Design and Synthesis of Novel Di-Boronic Acid-Based Chemical Glucose Sensors.

Abstract

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.