Abstract
Background: Cardioprotective effects of H2S are being suggested by numerous studies. Furthermore, H2S 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 H2S-releasing ibuprofen derivative. Methods: Following the synthesis of EV-34, a new H2S-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. H2S-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 H2S 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 H2S releasing ibuprofen derivative bearing anti-inflammatory properties.
Highlights
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications worldwide
During therapy with NSAIDs, patients are at risk of gastrointestinal and renal toxicity [2], which have long been known
We have designed a conceptually new H2S releasing derivative, a prodrug containing a relatively stable formaldehyde bis-acylal structural part, which supposedly can be hydrolyzed in physiological conditions by a specific esterase enzyme, releasing thiolacetic acid
Summary
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed medications worldwide. We have designed a conceptually new H2S releasing derivative, a prodrug containing a relatively stable formaldehyde bis-acylal structural part, which supposedly can be hydrolyzed in physiological conditions by a specific esterase enzyme, releasing thiolacetic acid This compound, according to Liu [27], can form hydrogen sulfide in a reaction cascade. This compound, according to Liu [27], can form hydrogen sulfi3doef i1n2 a reaction cascade
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