Design,Synthesis And Antitumor Activity Of Lipophilic Cations Containing Dichloroacetates

In this research group,we synthesized a series of quaternary ammonium salts of emodin and aloe-emodin long chain carbons.We found that these lipophilic cations exhibited better anticancer activity than traditional lipophilic cations such as rhodamine.they can not only be enriched in cancer cell mitochondria like rhodamine,but also contain quinone structures that can trap electrons leaking from the mitochondrial respiratory chain and transfer them to oxygen to form reactive oxygen species(ROS).ROS can damage the mitochondrial function of cancer cells in many ways,thereby destroying the mitochondrial energy supply pathway of cancer cells.In order to facilitate the covalent binding of lipophilic cations and glycolysis inhibitors,1,4-and 1,8-dihydroxyanthraquinones were selected as the leading compounds,long-chain quaternary ammonium salts were lipophilic cations.Chloroacetic acid is a glycolysis inhibitor,and finally the following drug synthesis and anti-cancer activity tests were performed:A series of 1,4(8)-dihydroxyanthraquinone quaternary ammonium salts and quaternary phosphonium salts were synthesized.The anticancer activity of these compounds showed good anticancer activity by test results.We know that steroidal lipophilic cations can easily kill cancer cells by destroying the mitochondrial energy supply pathway,which is in line with the anticancer drug design ideas.A series of dichloroacetate esters of 1,4-dihydroxyphosphonium quaternary ammonium salt and quaternary phosphonium salt was synthesized.The drug is easily hydrolyzed in the cell to quaternary hydroxyarsinium salt and dichloroacetic acid.Anti-cancer activity test results show that their anti-cancer activity is slightly higher than the corresponding compounds without dichloroacetate,indicating that the idea of combining lipophilic cations with glycolytic inhibitors is feasible,which still needs to be further improved.Dichloroacetic acid ester compounds of 1,4(8)-dihydroxyanthraquinone were synthesized and the activity test results showed that these compounds had almost no antitumor effect,indicating that the combination of a glycolysis inhibitor and anthraquinone cannot improve anti-cancer activity.However,it was found that there is tautomerism in the unilateral dichloroacetate product of 1,8-dihydroxyanthraquinone.This article has conducted in-depth research and interpretation of this phenomenon based on nuclear magnetic spectrum data and quantum chemical calculations.