Design and Synthesis of New Hybrid Molecules That Activate the Transcription Factor Nrf2 and Simultaneously Release Carbon Monoxide

Abstract

The transcription factor Nrf2 and its downstream target heme oxygenase-1 (HO-1) are essential protective systems against oxidative stress and inflammation. The products of HO-1 enzymatic activity, biliverdin and carbon monoxide (CO), actively contribute to this protection, suggesting that exploitation of these cellular systems may offer new therapeutic avenues in a variety of diseases. Starting from a CO-releasing compound and a chemical scaffold exhibiting electrophilic characteristics (esters of fumaric acid), we report the synthesis of hybrid molecules that simultaneously activate Nrf2 and liberate CO. These hybrid compounds, which we termed "HYCOs", release CO to myoglobin and activate the CO-sensitive fluorescent probe COP-1, while also potently inducing nuclear accumulation of Nrf2 and HO-1 expression and activity in different cell types. Thus, we provide here the first example of a new class of pharmacologically active molecules that target the HO-1 pathway by combining an Nrf2 activator coordinated to a CO-releasing group.

Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation

“…301–303 Recent innovation in this area also includes the development of nanoparticle delivery systems for CORMs, 303–304 as well as bifunctional hybrid molecules with both Nrf2-activating and CORM functions. 305 …”

Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions

“…In the eye HO-1 reduces inflammation, promotes corneal wound healing and its over-expression following hemin administration protects the retinas in streptozotocin-induced diabetic rats [8,9]. From a therapeutic perspective it is important to note that several electrophilic or plant-derived compounds possess the ability of activating the Nrf2/HO-1 axis [10][11][12][13][14] and reduce inflammation of the retina [15,16], suggesting that the identification of promising molecules that enhance the expression of endogenous antioxidant proteins in retinal tissue may have therapeutic value in the treatment of eye diseases. However, whether the retinal cellular response to Nrf2/HO-1 activators is affected by high glucose is currently unknown.…”

Fluorescent probes for imaging formaldehyde in biological systems

“…One emerging approach utilizes fluorescence-based probes, which offer high selectivity and sensitivity and can be used in situ . Reactivity-based fluorescent probes have been successfully employed to image a variety of biological analytes [34–36], including the carbonyl species carbon monoxide [37–41] and methylglyoxal [42], and recent efforts have focused on the development of reactivity-based probes for FA. This review aims to summarize the current progress toward creating responsive and selective fluorescent reporters for FA, along with an outlook toward improvements in the field.…”