Yueqin Zheng

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.

Toward Carbon Monoxide–Based Therapeutics: Critical Drug Delivery and Developability Issues

Carbon monoxide (CO) is an intrinsic signaling molecule with importance on par with that of nitric oxide. During the past decade, pharmacologic studies have amply demonstrated the therapeutic potential of carbon monoxide. However, such studies were mostly based on CO inhalation and metal-based CO-releasing molecules. The field is now at the stage that a major effort is needed to develop pharmaceutically acceptable forms of CO for delivery via various routes such as oral, injection, infusion, or topical applications. This review examines the state of the art, discusses the existing hurdles to overcome, and proposes developmental strategies necessary to address remaining drug delivery issues.

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.

3,6-Substituted-1,2,4,5-tetrazines: tuning reaction rates for staged labeling applications

Cycloaddition reactions involving tetrazines have proven to be powerful bioorthogonal tools for various applications. Conceivably, sequential and selective labeling using tetrazine-based reactions can be achieved by tuning the reaction rate. By varying the substituents on tetrazines, cycloaddition rate variations of over 200 fold have been achieved with the same dienophile. Upon coupling with different dienophiles, such as norbornene, the reaction rate difference can be over 14,000 fold. These substituted tetrazines can be very useful for selective labeling under different conditions.

Toward Hydrogen Sulfide Based Therapeutics: Critical Drug Delivery and Developability Issues

Hydrogen sulfide (H2S), together with nitric oxide (NO) and carbon monoxide (CO), belongs to the gasotransmitter family and plays important roles in mammals as a signaling molecule. Many studies have also shown the various therapeutic effects of H2S, which include protection against myocardial ischemia injury, cytoprotection against oxidative stress, mediation of neurotransmission, inhibition of insulin signaling, regulation of inflammation, inhibition of the hypoxia‐inducible pathway, and dilation of blood vessels. One major challenge in the development of H2S‐based therapeutics is its delivery. In this manuscript, we assess the various drug delivery strategies in the context of being used research tools and eventual developability as therapeutic agents.

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.

A metal-free turn-on fluorescent probe for the fast and sensitive detection of inorganic azides.

Sodium azide is toxic and widely used in agricultural, commercial products, and research laboratories. Thus it is of a significant environmental concern and there is a need for the development of a rapid detection method. A fluorogenic dibenzylcyclooctyne derivative (Fl-DIBO) is herein described as a fluorescent probe for the rapid detection of inorganic azide via Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC). Fl-DIBO was found to be highly selective toward NaN3 in comparison to other common anions with good sensitivity and detection limit of 10μM.

Homing in on an intracellular target for delivery of loaded nanoparticles functionalized with a histone deacetylase inhibitor

Functionalized nanoparticles (NPs) are usually used to enhance cellular penetration for targeted drug delivery that can improve efficacy and reduce side effects. However, it is difficult to exploit intracellular targets for similar delivery applications. Herein we describe the targeted delivery of functionalized NPs by homing in on an intracellular target, histone deacetylases (HDACs). Specifically, a modified poly-lactide-co-glycolideacid (FPLGA) was yielded by conjugation with an HDAC inhibitor. Subsequently, FPLGA was used to prepare functionalized FPLGA NPs. Compared to unmodified NPs, FPLGA NPs were more efficiently uptaken or retained by MCF-7 cells and showed longer retention time intracellular. In vivo fluorescence imaging also revealed that they had a higher accumulation and a slower elimination than unmodified NPs. FPLGA NPs loaded with paclitaxel exhibited superior anticancer efficacy compared with unmodified NPs. These results offer a promising approach for intracellular drug delivery through elevating the concentration of NPs.

Esterase-Sensitive Glutathione Persulfide Donor

An esterase-sensitive glutathione persulfide (GSSH) donor (BW-GP-401) is described. The release profile was studied by monitoring the formation of lactone and direct trapping of GSSH with 1-fluoro-2,4-dinitrobenzene (DNFB). The donor was examined for its inhibitory effect toward glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Under highly oxidative conditions, the donor also shows cytoprotective effects in H9c2 cardiomyocytes.