Molecules, 20:20955-20966, 2015
  7. Kikuchi T, Masumoto Y, In Y, Tomoo K, Yamada T, Tanaka R: Eringiacetal A, 5,6-seco-(5S,6R,7R,9S)-5,6:5,7:6,9-triepoxyergosta-8(14),22-diene-3β,7β-diol, an unusual ergostane sterol from the fruiting bodies of Pleurotus eryngii. Eur. J. Org. Chem., 2015:4645-4649, 2015
  8. Kikuchi T, Ikedaya A, Toda A, Ikushima K, Yamakawa T, Okada R, Yamada T, Tanaka R: Pyrazole alkaloids from watermelon (Citrullus lanatus) seeds. Phytochem. Lett., 12:94-97, 2015
  9. Kikuchi T, Ando H, Maekawa K, Arie H, Yamada T, Tanaka R: Two new ent-kaurane-type diterpene glycosides from zucchini (Cucurbita pepo L.) seeds. Fitoterapia, 107:69-76, 2015
  10. Inoue T, Matsui Y, Kikuchi T, Yamada T, In Y, Muraoka O, Sakai C, Ninomiya K, Morikawa T, Tanaka R: Carapanolides M-S from seeds of andiroba (Carapa guianensis, Meliaceae) and triglyceride metabolism-promoting activity in high glucose-pretreated HepG2 cells. Tetrahedron, 71:2753-2760, 2015
  11. 山田剛司（分担執筆）
    核磁気共鳴スペクトル測定法
    “よくわかる薬学機器分析”　 廣川書店 (2015)

2014年

  1. Shiraishi T, Saito T, Kagechika H, Hirano T, Development of a Novel Fluorescent Sensor to Detect a Specific Range of pH. Tetrahedron Lett., 55, 6784-6786, 2014.
  2. Fujii S, Sekine R, Kano A, Masuno A, Songkram C, Kawachi E, Hirano T, Tanatani A, Kagechika H, Structural development of p-carborane-based potent non-secosteroidal vitamin D analogs. Bioorg Med Chem. 22, 5891-901, 2014.
  3. Fujii S, Kano A, Masuno H, Songkram C, Kawachi E, Hirano T, Tanatani A, Kagechika H, Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs. Bioorg. Med. Chem. Lett., 24, 4515-4519, 2014.
  4. Fujii S, Kano A, Songkram C, Masuno H, Taoda Y, Kawachi E, Hirano T, Tanatani A, Kagechika H, Synthesis and structure-activity relationship of p-carborane-based non-secosteroidal vitamin D analogs. Bioorg. Med. Chem., 22, 1227-1235, 2014.
  5. Yamada T, Mizutani Y, Umebayashi Y, Inno N, Kawashima M, Kikuchi T, Tanaka R: Tandyukisin, a novel ketoaldehyde decalin derivative, produced by a marine sponge-derived Trichoderma harzianum. Tetrahedron Lett., 55:662-664, 2014
  6. Matsui Y, Kikuchi T, Inoue T, Muraoka O, Yamada T, Tanaka R: Carapanolides J-L from the seeds of Carapa guianensis (andiroba) and their effects on LPS-activated NO production. Molecules, 19:17130-17140, 2014
  7. Kikuchi T, Ueda S, Kanazawa J, Naoe H, Yamada T, Tanaka R: Three new triterpene esters from pumpkin (Cucurbita maxima) seeds. Molecules, 19:4802-4813, 2014
  8. Inoue T, Matsui Y, Kikuchi T, In Y, Muraoka O, Yamada T, Tanaka R: Carapanolides C-I from the seeds of andiroba (Carapa guianensis, Meliaceae). Fitoterapia, 96:56-64, 2014
  9. Asano A, Yamada T, Doi M: Modulating the structure of phenylalanine-incorporated ascidiacyclamide through fluorination. J. Pept. Sci., 20:794-802, 2014
  10. Kikuchi T, Ishii K, Ogihara E, Zhang J, Ukiya M, Tokuda H., Iida T, Tanaka R, Akihisa T Cytotoxic and apoptosis-inducing activities, and anti-tumor-promoting effects of cyanogenated and oxygenated triterpenes. Chem. Biodivers. 11:491-504, 2014
  11. 藤井晋也, 棚谷綾, 平野智也, 影近弘之「球状疎水性ファーマコフォアを有する非セコステロイド型VDR リガンドの創製研究」Vitamins (Japan), 88, 389-395, 2014
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