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2020 Fiscal Year Research-status Report

Application of gold-catalyzed glycosylation under aqueous condition for the tumor-localized in vivo synthesis of anticancer drugs

Research Project

Project/Area Number 19K15708
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

張 宗哲  国立研究開発法人理化学研究所, 開拓研究本部, 特別研究員 (00774853)

Project Period (FY) 2019-04-01 – 2022-03-31
Keywordsgold catalysis / artificial metalloenzyme / drug-release / metal-carrier / biocompatibility
Outline of Annual Research Achievements

To achieve an anticancer therapy in vivo based on a gold-catalyzed chemical glycosylation, a gold artificial metalloenzyme (ArM) was developed as a trigger for activation the gold-catalyzed chemical glycosylation. Moreover, the gold ArM also can catalyze the conversion of a prodrug into a anticancer drug for application in cancer therapy. The strategy is based on the gold-catalyzed activation of a phenanthridinium-based prodrug via hydroamination under physiological conditions. To make the prodrug strategy biocompatible, the gold ArM, rather than the free gold metal, was used a trigger for activation of the prodrug. The albumin-based gold ArM protected the catalytic activity of the bound gold metal even in the presence of up to 1 mM glutathione in vitro. The drug synthesized via the gold ArM exerted a therapeutic effect in cell-based assays, highlighting the potential usefulness of the gold ArM in anticancer applications.

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

In last year, the awardee has found a whole new leaving group that can be incorporated into glycan for gold-mediated chemical glycosylation on protein under physiological condition. To carry out the tumor-localized in vivo synthesis of anticancer drugs via chemical glycosylation, a tumor-targeting glycosylated gold artificial meatlloenzyme is a necessary trigger for the issue. In this year, the awardee succeeded to develop the gold artificial metalloenzyme (ArM) and demonstrated that the gold ArM can activate the whole new leaving group under physiological condition in good turnover number. The significant progress is a key step to achieve the goal of the study because gold ArM can be modified to a glycosylated gold ArM to promote in vivo chemical glycosylation on targeted tumor future.

Strategy for Future Research Activity

Next stage will focus on in vitro studies of drug synthesis via in vivo chemical glycosylation by the cancer-targeting the glycosylated gold ArM. Different kinds of cancer cell lines will be used in the vitro studies to confirm cell cytotoxicity assay. Using this work, the awardee will then apply it for in vivo drug release in mice experiment.

Causes of Carryover

Because of the novel corona virus disease (COVID-19). the research was stopped for few months so that the budget did not used so much. In next year, the awardee plan to buy more cancer cells for the research.

  • Research Products

    (6 results)

All 2021 2020

All Journal Article (3 results) (of which Peer Reviewed: 3 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Prodrug Activation by Gold Artificial Metalloenzyme‐Catalyzed Synthesis of Phenanthridinium Derivatives via Hydroamination2021

    • Author(s)
      Chang Tsung‐Che、Vong Kenward、Yamamoto Tomoya、Tanaka Katsunori
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 60 Pages: 2-11

    • DOI

      10.1002/anie.202100369

    • Peer Reviewed
  • [Journal Article] Enantioselective synthesis of cyclic and linear diamines by imine cycloadditions2020

    • Author(s)
      Chang Tsung‐Che、Pradipta Ambara R.、Tanaka Katsunori
    • Journal Title

      Chirality

      Volume: 32 Pages: 1160~1168

    • DOI

      10.1002/chir.23265

    • Peer Reviewed
  • [Journal Article] Bioorthogonal release of anticancer drugs via gold-triggered 2-alkynylbenzamide cyclization2020

    • Author(s)
      Vong Kenward、Yamamoto Tomoya、Chang Tsung-che、Tanaka Katsunori
    • Journal Title

      Chemical Science

      Volume: 11 Pages: 10928~10933

    • DOI

      10.1039/D0SC04329J

    • Peer Reviewed
  • [Presentation] Glycotargeting as metal carrier system for in vivo synthesis2021

    • Author(s)
      Tsung-Che Chang, Katsunori Tanaka
    • Organizer
      RIKEN-Max Planck Joint Research Center for System Chemical Biology the Seventh Symposium
    • Int'l Joint Research
  • [Presentation] Anticancer approach by a gold artificial metalloenzyme-catalyzed synthesis of quaternary ammonium derivatives via hydroamination2021

    • Author(s)
      Tsung-Che Chang, Tomoya Yamamoto, Katsunori Tanaka
    • Organizer
      日本化学会第101春季年会
  • [Presentation] Targeted delivery of an inhibitor of glycosyltransferase to cancer cells2020

    • Author(s)
      Tsung-Che Chang, Katsunori Tanaka
    • Organizer
      日本化学会第100春季年会

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Published: 2021-12-27  

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