Preparation of Maleimide-Based Enediynes with Propargyl Ester for Efficient Tumor Cell Suppression

Acyclic enediynes are much easier to be synthesized comparing to natural or synthetic cyclic enediynes. However, the conditions for their thermal reactions to produce free radicals through Bergman cyclization (BC) are typically demanding, limiting their applications as antitumor agents. On the other hand, the acyclic compounds with enyne-allene structures prone to proceed through Myers-Saito cyclization (MCS) under much milder conditions. Therefore, it is vital to design acyclic enediynes which can permit propargyl-allenyl rearrangement and then undergo MSC at low temperature for antitumor applications. In this work, we synthesized a series of maleimide-based enediyne compounds with propargyl ester functionalities. The facile propargyl-allenyl tautomerization assisted by the maleimide group enabled the formation of enyne-allene structures and the subsequent occurrence of MSC. The generation of free radicals, which further raised the reactive oxygen species level in physiological environments, was confirmed by electron paramagnetic resonance analysis. The highly reactive radicals showed excellent DNA-cleaving ability as confirmed with DNA gel electrophoresis. In addition, this kind of acyclic enediynes effectively inhibited the proliferation of HeLa cells with half inhibition concentration down to submicromolar level, comparable or even superior to many clinically used antitumor agents, showing promising application aspect.