Synthesis, Biological Evaluation and Action Mechanism Study of New Mitochondria-targeted Curcumin Derivative as Potential Antitumor Drugs.

Abstract

Mitochondria have emerged as important targets in cancer therapy due to their key role in regulating energy supply, maintaining redox homeostasis, and intrinsic apoptosis. Curcumin (CUR) has shown promise in inhibiting the proliferation and metastasis of cancer cells by inducing apoptosis and arresting cell cycle. Butthe clinical application of CUR has been limited by its low stability and poor tumor selectivity. The novel mitochondria-targeted curcumin derivatives were synthesized through the unilateral coupling (CUR-T) or bilateral coupling (CUR-2T) of curcumin's phenolic hydroxyl groups with triphenyl phosphorus via ester bond. The aim was to achieve better stability, higher tumor selectivity, and stronger curative efficacy. The results of stability and biological experiments indicated that both stability and cytotoxicity were arranged in descending order of CUR-2T > CUR-T > CUR. In ovarian cancer cells (A2780 cells), CUR-2T showed well-defined preferential selectivity towards cancer cells and exhibited efficient anticancer efficacy due to its superior mitochondria accumulation ability. Subsequently, the mitochondrial redox balance was disrupted, accompanied by increased ROS levels, decreased ATP levels, dissipated MMP, and increased G0/G1 phase arrest, leading to a higher apoptotic rate.