Design, synthesis, and in vitro and in vivo anticancer activity of mitochondrial targeted ferulic acid derivatives

Abstract

Ferulic acid, a natural active ingredient, mainly exerts antitumor activity by disrupting mitochondrial function and has the advantages of low toxicity and high efficiency. However, poor water solubility and low bioavailability have limited its further development. This article uses triphenylphosphonium salts (TPP⁺) with both amphiphilicity and tumor mitochondrial targeting to modify the structure of ferulic acid, and designs and synthesizes a series of TPP⁺ conjugated ferulic acid derivatives. Compared with ferulic acid, the water solubility, mitochondrial targeting and antitumor activity of TPP-conjugated ferulic acid derivatives were significantly enhanced. Among them, compound I₄ showed excellent anti-cervical cancer activity, mainly by reducing ATP synthesis and promoting ROS production, thus activating mitochondria-mediated apoptotic signaling to induce apoptosis in HeLa cells. I₄ also inhibited HeLa cell migration and caused cell cycle arrest to the G0/G1 phase. In the mouse model, the effective therapeutic concentration of I₄ was 2.5 mg/kg and the LD₅₀ was 98.11 mg/kg. I₄ demonstrated similar anti-cervical cancer activity, a larger therapeutic window and a higher safety profile than with the first-line anticancer agent cisplatin.

Keywords: Antitumor activity; Ferulic acid; Mitochondrial targeted; TPP+.