Strategies toward Metal‐Free Carbon Monoxide Prodrugs: An Update

Abstract

Carbon monoxide is an important gasotransmitter in mammals, with pleiotropic therapeutic potential against a wide range of human diseases. However, clinical translation of CO is severely hampered by the lack of a reliable CO delivery form. The development of metal‐free CO prodrugs is the key to resolving such delivery issues. Over the past three years, some new exciting progress has been made in this field. In this review, we highlight these advances and discuss related issues.

Metal Coordination Complexes as Therapeutic Agents for Ischemia-Reperfusion Injury

“…A more soluble CORM, 2 , is also able to reduce the effects of IRI. ,,− The primary limitation of 2 for this application, however, arises from its challenging synthesis and solvent-dependent speciation . Furthermore, recent studies suggest that some of the biological effects of this compound arise from the Ru byproducts rather than CO. − Based on these limitations, researchers have sought to develop CORMs with different transition metals , and metal-free CORMs. , The use of alternative metal CORMs, as specifically applied for IRI, is described below.…”

“…62 Furthermore, recent studies suggest that some of the biological effects of this compound arise from the Ru byproducts rather than CO. 63−66 Based on these limitations, researchers have sought to develop CORMs with different transition metals 27,67 and metal-free CORMs. 68,69 The use of alternative metal CORMs, as specifically applied for IRI, is described below.…”

Reactive Oxygen Species-Activated Metal-Free Carbon Monoxide Prodrugs for Targeted Cancer Treatment

“…To mitigate these limitations, tremendous efforts have been devoted to the development of CO prodrugs or CO-releasing molecules (CORMs) for controllable CO delivery, and some very exciting progress has been witnessed in this field. These CO donors can be generally divided into two categories, namely, metal-based − and metal-free CO prodrugs. − In the past decades, extensive efforts have been devoted to the development of metal-based CORMs, − and some of them have been widely employed for studying CO biology, such as CO’s anti-inflammatory effects. , In contrast, metal-free CO prodrugs are substantially underdeveloped due to the challenges to extrude CO from small organic molecules. Over the past decade, quite a few chemically diverse metal-free CO prodrugs have been elegantly devised using photoirradiation, − bioorthogonal chemistry, − ultrasound, or water , as the trigger, and some of them have been successfully applied in vivo to achieve localized CO delivery and recapitulated CO-associated pharmacological effects.…”

Type-I Photosensitizer-Triggered Controllable Carbon Monoxide Release for Effective Treatment of Staph Skin Infection

“…As an effective therapeutic modality for bacteria, photodynamic therapy (PDT) has attracted increasing attention in recent years owing to its high controllability and noninvasive properties. , PDT employs photosensitizers (PSs) and external light source to generate cytotoxic ROS through electron/energy transfer processes, , leading to damage to bacterial membranes and DNA. − In addition, apart from direct phototoxic effects on pathogens, PDT can also serve as an activator to modulate certain gas molecule release through photo­oxidation reaction, which could induce the specific activation of antibacterial pathways, leading to better antibacterial therapeutic effect. To date, most studies have focused on the development of type-II PSs to trigger photoresponsive CORMs for the CO treatment of various diseases. ,− Interestingly, compared with type-II ROS, type-I ROS generation requires only a small amount of oxygen and can also trigger CO generation from CO-releasing metal carbonyls via a Fenton-like reaction, , which indicates that the combination of type-I PSs and photoresponsive CORMs might overcome the shortcomings of type-II PS-based CO production strategies under hypoxia conditions. To develop such a nanosystem, strong type-I ROS yield and efficient photooxidation reaction for CO release are desirable.…”