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Development of polycyclic heterocyclic compounds as GPCR analogues

Research Project

Project/Area Number 17K08369
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Drug development chemistry
Research InstitutionYokohama College of Pharmacy (2019)
Health Sciences University of Hokkaido (2017-2018)

Principal Investigator

HATAE Noriyuki  横浜薬科大学, 薬学部, 教授 (30449912)

Co-Investigator(Kenkyū-buntansha) 町支 臣成  福山大学, 薬学部, 教授 (10248297)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords多環縮環型複素環 / フラン環 / ペリ環状反応 / Gタンパク質共役型受容体 / アゴニスト / 抗腫瘍活性物質 / 生物活性物質 / 分子内環状付加反応 / セロトニン受容体 / GPCR / 5-HT2C receptor / agonist / benzofuro[3,2-c]pyridine / naphto[1,8-bc]furan
Outline of Final Research Achievements

G protein coupled receptors (GPCRs) are identified the 7th transmembrane receptor, and take essential roles in many pshysiological homeostasis. Serotonin 2C receptor (5-HT2C receptor) classifies as seventh transmembrane domain receptors coupled to G proteins (GPCRs). It was expressed on the central nervous system; relatively higher expressed at amygdala, hippocampus, and hypothalamus. As the receptor was related to the emotion and food intake according to the analysis on 5-HT2C receptor KO mice, and the lorcaserin was discovered against anti-obesity drug. In current study, we synthesized benzofuro[3,2-c]pyridine analogues by using MW-assisted thermal electrocyclic reaction, and assessed their efficacy against 5-HT2C activation. Furthermore, some polycyclic heterocycles were indicated potent antiproliferative activity in tumor cells.

Academic Significance and Societal Importance of the Research Achievements

Gタンパク質共役型受容体のX線結晶構造解析の発展に伴って、そのアンタゴニストの開発では、SBDD(Structure based drug design)が適応され始めてきている。一方、GPCRアゴニストの開発では、アゴニストと受容体の複合体解析の結果が乏しく、未だ化合物ライブラリーに依存した創薬が主流である。本研究では、構造的に強固な5HT2Cアゴニストを創生したことで、アゴニストの立体構造を基に、ファーマコフォアの構築を模索することが可能と考えられる。
また、多環縮環型複素環ライブラリーより、新規抗腫瘍活性物質の創生に成功しており、保健医療の分野においても多大な貢献が確信される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (17 results)

All 2020 2019 2018 2017 Other

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (12 results) (of which Int'l Joint Research: 1 results) Remarks (1 results)

  • [Journal Article] First asymmetric enantioselective total synthesis of phenanthridine alkaloid, (S)-(+)-asiaticumine and its enantiomer.2019

    • Author(s)
      Takashi Nishiyama, Shuuya Takaiwa, Rika Kotouge, Satomi Tani, Rikako Yoshinaga, Erina Hamada, Mai Endo, Yuka Sugino, Noriyuki Hatae, Satoshi Hibino, Tominari Choshi
    • Journal Title

      Tetrahedron Letters

      Volume: 60 Issue: 48 Pages: 151278-151278

    • DOI

      10.1016/j.tetlet.2019.151278

    • NAID

      120007018376

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Concise synthesis of kalasinamide, marcanine A, and geovanine, and antiproliferative activity evaluation of their azaanthracenones2019

    • Author(s)
      Takashi Nishiyama, Noriyuki Hatae, Kyohko Chikaraishi, Keisuke Uchida, Chika Yokoyama, Satoshi Hibino, Tominari Choshi
    • Journal Title

      HETEROCYCLES

      Volume: 99 Issue: 1 Pages: 415-415

    • DOI

      10.3987/com-18-s(f)36

    • NAID

      120007018375

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synthesis and cytotoxicity of pyrido[4,3-b]carbazole alkaloids against HCT-116 and HL-60 cells2018

    • Author(s)
      Tomoki Itoh, Noriyuki Hatae, Takashi Nishiyama, Tominari Choshi, Satoshi Hibino, Teruki Yoshimura, Minoru Ishikura
    • Journal Title

      Medicinal Chemistry Research

      Volume: 27 Issue: 2 Pages: 412-419

    • DOI

      10.1007/s00044-017-2068-6

    • NAID

      120007018401

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Synthesis of N-w-phenylalkyl-4-(p-chlororphenyl)-piperidin-4-ol analogues with potent antiproliferative activity against HCT-116 cells2018

    • Author(s)
      Noriyuki Hatae, Eiko Kujime, Keigo Yano, Mami Kizuka, Rina Ashida, Tominari Choshi, Takashi Nishiyama, Chiaki Okada, Tatsunori Iwamura, Teruki Yoshimura
    • Journal Title

      HETEROCYCLES

      Volume: 97 Issue: 1 Pages: 560-560

    • DOI

      10.3987/com-18-s(t)25

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Presentation] Benzofuropyridine類を用いた新規 5-HT2C アゴニストの探索2020

    • Author(s)
      市川裕樹,西山卓志,鈴木真一,日比野俐,町支臣成,波多江典之
    • Organizer
      日本薬学会 第 140 年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Ellipticine quinoneと類縁体の合成と抗腫瘍活性評価2019

    • Author(s)
      西山卓志,波多江典之,町支臣成
    • Organizer
      第61回天然有機化合物討論会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Synthesis of 4-Aroyl-5-arylpyrazoles and 4-Aroyl-3-arylpyrazoles via the Reaction of Enaminodiketones with Substituted Hydradines.2019

    • Author(s)
      Takashi Nishiyama, Rika Kotouge, Akira Yamauchi, Noriyuki Hatae, Tominari Choshi
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 四環性thienonaphthofuran型骨格構築法の開発2019

    • Author(s)
      市川祐樹,西山卓志,鈴木真一,町支臣成,波多江典之
    • Organizer
      第45回反応と合成の進歩シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 5-HT2Cアゴニスト活性を有するbenzofuro[3,2-c]pyridine類の創生2019

    • Author(s)
      市川裕樹,西山卓志,鈴木真一,日比野俐,町支臣成,波多江典之
    • Organizer
      第37回メディシナルケミストリーシンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 2-シアノ-1-プロパルギルインドールの[6+1]付加環化反応を用いたAzepino[1,2-e]indole合成2018

    • Author(s)
      飯岡稜也,Febria Elvy Sasanti,波多江典之,吉松三博
    • Organizer
      第48回複素環化学討論会
    • Related Report
      2018 Research-status Report
  • [Presentation] Azafluorenone 骨格を有する Onychine の全合成とindeno [1,2-c]isoquinoline 類への応用2018

    • Author(s)
      西山卓志、藤脇孝哉、波多江典之、日比野俐、町支臣成
    • Organizer
      第44回 反応と合成の進歩シンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] ビニルチオフェンとアレニルエーテルとの分子内環状付加反応の開発2018

    • Author(s)
      波多江典之、岡田知晃、吉村昭毅
    • Organizer
      第44回 反応と合成の進歩シンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] Benzofuro[3,2-c]pyridine類の合成と新規5HT2Cアゴニストの探索研究2018

    • Author(s)
      小橋川花、波多江典之、西山卓志、豊田栄子、吉村昭毅、町支臣成
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Carbazole-1,4-quinone類の簡便合成法の開発と抗腫瘍活性の解析2017

    • Author(s)
      伊藤智貴、西山卓志、波多江典之、阿部睦、吉村昭毅、日比野俐、町支臣成、石倉稔
    • Organizer
      日本薬学会北海道支部第144回例会
    • Related Report
      2017 Research-status Report
  • [Presentation] Pyrido[4,3-b]carbazole 類の合成と抗腫瘍活性の解析2017

    • Author(s)
      波多江典之,伊藤智貴,西山卓志,町支臣成,日比野俐,石倉稔
    • Organizer
      第35回 メディシナルケミストリーシンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] アリールオレフィンとアレンとの分子内環状付加反応の開発2017

    • Author(s)
      波多江典之、岡田知晃、吉村昭毅
    • Organizer
      第43回 反応と合成の進歩シンポジウム
    • Related Report
      2017 Research-status Report
  • [Remarks] 横浜薬科大学薬品反応学研究室ホームページ

    • URL

      https://www.hamayaku.ac.jp/lab/la_04.html

    • Related Report
      2019 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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