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Drug discovery research based on dinuclear platinum complexes with markedly high antitumor activity

Research Project

Project/Area Number 15K07905
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Physical pharmacy
Research InstitutionSuzuka University of Medical Science

Principal Investigator

Komeda Seiji  鈴鹿医療科学大学, 薬学部, 准教授 (60425056)

Co-Investigator(Kenkyū-buntansha) 植村 雅子  鈴鹿医療科学大学, 薬学部, 助教 (70511997)
Co-Investigator(Renkei-kenkyūsha) HIRAMOTO Keiichi  鈴鹿医療科学大学, 薬学部, 助教 (90251793)
HARUSAWA Shinya  大阪薬科大学, 薬学部, 教授 (90167601)
YONEYAMA Hiroki  大阪薬科大学, 薬学部, 助教 (90627001)
YOSHIKAWA Yuko  同志社大学, 生命医科学部, 嘱託講師 (80291871)
Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords白金錯体 / 制がん剤 / DDS / 創薬 / 難治性がん / 白金製剤 / 白金制がん剤 / 金属錯体 / 核酸 / 大腸がん / 細胞内取込 / 薬物耐性
Outline of Final Research Achievements

New tetrazolato-bridged dinuclear platinum(II) complexes were designed and synthesized to combine with DDS carrier or to introduce halogen into the complexes. Our in vivo study using mice with a subcutaneous homograft of Colon-26 colorectal cancer cells indicates that the tetrazolato-bridged dinuclear platinum(II) complexes are promising next-generation platinum-based drug candidates with markedly high and long-lasting antitumor efficacy. Indeed, the tumour growth in mice treated with the lead compound was much slower than that in mice treated with platinum-based drug oxaliplatin, which is used for the treatment of colorectal cancer. Even more remarkable, the lead compound exhibited high tumor-reduction effects against large-sized tumours, which sustained for a few weeks after a single intravenous dose of the compound.

Report

(3 results)
  • 2017 Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report

Research Products

(18 results)

All 2017 2016 2015 Other

All Journal Article Presentation Book Remarks

  • [Journal Article] Conformational transition of DNA by dinuclear Pt(II) complexes causes cooperative inhibition of gene expression2017

    • Author(s)
      Shimizu, Y.; Yoshikawa, Y.; Kenmotsu, T.; Komeda, S.; Yoshikawa, K.
    • Journal Title

      Chemical Physics Letters

      Volume: 678 Pages: 123-129

    • DOI

      10.1016/j.cplett.2017.04.039

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Specific Conformational Change in Giant DNA Caused by Anticancer Tetrazolato-Bridged Dinuclear Platinum(II) Complexes: Middle-Length Alkyl Substituents Exhibit Minimum Effect2017

    • Author(s)
      S. Komeda, H. Yoneyama, M. Uemura, A. Muramatsu, N. Okamoto,
    • Journal Title

      Inorganic Chemistry

      Volume: 56 Pages: 802-811

    • DOI

      10.1021/acs.inorgchem.6b02239

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The phosphate clamp as recognition motif in platinum-DNA interactions2016

    • Author(s)
      Komeda, S.; Qu, Y.; Mangrum, J. B.; Hegmans, A.; Williams, L. D.; Farrell, N. P.
    • Journal Title

      Inorganica Chimica Acta

      Volume: 81 Pages: 2399-2404

    • DOI

      10.1016/j.ica.2016.04.052

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Chromatin Folding and DNA Replication Inhibition Mediated by a Highly Antitumor-active Tetrazolato-bridged Dinuclear Platinum(II) Complex2016

    • Author(s)
      Imai R, Komeda S, Shimura M, Tamura S, Matsuyama S, Nishimura K, Rogge R, Matsunaga A, Hiratani I, Takata H, Uemura M, Iida Y, Yoshikawa Y, Hansen JC, Yamauchi K, Kanemaki MT, Maeshima K.
    • Journal Title

      Scientific Reports

      Volume: 6 Pages: 24712-24712

    • DOI

      10.1038/srep24712

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Highly efficient uptake into cisplatin-resistant cells and the isomerization upon coordinative DNA binding of anticancer tetrazolato-bridged dinuclear platinum(II) complexes.2015

    • Author(s)
      Uemura M, Hoshiyama M, Furukawa A, Sato T, Higuchi Y, Komeda S.
    • Journal Title

      Metallomics

      Volume: 7 Pages: 1488-1496

    • DOI

      10.1039/c5mt00174a

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Presentation] 顕著な抗腫瘍効果を有する白金(II)二核錯体のユニークな作用機構2017

    • Author(s)
      植村 雅子、米田 誠治、吉川 研一、吉川 祐子、春沢 信哉、米山 弘樹
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台市
    • Year and Date
      2017-03-24
    • Related Report
      2016 Research-status Report
  • [Presentation] Significant effect of dinuclear Pt(II) complexes on the higher-order structure of genomic DNA2016

    • Author(s)
      Shimizu, Y.; Yoshikawa, Y.; Uemura, M.; Kenmotsu, T.; Komeda, S.; Yoshikawa, K.
    • Organizer
      8th Asian Biological Inorganic Chemistry Conference
    • Place of Presentation
      ニュージーランド オークランド
    • Year and Date
      2016-12-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Structure-activity relationships and DNA compaction efficiencies of anticancer tetrazolato-bridged dinuclear platinum(II) complexes2016

    • Author(s)
      Komeda, S.
    • Organizer
      8th Asian Biological Inorganic Chemistry Conference
    • Place of Presentation
      ニュージーランド オークランド
    • Year and Date
      2016-12-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Covalent interaction of anticancer azolato-bridged dinuclear platinum(II) complexes with nucleotide and double-helical DNA2016

    • Author(s)
      Uemura, M.; Komeda, S.
    • Organizer
      金属の関与する生体関連反応シンポジウム (SRM2016)
    • Place of Presentation
      札幌市
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report
  • [Presentation] Biological efficiency of anticancer tetrazolato-bridged dinuclear platinum(II) complexes with different length of alkyl substituent in relation to the structural effect of DNA2016

    • Author(s)
      Komeda, S.; Uemura, M.; Yoneyama, H.; Muramatsu, A.; Okamoto, N.; Harusawa, S.; Yoshikawa, Y.; Yoshikawa, K.
    • Organizer
      金属の関与する生体関連反応シンポジウム (SRM2016)
    • Place of Presentation
      札幌市
    • Year and Date
      2016-06-16
    • Related Report
      2016 Research-status Report
  • [Presentation] 長短鎖アルキル基を導入した制がんテトラゾラト架橋白金(II)二核錯体の細胞 内取込およびDNA凝縮能2016

    • Author(s)
      米田誠治, 植村雅子, 米山弘樹, 岡本直人, 村松 晃, 福田青郎, 小西宏明, 髙木 陽光, 松﨑 健, 春沢信哉, 吉川祐子, 今中忠行, 吉川研一
    • Organizer
      日本薬学会 第136年会 横浜市 年月日201603-201603
    • Place of Presentation
      横浜市
    • Year and Date
      2016-03-26
    • Related Report
      2015 Research-status Report
  • [Presentation] Azolato-bridged dinuclear platinum(II) complexes with markedly high in vivo antitumor efficacy against pancreatic cancer and unique in vitro cytotoxicity profiles2015

    • Author(s)
      Seiji Komeda
    • Organizer
      1st International Symposium on Clinical and Experimental Metallodrugs in Medicine: Cancer Chemotherapy
    • Place of Presentation
      米国ハワイ州
    • Year and Date
      2015-12-13
    • Related Report
      2015 Research-status Report
  • [Presentation] Cellular uptake and DNA compaction of anticancer tetrazolato-bridged dinuclear platinum(II) complexes with various substituents at tetrazole C52015

    • Author(s)
      Uemura, M; Yoneyama, H; Yoshikawa, T; Tsuchiya, T; Hoshiyama, M; Sato, T; Yoshikawa, K; Harusawa, S; Komeda, S
    • Organizer
      1st International Symposium on Clinical and Experimental Metallodrugs in Medicine: Cancer Chemotherapy
    • Place of Presentation
      米国ハワイ州
    • Year and Date
      2015-12-13
    • Related Report
      2015 Research-status Report
  • [Presentation] 遷移金属二核錯体を用いた 次世代制がん剤の開発2015

    • Author(s)
      米田誠治
    • Organizer
      三重大学・鈴鹿医療科学大学 合同産学官交流フォーラム
    • Place of Presentation
      津市
    • Year and Date
      2015-10-09
    • Related Report
      2015 Research-status Report
  • [Presentation] Action of novel anticancer-active, dinuclear platinum complexes with ester group on the higher order structure and genomic activity of DNA2015

    • Author(s)
      Shimizu, Y; Yoshikawa, Y; TaTsuchiya, T; Hiroki Yoneyama, H; Harusawa, S; Komeda, S; Imanaka, T; Kenmotsu, T; Yoshikawa, K.
    • Organizer
      第53回生物物理学会日本薬学会
    • Place of Presentation
      金沢市
    • Year and Date
      2015-09-13
    • Related Report
      2015 Research-status Report
  • [Presentation] Cellular uptake and DNA compaction of anticancer tetrazolato-bridged dinuclear platinum(II) complexes with various substituents at tetrazole C52015

    • Author(s)
      Uemura, M; Yoneyama, H; Yoshikawa, T; Tsuchiya, T; Hoshiyama, M; Sato, T; Yoshikawa, K; Harusawa, S; Komeda, S
    • Organizer
      第25回金属の関与する生体関連反応シンポジウム
    • Place of Presentation
      長崎市
    • Year and Date
      2015-05-30
    • Related Report
      2015 Research-status Report
  • [Book] パートナー分析化学II 改訂第3版2017

    • Author(s)
      能田 均、萩中 淳、山口政俊 、水野 初、本間 浩、米田誠治、山下幸和、北村陽二、黒沢隆夫、明樂一己、藤岡稔弘、石濱 泰、大江知行、眞野成康、吉田秀幸 巴山 忠、寺西正憲、金田典雄、畑中保丸、友廣岳則 他
    • Total Pages
      332
    • Publisher
      南江堂
    • Related Report
      2016 Research-status Report
  • [Remarks] Publications | 鈴鹿医療科学大学 薬学部 機器分析学研究室

    • URL

      http://www.asahi-net.or.jp/~ij4s-kmd/publications/index.html

    • Related Report
      2016 Research-status Report

URL: 

Published: 2015-04-16   Modified: 2019-03-29  

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