Author:
Wang Sibei,Zhang Qi,Peng Maoqin,Xu Jing,Guo Yuanqiang
Abstract
α-Mangostin, a natural xanthone, was found to have anticancer effects, but these effects are not sufficient to be effective. To increase anticancer potential and selectivity, a triphenylphosphonium cation moiety (TPP) was introduced to α-mangostin to specifically target cancer cell mitochondria. Compared to the parent compound, the cytotoxicity of the synthesized compound 1b increased by one order of magnitude. Mechanistic analysis revealed that the anti-tumor effects were involved in the mitochondrial apoptotic pathway by prompting apoptosis and arresting the cell cycle at the G0/G1 phase, increasing the production of reactive oxygen species (ROS), and reducing mitochondrial membrane potential (Δψm). More notably, the antitumor activity of compound 1b was further confirmed by zebrafish models, which remarkably inhibited cancer cell proliferation and migration, as well as zebrafish angiogenesis. Taken together, our results for the first time indicated that TPP-linked 1b could lead to the development of new mitochondrion-targeting antitumor agents.
Funder
National Natural Science Foundation of China
Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, Hainan Normal University
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
Reference39 articles.
1. Strategies for targeted drug delivery in treatment of colon cancer: Current trends and future perspectives. Drug Discov;Banerjee;Today,2017
2. Small molecules in targeted cancer therapy: Advances, challenges, and future perspectives;Zhong;Sig. Transduct. Target Ther.,2021
3. Mitochondria-targeted triphenylphosphonium-based compounds: Syntheses, mechanisms of action, and therapeutic and diagnostic applications;Zielonka;Chem. Rev.,2017
4. Mitochondria as the central control point of apoptosis;Desagher;Trends Cell Biol.,2000
5. Luo, Y., Ma, J., and Lu, W. (2020). The significance of mitochondrial dysfunction in cancer. Int. J. Mol. Sci., 21.
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