Design, Synthesis and Bioactive Evaluation of Topo I/c-MYC Dual Inhibitors to Inhibit Oral Cancer via Regulating the PI3K/AKT/NF-κB Signaling Pathway

This is the authors' abstract. We don't add key points for this paper.

The significantly rising incidence of oral cancer worldwide urgently requires the identification of novel, effective molecular targets to inhibit the progression of malignancy. DNA topoisomerase I (Topo I) is a well-established target for cancer treatment, and many studies have shown that different cancer cell genes could be targeted more selectively with one type of Topo I inhibitor. In this report, a new scaffold pyridothieno[3,2-c]isoquinoline 11,11-dioxide was designed via the combination of the key fragment or bioisoster of Topo I inhibitor azaindenoisoquinolines and G-quadruplex binder quindoline. Thirty-two target derivatives were synthesized, among which compounds 7be, with potent Topo I inhibition, exhibited effective antiproliferative activity against Cal27, one of the oral cancer cell lines highly expressing Topo I protein. Further studies indicated that 7be could also inhibit the activation of PI3K/AKT/NF-κB pathway and downregulate the level of c-MYC, repress the colony formation and the migration of Cal27 cells and trigger apoptosis and autophagy. Molecular docking indicated that 7be could interact with the complex of Topo I and DNA via a mode similar to the indenoisoquinolines. The results of the Cal27 xenograft model confirmed that 7be exhibited promising anticancer efficacy in vivo, with tumor growth inhibition (TGI) of 64.7% at 20 mg/kg.