Betulin Acid Ester Derivatives Inhibit Cancer Cell Growth by Inducing Apoptosis through Caspase Cascade Activation: A Comprehensive In Vitro and In Silico Study

Betulin, or naturally occurring triterpene, possesses promising antiproliferative activity. To further explore this potential, thirty-eight betulin acid ester derivatives modified at the C-28 position were tested for antitumor activities. Four human cancer cell lines, MV4-11 (leukemia), A549 (lung), PC-3 (prostate), MCF-7 (breast) as well as the normal BALB/3T3 (mouse fibroblasts) cell line were examined using MTT and SRB assays. A few derivatives exhibited strong antiproliferative activity with IC50 values between 2 and 5 µM. Subsequent mechanistic studies revealed that some derivatives induced apoptosis by inducing caspase-3/7 activity. A strong structure–activity correlation of tested compounds has been proposed along with experimental and in silico pharmacokinetic properties.