Synthesis of 3- O-Acetyl-11-keto-β-boswellic Acid (AKBA)-Derived Amides and Their Mitochondria-Targeted Antitumor Activities

In this study, we designed and synthesized a series of amide and mitochondria-targeted derivatives of 3-O-acetyl-11-keto-β-boswellic acid (AKBA), using an ethylenediamine moiety as the linker. Among them, compound 5e, a mitochondria-targeting derivative, demonstrated significantly enhanced antitumor activity compared to the parent compound AKBA.

Compound 5e induced pronounced vacuolization in A549 lung cancer cells and triggered the production of reactive oxygen species (ROS) in a time- and dose-dependent manner. Although the antioxidant N-acetylcysteine (NAC) effectively reduced ROS levels, it failed to prevent the vacuolization and cell death caused by 5e, suggesting that 5e’s cytotoxic effects are not solely ROS-dependent.

Mechanistic studies revealed that 5e led to the abnormal opening of the mitochondrial permeability transition pore (MPTP) and a decrease in mitochondrial membrane potential, indicating mitochondrial dysfunction. Additionally, 5e induced cell cycle arrest at the G0/G1 phase without triggering apoptosis.

Conclusion:
Compound 5e exhibits superior antiproliferative activity through a distinct mechanism involving mitochondrial disruption, ROS generation, and non-apoptotic cell death, positioning it as a promising candidate for cancer therapy based on novel modes of action.