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.

本项目旨在通过对分子内螺环化反应的量子化学预测，合理设计荧光探针，寻找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以预测新型荧光分子的性质，（ii）合成具有有希望的性质的新型Si-或C-Rhodol的氨基酸和糖衍生物的文库;（iii）使用这些探针来可视化结肠癌和胃癌以及（iv）理解它们在癌性结肠和胃组织的临床标本中的氨基肽酶和糖苷酶的过度表达。本财年，用于预测未知含硅玫瑰醇的pKcycl值的计算模型扩展到含碳玫瑰醇，并获得了令人满意的pKcycl预测结果，并通过显着增强的合成途径合成了与糖和氨基酸部分结合的化合物。具有2个甲基的4ThP化合物显示出非常合适的性质，因此合成用于在癌性样本中进行测试。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变成荧光，而正常组织几乎没有显示荧光增加。建立了一条通用的合成路线和计算模型。

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