Rheumatoid Arthritis (RA) is a chronic and systemic autoimmune disease which primary affect the lining of the joints, inducing ache symptoms deeply impacting life quality of the patients. Moreover, the chronic inflammation typical of RA has been related with higher cancer incidence. Currently RA pharmacological treatments include drugs acting to slow or stop the course of the disease and those acting to ease the symptoms. However, despite recent progresses in RA treatment there is still no effective cure. Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most used drugs to control the symptoms of RA although their prolonged use is highly hampered by gastric and cardiovascular toxicity issues. Association of NSAIDs with therapeutic agents able to mitigate their adverse effects, also contributing to their anti-inflammatory activity would be of great interest for the global community. By exploiting the ¿hybridization approach¿, this project aims to combine the anti-inflammatory action of NSAIDs with the gastro- and cardio-protective activities of Carbon Monoxide (CO), released in a controlled manner by a metallo-organic scaffold properly installed on the Oxicam nucleous. Cobalt and Manganese containing CO-RM/NSAID hybrids will be designed, synthetized and assayed for their CO releasing properties, by means of the widely used Myoglobin carbonylation assay, available in-house. The anti-inflammatory and pain relieving activities will be evaluated in both in vitro and in vivo models of RA. By using a ratiometric fluorescent probe, the CO release from CO-RM/NSAID will be assayed also in the cellular medium. The availability of solid preliminary data, the well-established synthetic and analytical methodologies, and the translational character of the proposal, make this project feasible and appealing for a large scientific community, allowing to gain more insights in inflammation-related diseases treatment.
Research inventiveness and potential for going beyond the state-of-the-art
The present proposal aims to the synthesis of a new family of anti-inflammatory agents, the CO-RM/NSAID hybrids. The anti-inflammatory and cytoprotective effects of CO are well known, as well as its gastroprotective properties, although the precise mechanisms underlying this effect have not been defined yet.[1] Many data on the beneficial effects of NO and H2S releasing NSAIDs for the treatment of inflammatory diseases have been reported, but no studies have been conducted on NSAIDs/CO releasers.[2] Very few examples of this kind of complexes have been reported in the literature, but none of them explored their potential as anti-inflammatory agents, being more focused on the study of their antitumor activities.[3,4] This project will contribute to fill the current literature gap on the use of NSAID/gasotransmitter hybrids, going one step further towards the development of potent and safer anti-inflammatory agents to be used for chronic disorders, such as RA. The potential of CO to contribute to the inflammation reduction, also counteracting the adverse effects associated to the prolonged use of NSAIDs is appealing and of great interest for the scientific community, also in light of the higher selectivity and stability of CO when compared to its congener gases. Moreover, the use of two different metallo-organic portions will allow to get more information on the mechanism underlying the cytoprotective effects of CO. The availability of solid preliminary data, the well-established synthetic and analytical methodologies and the current prolific collaborations with other research groups working in the field, make feasible the accomplishment of the research project¿s goals in the time window of 12 months. Moreover, this proposal comprises various scientific disciplines (i.e. chemistry, enzymology and molecular biology, among others) and possesses translational character, opening new perspectives for further studies in the field of inflammation-related diseases treatment.
References
[1] D. Babu, R. Motterlini, R. A. Lefebvre, Br. J. Pharmacol. 2015, 172, 1557¿1573.
[2] A. Danielak, J. L. Wallace, T. Brzozowski, M. Magierowski, Front. Pharmacol. 2021, 12, 758.
[3] F. Aman, M. Hanif, M. Kubanik, A. Ashraf, T. Söhnel, S. M. F. Jamieson, W. A. Siddiqui, C. G. Hartinger, Chem. - A Eur. J. 2017, 23, 4893¿4902.
[4] J. Li, J. Zhang, Q. Zhang, Y. Wang, Z. Bai, Q. Zhao, D. He, Z. Wang, J. Zhang, Y. Chen, Bioorganic Med. Chem. 2019, 27, 115071.