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

基于新型探针库构建，开发检测结直肠癌和胃癌的荧光探针

• 批准号: 19F19339
• 负责人: 浦野 泰照
• 金额: $ 1.41万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for JSPS Fellows
• 财政年份: 2019
• 资助国家: 日本
• 起止时间: 2019-11-08 至 2022-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-19F19339/
• 关键词: Fluorescence; Cancer; Tumor; Rhodol; Spiro-cyclic; Computer-based

This 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. This fiscal year, the computational model for the prediction of the pKcycl-values of unknown Si-containing rhodols was extended to C-containing rhodols, and got satisfying results of pKcycl prediction, and compounds bound to sugar and amino acid moieties were synthesized by a significantly enhanced synthetic pathway. The 4ThP compound with 2 methyl groups showed well suited properties and was thus synthesized to be tested in cancerous specimens. Indeed, we could show that the probe bound to beta-galactose specifically turned fluorescent in breast cancer samples, while normal tissue almost did not show an increase in fluorescence. In conclusion, a versatile synthesis pathway and a calculation model was established.

该项目旨在基于分子内螺环化的量子化学预测，通过合理设计荧光探针，找到合适的探针来检测各种癌症。该项目的目标包括：(i) 开发基于计算机的模型来预测新型荧光分子的特性，(ii) 合成具有前景的新型 Si- 或 C-Rhodol 的氨基酸和糖衍生物库特性; (iii) 使用这些探针观察结肠癌和胃癌，以及 (iv) 了解癌性结肠癌和胃组织临床标本中氨基肽酶和糖苷酶的过度表达。本财年，将未知含Si对甲酚的pKcycl值预测计算模型推广到含C对甲酚，得到了满意的pKcycl预测结果，并通过合成方法合成了与糖和氨基酸部分结合的化合物。显着增强的合成途径。具有 2 个甲基的 4ThP 化合物显示出非常合适的特性，因此被合成用于在癌症样本中进行测试。事实上，我们可以证明与 β-半乳糖结合的探针在乳腺癌样本中特异性地发出荧光，而正常组织几乎没有显示出荧光增加。总之，建立了通用的合成途径和计算模型。

项目成果

Rational design of fluorescence probes based on quantum chemical prediction of intramolecular spirocyclization

基于分子内螺环化量子化学预测的荧光探针合理设计

• 发表时间: 2020
• 作者: Sascha G. Keller;Ryo Tachibana;Mako Kamiya;Yasuteru Urano
• 通讯作者: Yasuteru Urano