3‐Deoxy‐3β‐syringoylamino‐betulinic acid Reduces Breast Tumor Growth and Lung Colonization, With Associated Downregulation of the RAS/RAF/MEK/ERK Pathway

Betulinic acid (BA) and its structural derivatives/analogs exhibit diverse biological activities particularly antitumor property, which has established them as attractive research topics in recent years. In the present work, 33 3‐substituted BA derivatives comprising 13 previously unreported ones were synthesized. Among them, a syringoyl analog (3‐deoxy‐3β‐syringoylamino‐betulinic acid [DSABA]) showed significantly enhanced cytostatic activity against specific tumor cell lines. Further in vitro antitumor evaluation revealed that DSABA induced cell death and G 0 /G 1 phase arrest, as well as inhibited the migration and invasion, of two breast cancer cell lines, and the in vivo antitumor efficacy was subsequently validated in an orthotopic autograft mouse model. Mechanistically, DSABA may exert its antitumor effect by modulating the RAS/RAF/MEK/ERK signaling pathway, as evidenced by a series of in vitro and in vivo experiments. In conclusion, this study has identified DSABA as a promising antitumor candidate, providing a foundation for the future investigation of related structural analogs.