Design, synthesis and anti-tumor activity of novel benzothiophenonaphthalimide derivatives targeting mitochondrial DNA (mtDNA) G-quadruplex

A series of new naphthalimide derivatives, benzothiophenonaphthalimides (7a-7g, 8a-8g), were designed and synthesized, of which compounds 8a-8g are hydrochloride salts of corresponding compounds 7a-7g. All compounds presented different anti-tumor activities for tumor cells tested by the CCK-8 assay. In particular, compound 7c displayed the strongest anti-tumor activity with an IC50 value of 0.59 +/- 0.08 mu M and the best selectivity for HepG2 cells. At the same time, it was observed that 7c could induce HepG2 cell apoptosis, hinder cancer cell migration and arrest the cell cycle at the G2/M phase. Further mechanism studies revealed that 7c selectively induced a G-rich HRCC DNA sequence in the mitochondria to form a G-quadruplex structure (G4) and stabilized it, which mediated the decrease in mitochondrial membrane potential and the production of reactive oxygen species, causing mitochondrial dysfunction. Finally, this led to proliferative inhibition and apoptosis of cancer cells and protective autophagy by promoting the expression of p-Erk1/2. The in vivo experimental results indicated that the compound 8c as a salt of 7c showed significant in vivo anti-tumor efficacy in the HepG2xenograft mouse model with a tumor growth inhibition rate of 51.4% at a dose of 15 mg/kg. These results suggest that 7c possesses a different anti-tumor mechanism from the previous main reported mechanism of naphthalimide derivatives, which targets the nucleus. In brief, 7c has good anti-tumor activity in vitro and in vivo and may act as a leading compound in development of drugs against liver cancer.

Automated summary

A series of new naphthalimide derivatives have been designed and synthesized, among which compound 7c displayed the strongest anti-tumor activity with the best selectivity for HepG2 cells. It was found that 7c induced HepG2 cell apoptosis, hindered cancer cell migration, and arrested the cell cycle at the G2/M phase. Mechanism studies revealed that 7c selectively induced a G-rich HRCC DNA sequence in the mitochondria to form a G-quadruplex structure, causing mitochondrial dysfunction and ultimately leading to proliferative inhibition and apoptosis of cancer cells.