Syntheses, toxicities and anti-inflammation of H2S-donors based on non-steroidal anti-inflammatory drugs

Three series of H₂S donors based on NSAIDs were synthesized and characterized by ¹H-NMR, IR and ESI-HRMS. The H₂S-release abilities of all compounds were evaluated in the presence of TECP or cysteine. The results show all compounds were fast H₂S-releasers, and their half-lives were in range of 0-20 min. Under the same condition, H₂S released from compound 9 was more than any other compounds. In cytotoxicity aspect, all compounds but 1 and 2 displayed much lower toxicities to both LO2 and HepG2 cell lines, and the IC₅₀ values of most compounds were over 800 μM. Compounds 1 and 2 had a stronger anti-proliferative activity to both cell lines, but they displayed lower toxicities to LO2 than to HepG2. Based on the cytotoxicity, the developmental toxicities of the compounds were assessed using zebrafish embryos. The results show all tested compounds 2, 9 and 15 had effects on the mortality, hatching rate and spontaneous movements of zebrafish embryos, and caused embryos teratogenesis; and the compounds had dose-dependent toxicities to both embryonic and larval zebrafish. In addition, all compounds had a better anti-inflammatory activity. In the test of anti-inflammatory activities, the tested compounds all reduced the levels of intracellular nitrite and pro-inflammatory cytokines (TNF-α, COX-2), increased the levels of anti-inflammatory cytokines (IL-10, HO-1). All these suggest these H₂S donors based on NSAIDs have a potential to be a candidate medicine.

Anti-inflammatory; H(2)S-donors; NSAIDs; Toxicity.