Improved anti-tumor activity of fluorinated camptothecin derivatives 9-fluorocamptothecin and 7-ethyl-9-fluorocamptothecin on hepatocellular carcinoma by targeting topoisomerase I.

[Display omitted] • Design and synthesis of two new fluorinated CPT derivatives, 9-fluorocamptothecin ( A1 ) and 7-ethyl-9-fluorocamptothecin ( A2 ). • Compounds A1 and A2 have effective activities against six human cancer cell lines in vitro , with IC 50 values ranging from 0.12 μM to 0.77 μM and 0.006 μM to 0.25 μM. • Compounds A1 and A2 exhibit enhanced anti-tumor activity in both primary and xenograft HCC mouse models compared to topotecan. • Compounds A1 and A1 not only inhibit enzymatic activity of topoisomerase I, but also promote its degradation, thus playing an anti-tumor role. Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin ( A1 ) and 7-ethyl-9-fluorocamptothecin ( A2 ), in this study. In vitro , A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo , A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings. [ABSTRACT FROM AUTHOR]