Design, synthesis, and activity evaluation of Asiatic acid derivatives as Survivin inhibitors

Abstract

Asiatic acid, a triterpenoid isolated from Centella asiatica, putatively functions through inhibition of Survivin-a member of the Inhibitor of Apoptosis Protein (IAP) family that modulates tumor survival. Taking GDP366 and LQZ-7I, two Survivin inhibitors of preclinical stage, as reference compounds, two classes of novel Asiatic acid derivatives (24 compounds in total) were designed and synthesized. These compounds demonstrated favorable docking capabilities and binding modes with the three-dimensional crystal structure of Survivin. The MTT assay demonstrated that these compounds exhibited anti-proliferative effects against A549 and MCF-7 cell lines, with compounds I₃, I₉, II₃, II₅, and II₁₂ showing potency comparable to the positive control drug. Furthermore, Western blot analysis revealed that compound II₃ dose-dependently reduced Survivin protein levels. Compound II₃ provides a valuable reference for further research on Survivin inhibitors.

Keywords: Antitumor activity; Asiatic acid derivatives; Molecular docking; Survivin inhibitors.