Head‐to‐Head Comparison of Selected Extra‐ and Intracellular CO‐Releasing Molecules on Their CO‐Releasing and Anti‐Inflammatory Properties

Abstract

Over the past decade, a variety of carbon monoxide releasing molecules (CORMs) have been developed and tested. Some CORMs spontaneously release CO once in solution, while others require a trigger mechanism to release the bound CO from its molecular complex. The modulation of biological systems by CORMs depends largely on the spatiotemporal release of CO, which likely differs among the different types of CORMs. In spontaneously releasing CORMs, CO is released extracellularly and crosses the cell membrane to interact with intracellular targets. Other CORMs can directly release CO intracellularly, which may be a more efficient method to modulate biological systems. In the present study, we compared the efficacy of extracellular and intracellular CO-releasing CORMs that either release CO spontaneously or require an enzymatic trigger. The efficacy of such CORMs to modulate HO-1 and VCAM-1 expression in TNF-α-stimulated human umbilical vein endothelial cells (HUVEC) was evaluated.

Synthesis and Biological Evaluation of Water‐Soluble Esterase‐Activated CO‐Releasing Molecules Targeting Mitochondria

“…We also cannot exclude that the combination of CO and hydrolysis products are mediating toxicity and that quantitative and qualitative differences herein explains the higher toxicity of the A’‐type Mito‐CORMS. Nonetheless, in agreement with our earlier studies, [7d,e,g] we assume the rate of CO liberation in living cells is the pivotal criterion for toxicity. However, another possible explanation would be that Mito‐CORMs 2/3 ‐ B act in the opposite way, which would mean that the B variants release CO more slowly in living cells.…”

“…In a recent study, we demonstrated that the anti‐inflammatory properties of CORMs depend on the amount of CO released rather then intra‐ or extra‐cellular production, [7g] in accordance to the results of Berreau [15] . Given the promising properties of our iron‐based ET‐CORMs, we were now interested in whether such compounds could also be used to study CO release in specific organelles compared with normal intracellular CO release.…”

“…Early investigations of the effect of CO on mitochondria were performed using either gaseous CO or first generation CORMs, such as CORM ‐ 2 and CORM ‐ 3 [9b,10] . However, as reported by various research groups, the amounts of CO released from CORM ‐ 2 or CORM ‐ 3 are small and undefined, and some effects of these compounds may even be caused by the ruthenium rather than the CO [7g,11] . Therefore, alternative compounds need to be tested to determine the action of CO on mitochondria in a meaningful concentration‐dependent manner.…”

Partially Reduced MIL-100(Fe) as a CO Carrier for Sustained CO Release and Regulation of Macrophage Phenotypic Polarization

“…For example, CORM-3 failed to interfere with LPS/IFN-induced upregulation of TNF-α levels. 20,36 In this study, CO release from CO@ MIL-100(Fe) significantly alleviated the pro-apoptotic factors secretion of LPS-induced MA.…”

“…16−18 However, the first-generation CORMs that spontaneously release CO, such as CORM-2 and CORM-3, have been proved to be unable to deliver CO in a controllable fashion at all. 19 The recent study newly found that CORM-2 and CORM-3 could mainly liberate CO 2 not CO. 20 Therefore, the nextgeneration CORMs are progressing in the direction of slow and controllable CO release, which is based on nanoparticles, 21 photo-CORMs, 22 and enzyme-triggered CORMs (ET-CORMS). 20 Other CO-releasing materials based on organic carbon monoxide prodrugs have also attracted much attention because they can avoid the toxicity of transition metal elements to the human body and release CO in response to various exogenous and endogenous triggers, such as water, chemical reagents, esterase, ROS, and so on.…”