Design, synthesis and biological evaluation of 3-arylisoquinoline derivatives as topoisomerase IIα inhibitors for the therapy of small cell lung cancer

Abstract

There is a pressing need to search for efficient therapeutic molecular candidates for the treatment of small cell lung cancer (SCLC). Here, we designed a series of 3-arylisoquinoline derivatives by introducing either flexible tertiary amino groups or rigid imidazole rings, aiming to enhance anti-SCCL efficay. Among them, compound 52 with a symmetrical dibutylamine side chain demonstrated a remarkable inhibitory potency on Topoismerase II (Topo II). In vitro studies revealed that 52 exhibited superior inhibitory activity to etoposide against SCLC cells (IC50 = 0.6 μM in NCI-H446 cells and 0.1 μM in NCI-H1048 cells). Molecular docking studies indicated that 52 could intercalate into DNA strands. Comet assays accordingly confirmed it induced DNA damage, which subsequently triggered intrinsic mitochondrial apoptosis. Moreover, 52 effectively attenuated the phosphorylation of the PI3K/Akt/mTOR signaling pathway, which in turn effectively suppressed proliferation, invasion, and migration of SCLC cells. In the NCI-H446 cell-derived xenograft (CDX) model, 52 demonstrated a significant tumor inhibition effect. At a low dose of 2.5 mg/kg, the tumor inhibition rate was 71.58 %, and at a high dose of 5 mg/kg, it reached 88.16 %. In contrast, the positive control etoposide, at a dose of 5 mg/kg, only showed a tumor inhibition rate of 41.77 %, highlighting the superiority of 52. In addition, 52 exhibited a better safety profile in the tested mice. Overall, this study lays a solid foundation for the development of 3-arylisoquinoline compounds as potential anti-SCLC agents.