A ClO− triggered phenol derivative that induced mitochondrial damage for tumor therapy

Abstract

Mitochondrial proteome is comprised of more than 1000 different proteins, whose synergistic ensured the integrity and homeostasis of the proteome, thus provided a guarantee for the rapid and accurate regulation of mitochondrial activities. Based on this, mitochondrial proteins have become a compelling focus for the treatment and intervention of tumors. Phenol derivatives exhibited superior protein binding capacities and showed efficient antitumor activity through their interaction with specific target proteins. Selective delivery of phenol derivatives to the mitochondria can be achieved through lipophilic cations modification. However, lack stability of phenol hydroxyl group under physiological conditions, taken into account, an ClO−-activated mitochondria-targeting prodrug RCl was constructed in the present study. RCl was delivered into the mitochondria and rapidly released ROH when struck by the presence of high ClO− levels, the released ROH act on mitochondrial proteins, resulting in mitochondrial dysfunction, ATP inhibition and apoptosis of cancer cells. The vivo antitumor experiment results showed that the RCl displayed significantly antitumor efficacy in vivo which provided the rationale to the further development of anticancer drugs targeting mitochondria.