Synthesis and biological evaluation of novel hydrogen sulfide releasing glycyrrhetic acid derivatives

A series of hybrids, which are composed of glycyrrhetic acid (GA) and slowly hydrogen sulfide-releasing donor ADT-OH, were designed and synthesized to develop anticancer and anti-inflammatory agents. Most of the compounds, whose inhibitory rates were comparable to or higher than those of GA and aspirin, respectively, significantly inhibited xylene-induced ear edema in mice. Especially, compound V₄ exhibited the most potent inhibitory rate of 60.7%. Furthermore, preliminary structure–activity relationship studies demonstrated that 3-substituted GA derivatives had stronger anti-inflammatory activities than the corresponding 3-unsubstituted GA derivatives. In addition, anti-proliferative activities of compounds V_1?9 were evaluated in three different human cancer cell lines. Compound V₄ showed the most high potency against all three tumor cell lines with IC₅₀ values ranging from 10.01?μM in Hep G2 cells to 17.8?μM in MDA-MB-231 cells, which were superior to positive GA.