Synthesis and in vivo screening of isosteviol derivatives as new cardioprotective agents

Isosteviol, an ent-beyerane diterpenoid, has been repeatedly reported to possess potent cardioprotective activity. With the aim of discovering new cardioprotective derivatives from isosteviol, 47 compounds, including 40 new ones, were synthesized and evaluated in vivo using the easy-handling and efficient zebrafish model. The structure-activity relationship of this type of compounds was thus discussed. Of these compounds, new derivative 15d exhibited the most pronounced efficacy in vivo. Our results indicated that 15d could effectively prevent the doxorubicin-induced morphological distortions and cardiac dysfunction in zebrafish. Its cardioprotective activity is much better than that of isosteviol, and Levosimendan in zebrafish model. The molecular mechanism underlying in H9c2 cells indicated that 15d protected cardiomyocyte death and damage through inhibiting the reactive oxygen species overproduction, restoring the mitochondrial membrane potential and maintaining morphology of mitochondrial. Thus, 15d merits further development as a potential cardioprotective clinical trial candidate. The present study is a successful example to combine synthesis, structure-activity relationship study and in vivo screening to effectively discover new cardioprotective agents from isosteviol.