Kaili Ji

Esterase-Sensitive Prodrugs with Tunable Release Rates and Direct Generation of Hydrogen Sulfide†

Prodrugs that release hydrogen sulfide upon esterase-mediated cleavage of an ester group followed by lactonization are described herein. By modifying the ester group and thus its susceptibility to esterase, and structural features critical to the lactonization rate, H2 S release rates can be tuned. Such prodrugs directly release hydrogen sulfide without the involvement of perthiol species, which are commonly encountered with existing H2 S donors. Additionally, such prodrugs can easily be conjugated to another non-steroidal anti-inflammatory agent, leading to easy synthesis of hybrid prodrugs. As a biological validation of the H2 S prodrugs, the anti-inflammatory effects of one such prodrug were examined by studying its ability to inhibit LPS-induced TNF-α production in RAW 264.7 cells. This type of H2 S prodrugs shows great potential as both research tools and therapeutic agents.

Hydrogen sulfide prodrugs-a review.

Hydrogen sulfide (H2S) is recognized as one of three gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). As a signaling molecule, H2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H2S prodrugs for various reasons. In this review, we summarize different H2S prodrugs, their chemical properties, and some of their potential therapeutic applications.

Click and Release: SO2 Prodrugs with Tunable Release Rates

Employing an intramolecular cycloaddition reaction, we have developed a series of SO2 prodrugs with tunable release rates with half-lives ranging from minutes to days.

Organic CO-prodrugs: Structure CO-release rate relationship Studies

Carbon monoxide (CO) is an endogenously produced gasotransmitter in mammals, and may have signaling roles in bacteria as well. It has many recognized therapeutic effects. A significant challenge in this field is the development of pharmaceutically acceptable forms of CO delivery with controllable and tunable release rates. Herein, the structure-release rate studies of the first class of organic CO prodrugs that release CO in aqueous solution at neutral pH is described.

Toward Direct Protein S-Persulfidation: A Prodrug Approach That Directly Delivers Hydrogen Persulfide

A general strategy of delivering hydrogen persulfide (H2S2) is described herein. Esterase- and phosphatase-sensitive H2S2 prodrugs with tunable release rates have been synthesized. Their utility is validated in examining protein S-persulfidation. With this unique approach of directly delivering H2S2, our findings reaffirmed that S-persulfidation leads to decreased activity of glyceraldehyde 3-phosphate dehydrogenase. This new approach complements available prodrugs/donors that directly deliver a single species, including hydrogen sulfide, perthiol, and COS, and will be very useful as part of the toolbox for delineating the mechanisms of sulfur signaling.

Tuning the reaction rates of fluoride probes for detection in aqueous solution

Fluoride detection in aqueous solution has drawn much attention. Most fluoride probes are based on the cleavage of a silyl group by fluoride for the generation of fluorescence. However, such a reaction is generally slow in aqueous solution. Herein we successfully demonstrate the concept that increasing the hydrophilicity of a pendent group enhances the reactivity of a silyl-based probe for fluoride detection in aqueous solution. By applying this concept, we also developed a new probe with a pendent PEG unit (BW-F-204), which showed excellent fluoride sensing ability both in aqueous solution and in cell culture.

Organic CO Prodrugs Activated by Endogenous ROS

CO prodrugs with triggered release mechanisms are highly desirable for targeted delivery. Herein described are organic CO prodrugs that are activated by ROS and thus can be used to selectively deliver CO to cells with elevated ROS levels. Such CO prodrugs can serve as powerful tools for targeted delivery to disease sites with elevated ROS levels and to explore the therapeutic applications of CO.

Click and Fluoresce: A Bioorthogonally Activated Smart Probe for Wash-Free Fluorescent Labeling of Biomolecules.

Bioorthogonally activated smart probes greatly facilitate the selective labeling of biomolecules in living system. Herein, we described a novel type of smart probes with tunable reaction rates, high fluorescence turn-on ratio, and easy access. The practicality of such probes was demonstrated by selective labeling of lipid and hCAII in Hela cells.

Chapter 5:Synthetic Receptors for Carbohydrates

The chapter summarizes the design and development of synthetic receptors that can selectively target various types of carbohydrate structures, including monosaccharides, oligosaccharides, and glycoconjugates. Biological carbohydrate receptors are called lectins and X-ray crystal structures of their binding pockets show that effective receptor/carbohydrate association is achieved by a synergistic network of polar and nonpolar interactions. The different categories of synthetic carbohydrate receptors are described (boronic acids, organic macrocycle and cleft-shaped molecules, and metal coordination complexes), along with their binding properties and how they can be utilized for diagnostic or therapeutic applications. Examples include efforts to create solution-state chemosensors for mono- and disaccharides. Also described is recent work to detect cell surface glycoconjugates, which are often disease-specific biomarkers and thus valuable molecular targets for biomedical imaging or drug targeting. The chapter concludes with a summary of current challenges and likely future directions.