Development of novel drug leads based on rare tropical resources

• Project/Area Number: 18H02583
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: Kanazawa University
• Principal Investigator: Goto Kyoko 金沢大学, 薬学系, 准教授 (50180245)
• Co-Investigator(Kenkyū-buntansha): 三宅 克典 東京薬科大学, 薬学部, 講師 (20597687) ; 斎藤 洋平 金沢大学, 先進予防医学研究センター, 助教 (90723825)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,160,000 (Direct Cost: ¥13,200,000、Indirect Cost: ¥3,960,000); Fiscal Year 2021: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: 熱帯雨林産植物 / 生物活性天然物 / 熱帯資源 / 創薬リード / 生理活性天然物 / 熱帯林産植物 / 抗腫瘍活性

Outline of Final Research Achievements

Over 50 novel natural products were isolated from phytochemically untouched rainforest plants, elucidated their chemical structure, and evaluated for antiproliferative activity against tumor cell lines. The synthetic routs of bioactive natural products were developed, and various derivatives were synthesized. The structure-activity relationships and their mechanisms of action of bioactive derivatives were also investigated.

Academic Significance and Societal Importance of the Research Achievements

熱帯雨林は生物多様性に富むことが知られ、生息する植物からこれまでに多くの医薬品が誕生してきた。アメリカ国立がん研究所NCIが所有する、抗腫瘍活性を有し且つ未解析の熱帯雨林産植物エキスから単離した新規天然物、ならびに合成を通して得られた生物活性天然物誘導体は、構造多様性に富む化合物ライブラリーの拡充につながり、がんや新型感染症等に対する将来の創薬研究への寄与が期待できる。

Research Products

• [Int'l Joint Research] アメリカ国立がん研究所/ノースカロライナ大学(米国)
• [Int'l Joint Research] ハサヌディン大学(インドネシア)
• [Int'l Joint Research] ノースカロライナ大学/国立がん研究所/デューク大学(米国)
• [Int'l Joint Research] ハサヌディン大学(インドネシア)
• [Int'l Joint Research] 米国国立がん研究所/ノースカロライナ大学(米国)
• [Journal Article] Chemical space expansion of flavonoids: Induction of mitotic inhibition by replacing ring-B with a 10π-electron system, benzo[b]thiophene (2022)
  • Author(s): Hirazawa S, Saito Y, Sagano M, Goto M, Nakagawa-Goto K.
  • Journal Title: J. Nat. Prod Volume: 85 Pages: 136-147
  • DOI: 10.1021/acs.jnatprod.1c00867
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel Seco-phenanthroquinolizidine Alkaloids from Indonesian Boehmeria virgata, Phytochem (2021)
  • Author(s): Rahim A, Saito Y, Miyake K, Goto M, Nakagawa-Goto K
  • Journal Title: Phytochem. Lett. Volume: 45 Pages: 132-126
  • DOI: 10.1016/j.phytol.2021.08.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Boroxazolidone Formation under Physiological Conditions as a Tool for the Chemical Modification of Biomolecules (2021)
  • Author(s): Saito Y, Yoshida N, Nakagawa-Goto K,
  • Journal Title: Chem. Lett. Volume: 50 Issue: 9 Pages: 1695-1698
  • DOI: 10.1246/cl.210352
  • NAID: 130008088232
  • ISSN: 0366-7022, 1348-0715
  • Peer Reviewed
• [Journal Article] α-Trifluoromethyl Chalcones as Potent Anticancer Agents for Androgen Receptor-Independent Prostate Cancer (2021)
  • Author(s): Saito Y, Mizokami A, Izumi K, Naito R, Goto M, Nakagawa-Goto K
  • Journal Title: Molecules Volume: 26 Pages: 2812-2825
  • DOI: 10.3390/molecules26092812
  • Peer Reviewed / Open Access
• [Journal Article] Effects of substituent pattern on the intracellular target of antiproliferative benzo[b]thiophenyl chromone derivatives (2021)
  • Author(s): Saito Y, Taniguchi Y, Hirazawa S, Miura Y, Tsurimoto H, Nakayoshi T, Oda A, Hamel E, Yamashita K, Goto M, Nakagawa-Goto K
  • Journal Title: Eur. J. Med. Chem. Volume: 222 Pages: 113578-113578
  • DOI: 10.1016/j.ejmech.2021.113578
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthesis of Thio-lignane Analogue, Bioequivalent Salvinal without Unfavored Aldehyde (2021)
  • Author(s): Saito Y, Kobayashi Y, Yoshida N, Goto M, Nakagawa-Goto K
  • Journal Title: J. Org. Chem Volume: 86 Pages: 7092-7106
  • DOI: 10.1021/acs.joc.1c00348
  • Peer Reviewed
• [Journal Article] Bicyclic Chalcones as Mitotic Inhibitors for Overcoming Androgen Receptor-Independent and Multidrug Resistant Prostate Cancer (2021)
  • Author(s): Saito Y, Mizokami M, Maeda S, Takahashi K, Izumi K, Goto M, Nakagawa-Goto K
  • Journal Title: ACS Omega Volume: 6 Pages: 4842-4849
  • DOI: 10.1021/acsomega.0c05822
  • Peer Reviewed
• [Journal Article] Novel furoquinolinones from an Indonesian Plant, Lunasia amara (2020)
  • Author(s): M. Yamashita, Y. Saito, A. Rahim, S. iFukuyoshi, K. Miyake, M. Goto, K. Nakagawa-Goto
  • Journal Title: Tetrahedron Lett Volume: in press Pages: 151861-151861
  • DOI: 10.1016/j.tetlet.2020.151861
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] First Total Synthesis of a Pavine Alkaloid, (±)-Neocaryachine, and its Optical Resolution (2020)
  • Author(s): Miura Y, Saito Y, Goto M, Nakagawa-Goto K.
  • Journal Title: Chem. Pharm. Bull Volume: 68 Pages: 899-902
  • DOI: 10.1248/cpb.c20-00370
  • NAID: 130007893858
  • Peer Reviewed
• [Journal Article] Development of an efficient scale-up synthesis for β3-adrenergic receptor agonist, ritobegron ethyl hydrochloride (2020)
  • Author(s): Sonehara J, Tamai T, Isawa H, Hotei Y, Kasai K, Kikuchi N, Ishikawa T, Kobayashi M, Ozawa T, Suzuki R, Kobayashi M, Ainai T, Nishimura M, Saito Y, Nakagawa-Goto K
  • Journal Title: Org. Proc. Res. Dev Volume: 24 Pages: 1675-1682
  • DOI: 10.1021/acs.oprd.0c00278
  • Peer Reviewed
• [Journal Article] Palasanines A-E, 3,4-Methylenedioxyquinoline Alkaloids Fused with a Phenyl-14-oxabicyclo[3.2.1]octane Unit from Melochia umbellata var. deglabrata (2020)
  • Author(s): Rahim A, Saito Y, Fukuyoshi S, Miyake K, Goto M, Chen CH, Alam G, Lee KH, Nakagawa-Goto K.
  • Journal Title: J. Nat. Prod. Volume: 83 Pages: 2931-2939
  • DOI: 10.1021/acs.jnatprod.0c00454
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anti-proliferative and chemosensitizing effects of diarylheptanoids on human tumor cell lines (2019)
  • Author(s): Miyagishi S, Saito Y, Goto M, Nakagawa-Goto K
  • Journal Title: ACS Omega Volume: 4 Pages: 2053-2062
  • DOI: 10.1021/acsomega.8b03215
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synthesis of 4-epi-parviflorons A, C, and E: structure-activity relationship study of antiproliferative abietane derivatives. (2019)
  • Author(s): Miyajima, Y.; Saito, Y.; Takeya, M.; Goto, M.; Nakagawa-Goto, K.
  • Journal Title: J Org Chem Volume: 84 Pages: 3239-3248
  • DOI: 10.1021/acs.joc.8b02832
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Spiro[3.5]nonenyl meroterpenoid lactones, cryptolaevilactones G-L, an ionone derivative and total synthesis of cryptolaevilactone M from Cryptocarya laevigata (2019)
  • Author(s): Tsurumi F, Miura Y, Nakano M, Saito Y, Fukuyoshi S, Newman DJ, O’Keefe BR, Lee KH, Nakagawa-Goto K
  • Journal Title: J Nat Prod Volume: 82 Pages: 2368-2378
  • DOI: 10.1021/acs.jnatprod.8b00732
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prenylated acetophloroglucinol dimers from Acronychia trifoliolata: Structure elucidation and total synthesis (2019)
  • Author(s): Miyake K, Morita C, Suzuki A, Matsushita N, Saito Y, Goto M, Newman DJ, O’Keefe BR, Lee KH, Nakagawa-Goto K
  • Journal Title: J Nat Prod Volume: 82 Pages: 2852-2858
  • DOI: 10.1021/acs.jnatprod.9b00596
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Isolation, Structure Elucidation, and Antiproliferative Activity of Butanolides and Lignan Glycosides from the Fruit of Hernandia nymphaeifolia (2019)
  • Author(s): Aimaiti S, Saito Y, Fukuyoshi S, Goto M, Miyake K, Newman DJ, O’Keefe BR, Lee KH, Nakagawa-Goto K
  • Journal Title: Molecules Volume: 24 Pages: 4005-4021
  • DOI: 10.3390/molecules24214005
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Antiproliferative alkaloids from Alangium longiflorum, an endangered tropical plant species (2018)
  • Author(s): Takeuchi M, Saito Y, Goto M, Miyake K, Newman DJ, O’Keefe BR, Lee KH, Nakagawa-Goto K.
  • Journal Title: J Nat Prod Volume: 81 Pages: 1884-1891
  • DOI: 10.1021/acs.jnatprod.8b00411
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 5’-Chloro-2,2’-dihydroxychalcone and Related Flavanoids as Treatments for Prostate Cancer (2018)
  • Author(s): Saito Y, Mizokami A, Tsurimoto H, Izumi K, Goto M, Nakagawa-Goto K
  • Journal Title: Eur J Med Chem Volume: 157 Pages: 1143-1152
  • DOI: 10.1016/j.ejmech.2018.08.069
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 抗トリプルネガティブ乳がんを志向したノルエレモフィラン誘導体の合成と構造活性相関研究 (2022)
  • Author(s): 中山わかな，前田 紗弥加，佐賀野 桃子，斎藤 洋平，後藤（中川）享子
  • Organizer: 日本薬学会第142年会
• [Presentation] 熱帯雨林産植物Trichilia rubescensの成分探索と生理活性評価 (2022)
  • Author(s): 賽旦夏阿木提，斎藤 洋平，三宅克典，David J. Newman， Barry O’Keefe，後藤（中川）享子
  • Organizer: 日本薬学会第142年会
• [Presentation] ジアリールボリン酸を利用した標的タンパク質同定法の開発 (2022)
  • Author(s): 田部井透矢，後藤（中川）享子，斎藤洋平
  • Organizer: 日本化学会102年会
• [Presentation] プレニルアセトフェノン二量体、アクロトリフォリオラン Aの合成研究 (2022)
  • Author(s): 新田夕莉，松下夏子，斎藤洋平，後藤（中川）享子
  • Organizer: 日本化学会102年会
• [Presentation] 抗腫瘍活性キノロンアルカロイドWaltherione A の全合成 (2021)
  • Author(s): 下井涼介，三浦悠太，斎藤洋平，後藤（中川）享子
  • Organizer: 第50回複素環化学討論会
• [Presentation] スピロ[3.5]ノナン骨格含有天然物Cryptolaevilactone類モデル化合物の合成研究 (2021)
  • Author(s): 三浦悠太，斎藤洋平，後藤（中川）享子
  • Organizer: 第47回反応と合成の進歩シンポジウム
• [Presentation] Drug discovery and development based on natural products (2021)
  • Author(s): 後藤（中川）享子
  • Organizer: 1st Makassar International Conference in Pharmaceutical Sciences
  • Int'l Joint Research / Invited
• [Presentation] モノテルペン－ポリケチドCryptolaevilactone類の合成研究 (2021)
  • Author(s): 三浦悠太，斎藤洋平，後藤（中川）享子
  • Organizer: 日本薬学会第141年会
• [Presentation] ブロモエレモフィランPC-Aの全合成と抗トリプルネガティブ乳がん選択性における構造活性相関研究 (2021)
  • Author(s): 前田 紗弥加，佐賀野 桃子，斎藤 洋平，後藤（中川）享子
  • Organizer: 日本薬学会第141年会
• [Presentation] 再燃前立腺がんに有効なα置換フェニルスチリルケトン誘導体の創出と作用機序に関する研究 (2021)
  • Author(s): 斎藤 洋平，溝上 敦，泉 浩二，内藤 伶奈人，後藤 益生，後藤（中川）享子
  • Organizer: 日本薬学会第141年会
• [Presentation] 生体分子の化学修飾を志向した温和な条件におけるボロキサゾリドン形成 (2021)
  • Author(s): 斎藤洋平，吉田菜々美，後藤（中川）享子
  • Organizer: 日本化学会第101春季年会
• [Presentation] スピロ[3.5]ノナン骨格含有メロテルペノイドCryptolaevilactone類の全合成研究 (2020)
  • Author(s): 三浦悠太，斎藤洋平，後藤（中川）享子
  • Organizer: 日本薬学会第140年会
• [Presentation] トリプルネガティブ乳がん選択的な細胞増殖抑制効果をもつエレモフィラン型セスキテルペンPC-Aの合成 (2020)
  • Author(s): 前田 紗弥加，佐賀野 桃子，斎藤 洋平，後藤（中川）享子
  • Organizer: 日本薬学会第140年会
• [Presentation] 勢抵抗性前立腺がんに有効なカルコン誘導体の創出と標的タンパク質の探索 (2020)
  • Author(s): 斎藤 洋平，溝上 敦，泉 浩二，内藤 伶奈人，後藤 益生，後藤（中川）享子
  • Organizer: 日本薬学会第140年会
• [Presentation] 薬用生理活性天然物の単離精製・合成・メディシナルケミストリーへの展開 (2020)
  • Author(s): 後藤（中川）享子
  • Organizer: 日本薬学会第140年会
  • Invited
• [Presentation] Thio-salvinal 誘導体群の合成，がん細胞増殖抑制効果と構造活性相関研究 (2019)
  • Author(s): 吉田奈々美，小林由希子，斎藤洋平，後藤益生，後藤（中川）享子
  • Organizer: 日本薬学会第139年会
• [Presentation] トリプルネガティブ乳がん選択的に増殖抑制活性を示す天然物誘導体プローブの設計と合成 (2019)
  • Author(s): 坂田耕一，斎藤洋平，後藤（中川）享子
  • Organizer: 日本薬学会第139年会
• [Presentation] Cryptocarya laevigata由来モノテルペン-ポリケチドcryptolaevilactones A-Fの合成 (2019)
  • Author(s): 三浦悠太，斎藤洋平，後藤（中川）享子
  • Organizer: 日本薬学会第139年会
• [Presentation] Acronychia trifoliolata 由来の新規アセトフェノンダイマー類の合成とがん細胞増殖抑制効果 (2019)
  • Author(s): 松下夏子，森田千尋，斎藤洋平，後藤益生，後藤（中川）享子
  • Organizer: 日本薬学会第139年会
• [Presentation] Cryptocarya laevigata由来モノテルペン-ポリケチドcryptolaevilactones A–Fの合成 (2019)
  • Author(s): 三浦悠太，斎藤洋平，後藤（中川）享子
  • Organizer: 日本薬学会第139年会
• [Presentation] 生理活性フラボノイドTEDB-TBのアミノ誘導体合成と活性評価 (2018)
  • Author(s): 斎藤 洋平，小林 佑希子，後藤 益生，後藤（中川） 享子
  • Organizer: 日本ケミカルバイオロジー学会 第 13回年会
• [Presentation] エレモフィラン型セスキテルペンPC-Aの合成とトリプルネガティブ乳がん細胞選択的増殖抑制評価 (2018)
  • Author(s): 佐賀野桃子，斎藤洋平，後藤益生，後藤（中川）享子
  • Organizer: 第36回メディシナルケミストリーシンポジウム
• [Presentation] ジアリールヘプタノイド誘導体のがん化学療法増感効果 (2018)
  • Author(s): 宮岸佐衣，斎藤洋平，後藤益生，後藤（中川）享子
  • Organizer: 第36回メディシナルケミストリーシンポジウム
• [Presentation] 各種ベンゾチオフェンフラボノイド誘導体の合成とがん細胞増殖抑制効果 (2018)
  • Author(s): 平澤幸香 ，谷口由花子，佐賀野桃子，斎藤洋平，後藤益生，後藤（中川）享子
  • Organizer: 第36回メディシナルケミストリーシンポジウム