Goldberg Doron, Bentwich Isaac, Haran Yossi, Getter Tamar
BioAI Drug Safety Prediction Platform, Quris, HaNatsiv St 6, Tel Aviv-Yafo, 6701033, Israel.
ACS Omega. 2025 Mar 11;10(11):10812-10825. doi: 10.1021/acsomega.4c06237. eCollection 2025 Mar 25.
Chemical-based fluorescent sensors with the capability of long-term stability and low cost are promising agents in clinical diagnosis and medical research. Measuring glucose levels inside cells and their surroundings provides insight into cellular metabolic homeostasis and may be employed as an indicator for potential pathological conditions. Anthracene-based diboronic acid (BA) derivatives offer a reversible and covalent binding mechanism for glucose recognition, which enables robust and continuous glucose monitoring. To improve its poor solubility and biological applicability, a diboronic acid chemical structure design was explored. To date, several anthracene-based ortho-amino methylphenyl boronic acid glucose-sensors have been developed. Most recently, the structure of Mc-CDBA (((((2-(methoxycarbonyl) anthracene-9,10-diyl) bis (methylene)) bis(methylazanediyl)) bis(methylene)) bis(4-cyano-2,1-phenylene)) diboronic acid was disclosed. Mc-CDBA exhibits suitable water-solubility and sensitivity toward glucose, with limited modification sites and suitability to extra-cellular applications. Here, we present a palette of Mc-CDBA derivatives: carboxylic (BA), amid (BA 5) and acryl (BA 21)-based Mc-CDBA sensors for extra- and intracellular glucose monitoring, respectively. The developed chemical glucose sensors were designed to obtain a final product with fewer synthetic steps, allowing easier scale-up capacity. Moreover, we showed that ortho-amino site modifications do not interfere with the sensor activity, allowing alternative water solubility solutions without chemically modifying the chromophore/aromatic subunits within the molecule. Among these probes, we also developed an extracellular hydrogel-embedded sensor (BA 21) to monitor extracellular glucose levels under persistent solution flow, a feature that is lacking in other glucose sensors. The synthesized derivatives could serve as diverse fluorescent sensors for glucose monitoring in medical applications.
具有长期稳定性且成本低廉的化学基荧光传感器是临床诊断和医学研究中很有前景的试剂。测量细胞内部及其周围环境中的葡萄糖水平有助于深入了解细胞代谢稳态，并可用作潜在病理状况的指标。基于蒽的二硼酸（BA）衍生物为葡萄糖识别提供了一种可逆的共价结合机制，能够实现可靠且连续的葡萄糖监测。为了改善其较差的溶解性和生物适用性，人们探索了二硼酸化学结构设计。迄今为止，已经开发了几种基于蒽的邻氨基甲基苯基硼酸葡萄糖传感器。最近，公开了Mc-CDBA（(((2-(甲氧基羰基)蒽-9,10-二基)双(亚甲基))双(甲基氮杂二基))双(亚甲基))双(4-氰基-2,1-亚苯基))二硼酸的结构。Mc-CDBA对葡萄糖表现出合适的水溶性和灵敏度，修饰位点有限且适用于细胞外应用。在此，我们展示了一系列Mc-CDBA衍生物：分别用于细胞外和细胞内葡萄糖监测的基于羧酸（BA）、酰胺（BA 5）和丙烯酸酯（BA 21）的Mc-CDBA传感器。所开发的化学葡萄糖传感器旨在通过更少的合成步骤获得最终产品，从而更易于扩大生产规模。此外，我们表明邻氨基位点修饰不会干扰传感器活性，无需对分子内的发色团/芳香亚基进行化学修饰即可获得替代的水溶性解决方案。在这些探针中，我们还开发了一种细胞外水凝胶包埋传感器（BA 21），用于在持续溶液流动下监测细胞外葡萄糖水平，这是其他葡萄糖传感器所缺乏的特性。合成的衍生物可作为多种荧光传感器用于医学应用中的葡萄糖监测。
