Xingyue Ji

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.

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.

Carbon monoxide protects the kidney through the central circadian clock and CD39.

Significance Tissue injury caused by lack of blood flow results in a series of adaptive responses of the body to ensure survival. Cellular production of carbon monoxide (CO) preserves organ function and promotes healing. How this occurs has remained elusive. Here we demonstrate using a model of ischemia reperfusion injury (IRI) of the kidney, mimicking kidney transplant, that safe administration of CO protects against IRI. Remarkably, this occurs through specific modulation of a gene that regulates energy metabolism (CD39) and one that controls circadian rhythm (Period 2). Collectively, we define here an innovative signaling pathway linking the brain and the kidney vis a vis a gas molecule. These data may have important therapeutic consequences for transplant recipients and victims of stroke. Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39−/− and Per2−/− mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

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.

Toward carbon monoxide based therapeutics: carbon monoxide in a pill

As one of the three known gasotransmitters, carbon monoxide (CO) has demonstrated therapeutic potential against a wide range of human diseases. However, development of CO as a therapeutic agent is severely impeded, primarily due to the lack of pharmaceutically acceptable delivery forms of CO. Gaseous CO may only have limited utility under carefully controlled clinical environment. As a result, there have been efforts in developing metal-based CO-releasing molecules and organic CO-releasing molecules that require light activation. We are interested in developing CO prodrugs, which are metal free and release CO spontaneously under physiological conditions without light irradiation. In this review, we summarize progress in this area with a focus on a recent patent and related publications.

Discovery and evaluation of triple inhibitors of VEGFR-2, TIE-2 and EphB4 as anti-angiogenic and anti-cancer agents

Receptor tyrosine kinases (RTKs), especially VEGFR-2, TIE-2, and EphB4, play a crucial role in both angiogenesis and tumorigenesis. Moreover, complexity and heterogeneity of angiogenesis make it difficult to treat such pathological traits with single-target agents. Herein, we developed two classes of multi-target RTK inhibitors (RTKIs) based on the highly conserved ATP-binding pocket of VEGFR-2/TIE-2/EphB4, using previously reported BPS-7 as a lead compound. These multi-target RTKIs exhibited considerable potential as novel anti-angiogenic and anticancer agents. Among them, QDAU5 displayed the most promising potency and selectivity. It significantly suppressed viability of EA.hy926 and proliferation of several cancer cells. Further investigations indicated that QDAU5 showed high affinity to VEGFR-2 and reduced the phosphorylation of VEGFR-2. We identified QDAU5 as a potent multiple RTKs inhibitor exhibiting prominent anti-angiogenic and anticancer potency both in vitro and in vivo. Moreover, quinazolin-4(3H)-one has been identified as an excellent hinge binding moiety for multi-target inhibitors of angiogenic VEGFR-2, Tie-2, and EphB4.

Click, Release, and Fluoresce: A Chemical Strategy for a Cascade Prodrug System for Codelivery of Carbon Monoxide, a Drug Payload, and a Fluorescent Reporter

A chemical strategy was developed wherein a single trigger sets in motion a three-reaction cascade leading to the release of more than one drug-component in sequence with the generation of a fluorescent side product for easy monitoring. As a proof of concept, codelivery of CO with the antibiotic metronidazole was demonstrated.