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新規プローブライブラリーの構築に基づく大腸がん・胃がん検出蛍光プローブの開発

Research Project

Project/Area Number 19F19339
Research Category

Grant-in-Aid for JSPS Fellows

Allocation TypeSingle-year Grants
Section外国
Review Section Basic Section 37030:Chemical biology-related
Research InstitutionThe University of Tokyo
Host Researcher 浦野 泰照  東京大学, 大学院薬学系研究科(薬学部), 教授 (20292956)
Foreign Research Fellow KELLER SASCHA  東京大学, 薬学研究科(研究院), 外国人特別研究員
Project Period (FY) 2019-11-08 – 2022-03-31
Project Status Granted (Fiscal Year 2021)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2021: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2020: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2019: ¥600,000 (Direct Cost: ¥600,000)
KeywordsFluorescence / Cancer / Tumor / Rhodol / Spiro-cyclic / Computer-based
Outline of Research at the Start

Goals of the project include: (i) development of a computer based model to predict properties of novel fluorescent molecules, (ii) synthesis and screening of a library of amino-acid and sugar Si-Rhodol-based probes that have promising properties; (iii) using those probes to visualize colon and stomach cancer as well as (iv) understanding of their overexpression of hydrolases in clinical specimens of cancerous colon and stomach tissue.

Outline of Annual Research Achievements

his project aims at finding suitable probes to detect various cancers by rational design of fluorescence probes based on a quantum chemical prediction of their intramolecular spiro-cyclization. Goals of the project include: (i) development of a computer-based model to predict properties of novel fluorescent molecules, (ii) the synthesis of a library of amino-acid and sugar derivatives of novel Si- or C-Rhodols that have promising properties; (iii) using those probes to visualize colon and stomach cancer as well as (iv) understanding of their overexpression of aminopeptidases and glycosidases in clinical specimens of cancerous colon and stomach tissue. Given the novel developed synthetic route which was even further enhanced fast and efficient synthesis of a huge variety of molecules is now possible. To develop a working model to predict the spiro-cyclization behavior of fluorescent probes, a library of several structurally different probes was synthesized, and their pKcycl-values were experimentally determined. After fine tuning of the in silica predicted values for said compounds the error margin was reduced to a satisfactory level. This should now allow us to predict the pKcycl-value for unknown molecules. Furthermore, the synthesis and the calculations could be expanded to C-Rhodols, which exhibit a different absorption and emission wavelength compared to the Si-Rhodols. This is important, since it would allow multi-color imaging of specimens.

Current Status of Research Progress
Current Status of Research Progress

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

Reason

To calculate the important pKcycl-value of potential probes the free energy gap between the closed and the open form is estimated by a computational chemistry approach. After synthesizing a large library of compounds and determining their chemical properties, the calculations fit well with the experimental values. This allows us now to calculate different unknown compounds and select a suitable structure to be used as the core of our probes. Also, the mentioned pathway allows easy coupling to amino acids or sugars. Furthermore, C-Rhodols started to be of interest, too, hence a small library was already synthesized. Using C-Rhodols and Si-Rhodols in tandem would allow multi-color imaging. One core structure bound to a sugar-moiety showed a strong increase in fluorescence when tested in breast cancer specimen. Said probe will be tested in colon and stomach cancers. Furthermore, the developed synthesis allows easy coupling of an amino acid and a sugar to the same molecule, rendering it an AND-gate probe. Only when both groups have been cleaved a strong fluorescence is detectable. These probes have not been extensively studied yet and might be of great interest.

Strategy for Future Research Activity

Since the calculations show satisfactory results, several possible structures are being calculated and the most suitable ones will be synthesized. In a straightforward manner, these probes will be bound to sugars or amino acids. The sugar or amino acid bound probes will then be tested on tumor specimen to find a suitable probe. Then the probes will be tested with purified enzymes but also with cancerous cell lines to verify their behavior in vitro. Since a small library of C-Rhodols has already been synthesized, we will also try to expand the strategy to these probes which show a different spectroscopic behavior. Necessary control experiments must be conducted to exclude false conclusions. Also, the AND-gate probes will be subject to explore their potential in cancer detection. The results of these experiments as well as the before mentioned synthetical pathway are subject to be published within next fiscal year.

Report

(2 results)
  • 2020 Annual Research Report
  • 2019 Annual Research Report

Research Products

(3 results)

All 2020 2019

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (2 results) (of which Int'l Joint Research: 2 results)

  • [Journal Article] Recent Progress in Small Spirocyclic, Xanthene-Based Fluorescent Probes2020

    • Author(s)
      G. Keller Sascha、Kamiya Mako、Urano Yasuteru
    • Journal Title

      Molecules

      Volume: 25 Pages: 5964-5964

    • DOI

      10.3390/molecules25245964

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Presentation] Rational design of fluorescence probes based on quantum chemical prediction of intramolecular spirocyclization2020

    • Author(s)
      Sascha G. Keller, Ryo Tachibana, Mako Kamiya, Yasuteru Urano
    • Organizer
      Resonance Bio International Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Rational design of fluorescence probes based on quantum chemical prediction of intramolecular spirocyclization2019

    • Author(s)
      Sascha G. Keller, Ryo Tachibana, Mako Kamiya, Yasuteru Urano
    • Organizer
      Resonance Bio International Symposium
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research

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Published: 2019-11-29   Modified: 2021-12-27  

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