Basic Pharmacological Characterization of EV-34, a New H(2)S-Releasing Ibuprofen Derivative

Gyöngyösi, Alexandra; Verner, Vivien; Bereczki, Ilona; Kiss-Szikszai, Attila; Zilinyi, Rita; Tósaki, Árpád; Bak, István; Borbás, Anikó; Herczegh, Pál; Lekli, István

Background: Cardioprotective effects of H(2)S are being suggested by numerous studies. Furthermore, H(2)S plays a role in relaxation of vascular smooth muscle, protects against oxidative stress, and modulates inflammation. Long-term high-dose use of NSAIDs, such as ibuprofen, have been associated with enhanced cardiovascular risk. The goal of the present work is the synthesis and basic pharmacological characterization of a newly designed H(2)S-releasing ibuprofen derivative. Methods: Following the synthesis of EV-34, a new H(2)S-releasing derivative of ibuprofen, oxidative stability assays were performed (Fenton and porphyrin assays). Furthermore, stability of the molecule was studied in rat serum and liver lysates. H(2)S-releasing ability of the EC-34 was studied with a hydrogen sulfide sensor. MTT (3-(4,5-dimethylthiazol 2-yl)-2,5-(diphenyltetrazolium bromide)) assay was carried out to monitor the possible cytotoxic effect of the compound. Cyclooxygenase (COX) inhibitory property of EV-34 was also evaluated. Carrageenan assay was carried out to compare the anti-inflammatory effect of EV-34 to ibuprofen in rat paws. Results: The results revealed that the molecule is stable under oxidative condition of Fenton reaction. However, EV-34 undergoes biodegradation in rat serum and liver lysates. In cell culture medium H(2)S is being released from EV-34. No cytotoxic effect was observed at concentrations of 10, 100, 500 µM. The COX-1 and COX-2 inhibitory effects of the molecule are comparable to those of ibuprofen. Furthermore, based on the carrageenan assay, EV-34 exhibits the same anti-inflammatory effect to that of equimolar amount of ibuprofen (100 mg/bwkg). Conclusion: The results indicate that EV-34 is a safe H(2)S releasing ibuprofen derivative bearing anti-inflammatory properties.