Camptothecin 20(S)-sulfonyl amidine derivative inhibits gastric cancer cell proliferation by targeting topoisomerase I to trigger the DNA damage-apoptosis cascade.

Gastric cancer remains a major global health burden, necessitating innovative breakthroughs in effective treatment strategies. Camptothecin, as a plant-derived anticancer agent, has long been a focus of research. Structural modification and optimization of the camptothecin core scaffold represent a highly promising approach for developing novel anticancer compounds, characterized by high efficacy and low toxicity. This study modified the C20 position of CPT, successfully synthesizing a series of novel 20(S)-sulfonyl amidine derivatives. Among these, XSJ151 and XSJ152 exhibited superior anti-gastric cancer activity. In AGS cells, the IC₅₀ values for XSJ151 and XSJ152 were 0.088 ± 0.002 μM and 0.096 ± 0.012 μM, respectively. In MGC803 cells, the IC₅₀ values were 0.592 ± 0.147 μM and 0.599 ± 0.133 μM, respectively. Mechanistic studies revealed that XSJ151 and XSJ152 exert their effects by targeting topoisomerase I, stabilizing the DNA-Topo I covalent complex, and inducing DNA double-strand breaks. This DNA damage activates the p53-p21 signaling pathway, specifically modulates the expression of cyclins, leading to G2/M phase cell cycle arrest, and disrupts the dynamic balance of Bcl-2 family proteins, thereby triggering the apoptotic program in gastric cancer cells. In summary, through the dual modulation of Topo I activity and the DNA damage response, XSJ151 and XSJ152 achieve selective targeting effects against gastric cancer cells.