In silico identification and biological evaluation of newly synthetic hinokiflavone derivatives as multi-kinase inhibitors with preferential Aurora A activity for ovarian cancer therapy.

Abstract

Aurora A kinase overexpression has been implicated in ovarian cancer progression, highlighting its potential as a therapeutic target. In this study, we performed structure-based virtual screening of our proprietary natural product database, identifying hinokiflavone (HNK) as a novel Aurora A inhibitor. Kinase profiling assays revealed that HNK exhibits multi-target inhibitory activity, with preferential potency against Aurora A and B. We developed the first efficient total synthesis of HNK derivatives featuring a key Chan-Lam coupling reaction. Based on the different positions of methoxy and hydroxyl groups in the structure of HNK and its derivatives, we also compared their molecular docking simulation and molecular dynamics simulation, and found that as the number of hydroxyl groups increased, the activity of inhibiting Aurora A gradually increased. The retention of hydroxyl groups at specific positions plays a crucial role in the activity of HNK. The aforementioned research provides a preliminary theoretical foundation for a subsequent structural modification.