A new series of glycyrrhetinic acid derivatives has been synthesized via the introduction of different heterocyclic rings conjugated with an α,β-unsaturated ketone in its ring A. These new compounds were screened for their antiproliferative activity in a panel of nine human cancer cell lines. Compound was the most active derivative, with an IC of 1.1 µM on Jurkat cells, which is 96-fold more potent than that of glycyrrhetinic acid, and was 4-fold more selective toward that cancer cell line. Further biological studies performed in Jurkat cells showed that compound is a potent inducer of apoptosis that activates both the intrinsic and extrinsic pathways.