Simone Carradori

“G. d’Annunzio” University of Chieti-Pescara, Italy

Title: Cobalt-based Carbon Monoxide Releasing Molecules (CORMs): Design, synthesis and anti-inflammatory activity

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Biography

Dr. Simone Carradori completed his PhD in “Pharmaceutical Sciences” at Sapienza University of Rome (Italy). Dr. Simone Carradori has collaborated and still collaborates with several departments abroad. Now he is assistant professor at the Department of Pharmacy of “G. d’Annunzio” University of Chieti-Pescara (Italy). The scientific activity is mainly focused on the characterization and synthesis of heterocyclic derivatives with potential biological activity, and is documented from about 186 papers in international peer-reviewed journals, one patent and participations in numerous conferences. He is in the Editorial Board of several peer-reviewed journals.

Abstract

Carbon monoxide (CO) is endogenously produced and it has been reported as an anti-inflammatory and cytoprotective gaseous substance at low concentrations. However, the administration of exogenous CO is complicated due to its gaseous state, and obtaining specific cell responses is challenging because of the lack of specialized targets. In this context, CO releasing molecules (CORMs) have attracted enormous interest, being reported to downregulate immune and inflammatory responses in both in vitro and in vivo models of diseases, such as Rheumatoid Arthritis (RA), Rotator Cuff Tears (RCTs) and Rotator Cuff Disease (RCD). In parallel, it has been broadly reported that Carbonic Anhydrase (CA; EC 4.2.1.1) is involved in the pathogenesis and maintenance of many inflammation-related diseases. Levels of the isoform IX have been found in human fetal tendons as a marker of mechanical stress, and an overexpression of CA IX and XII in inflamed joints has been recently reported. In this light, the synthesis of small molecule hybrids consisting of CA inhibitors or not linked to a CORM section (CAI-CORMs) has been proposed. This strategy aims at strengthening a counteraction of the sustained oxidative stress and inflammation occurring in many diseases. Evaluation of the CO released over time, performed by using a myoglobin carbonylation assay, revealed the organic portion linked to the CORM section to have a deep influence on the CO releasing properties. On the other hand, the DCH insertion did not highly hamper the CA inhibition. In vivo pain relief efficacy studies in the RA rat model showed that some derivatives were more efficient in terms of intensity as well as time distribution when compared to the single entities CAI and CORM administered separately, confirming the success of the hybridization strategy. These very promising results fostered our interest in studying the anti-inflammatory and anti-oxidant properties of such hybrids at a biological and molecular level on LPS-stimulated RAW 264.7 mouse macrophages and H2O2-stimulated tendon-derived human primary cells in comparison with N-acetyl cysteine (NAC) and the NSAID meloxicam, respectively. Our results revealed that compounds counteracted the induced inflammation and some hybrids displayed a better profile in terms of enhanced viability, decreased cytotoxicity, and augmented cell proliferation in both the cell model. In the inflamed tendon cell model, compound 7, as a potent superoxide scavenger, exerted its action inhibiting the NF-?B translocation and downregulating iNOS, whereas compound 2 was more effective in increasing collagen I deposition. Taken together, these data lay the grounds for further investigations in this field and pave the way for the use of CAI-CORMs in inflammatory-related diseases.