Antitumor activity of topoisomerase I targeted by camptothecin 7-propionyl derivatives against ampullary carcinoma.

Ampullary carcinoma (AC) is a rare cancer in the world, it is characterized by less attention, fewer models, no in-depth studies, and almost no drug research related to the treatment. Camptothecin (CPT), as the plant anticancer drug, has been the focus of research for a long time. It is a promising strategy to modify and optimize the CPT skeleton to obtain anticancer chemical entities showing low-toxicity and high-efficiency effects. In this study, the site 7 of CPT was modified to obtain a series of CPT derivatives, and their anti-AC activity was evaluated. Among them, compound XSJ110 inhibited the proliferation of DPC-X3 cells (IC50 = 0.133 ± 0.008 μM), which was significantly better than CPT (IC50 = 9.147 ± 0.159 μM). XSJ110 effectively inhibited the proliferation of DPC-X3 cells by inhibition of topoisomerase I (Topo I) activity. XSJ110 arrested cell cycle at G0/G1 phase, induced cell apoptosis, inhibited the proliferation of AC organoids and induced DNA damage. In vivo acute toxicity studies demonstrated that XSJ110 exhibited low toxicity, with no lethality or significant weight loss observed even at high doses. Collectively, these findings indicated that XSJ110 possesses superior activity coupled with favorable safety profiles, which is worthy of further clinical evaluation.