Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase I and II dual inhibitors for the therapy of liver cancer.

To explore novel topoisomerase inhibitors with high activity and druggability, 3-aryl isoquinoline alkaloids based on the corydamine modification and preliminary SARs of isoquinoline alkaloids in our previous works were re-designed. Currently, the design strategy is mainly revolved around the rigidity and flexibility of the molecular side chain and the molecular size. Consequently, not only the activity and druggability of the compound could be further improved, also the mechanism behind could been discovered. In vitro pharmacological studies, the outstanding nature with the excellent activity and the researchable depth of azepane-substituted compound 7 has been found through the vitro cytotoxicity test (IC ₅₀  = 1.93 μM in HuH7 cells and 2.10 μM in LM9 cells) and topoisomerase test. It was found that compound 7 had dual inhibitory effects on topoisomerase I and II, and its inhibitory activity on topoisomerase II is stronger than the positive drug etoposide. From the perspective of molecular docking, it had been verified that compound 7 could insert between DNA base pairs, which was consistent with the results of the DNA unwinding experiment. And the comet experiment confirmed 7 caused DNA damage. Meanwhile, compound 7 could inhibit cell proliferation, invasion and migration, and induce apoptosis by inhibiting PI3K/Akt/mTOR signaling pathway. Therefore, this study may lay a foundation for the discovery of 3-arylisoquinoline compounds with anti-liver cancer potential.
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