Design and synthesis of dual mitochondria-targeted biguanide derivatives as potential anticancer agents

Biguanides have been reported to have significant antitumor activity. However, the necessity of high therapeutic doses to manifest antitumor activity hinders their clinical translation. Mitochondrion targeting strategy using delocalized lipophilic cations as carriers is a promising way to improve the antitumor effect of small molecules and to reduce toxicity. Herein, we designed and synthesized a series of dual mitochondria-targeted biguanide derivatives using triphenylphosphonium and guanidinium as carriers. Among these, compound 7f showed an IC₅₀ value of 6.3 μM against J82 cells, a potency approaching that of cisplatin (IC₅₀ = 5.7 μM) with high selectivity (SI_{IC50SV-HUC-1/IC50}J82 > 15.9) towards J82 cells. Moreover, compound 7f accumulated in mitochondria and disordered the function of mitochondria by changing mitochondrial morphology, decreasing the production of ATP, increasing the production of ROS and decreasing MMP. Additionally, compound 7f inhibited the colony formation and migration of J82 cells and induced J82 cells apoptosis and ferroptosis. This work provides a potential candidate drug for bladder cancer therapy.