C‐28 esterification enhances the cytotoxicity of madecassic acid derivatives against HepG2 and KB cells

Madecassic acid (MA), a pentacyclic triterpenoid isolated from Centella asiatica , exhibits a broad spectrum of biological activities. Therefore, chemical structure modifications are necessary to develop new agents with improved anticancer potency. In this study, sixteen novel madecassic acid derivatives were synthesized via structural modifications involving either esterification or amidation at C‐28, combined with the A‐ring contraction as well as a tetrahydrofuran‐fused moiety. The synthesized structures were elucidated by analysis of their NMR and HRMS spectra. All new derivatives were tested in vitro for cytotoxicity against human oral carcinoma (KB) and human hepatocellular carcinoma (HepG2) using the MTT assay. Among them, the C‐28 ester derivatives 3 , 6 , and 9 exhibited potent cytotoxic activity in both HepG2 and KB cell lines, with values of IC 50 ranging from 5.25 to 6.26 µM. Notably, compound 9 emerged as the most potent analogue, with IC 50 values of 5.33 µM (KB) and 5.25 µM (HepG2). In contrast, derivatives with a five‐membered A‐ring, an α,β ‐unsaturated aldehyde, and acetylation at C‐6 and C‐23 exhibited decreased cytotoxic activity compared to their precursors. These findings suggest that esterification at C‐28 significantly increases cytotoxicity, whereas A‐ring modification may decrease its activity.