Methylated and mitochondria-targeted analogue of resveratrol with inhibition of tumor cell growth

Abstract The mitochondria are the energy and biosynthesis factory and the majority source of reactive oxygen species (ROS). The mitochondria play a vital role in carcinogenesis, so the mitochondria targeting drugs have been the focus of new drug discovery in cancer therapy. In this study, target mitochondrial stilbene compounds A1-A6 are synthesized by introducing lipophilic cationic triphenylphosphonium into the pharmacophore. Intriguingly, the strategy significantly improved the anticancer potential of parent resveratrol. Especially A4 ((E)-Triphenyl(4-(4-(3,4 dimethylstyryl)phenoxy)butyl)phosphoniumiodide) exerted the excellent anticancer activity in HeLa cells. The mechanism study showed that A4 could effectively decrease cyclin D1/cyclin E1 level to arrest the cell cycle in G0/G1, and target the mitochondria to induce apoptosis referring the cross-talk of the decreased ATPase activity, elevated ROS and increased cytosolic Ca2+ to inhibit tumor cell proliferation. Overall, this study is evidence that the target mitochondria drug discovery is an excellent strategy for exploiting the drug potential in cancer therapy.