Novel A-ring cleaved glycyrrhetinic acid derivatives: Synthesis and evaluation of antiproliferative activity

Cancer is a leading cause of death worldwide. Its global incidence continues to rise due to the aging and growth of the world population. Plants have been a major source of highly effective conventional drugs for cancer treatment and nowadays they play an important role as a source of leads for the development of potential new agents. The plant-derived triterpenoids are proving to be interesting leading compounds as reported in many scientific papers emerging in this field.

Glycyrrhetinic acid (GA) is the hydrolyzed metabolite of glycyrrhizin, a major pentacyclic triterpenoid saponin obtained from the roots of licorice, that has been shown to inhibit tumor initiation and proliferation in several cancer cell lines. Nevertheless, it lacks potency and selectivity as an antitumor agent. In this regard, a series of novel GA derivatives was synthesized via the opening of its A-ring, along with the coupling of an amino acid. The antiproliferative activity of the derivatives was evaluated against a panel of nine human cancer cell lines. Compound 17 was the most active compound, with an IC₅₀ of 6.1 µM on Jurkat cells, which is 17-fold more potent than its parental compound, and was up to 10 times more selective toward that cancer cell line. Further biological investigation in Jurkat cells indicated that compound 17 may act through arresting cell cycle progression at the S phase and inducing of apoptosis.