Authors
Yixuan Zhang, Hong Wang, Feilong Zhou, Guangming Wang, Meilin Zhu, Fangtian Fan, Xinhua Liu
Published in
European journal of medicinal chemistry. Volume 318. Pages 119163. Jul 22, 2026. Epub Jul 22, 2026.
Abstract
Camptothecin (CPT) and its derivatives are clinically validated topoisomerase I (Topo I) inhibitors with broad-spectrum antitumor activity. Based on the stabilization of the covalent DNA-Topo I complex, modification at the 10-position of the CPT scaffold represents a promising strategy to enhance binding affinity. Herein, the rational design, synthesis, and biological evaluation of novel 10-substituted CPT derivatives guided by molecular dynamics (MD) simulations are presented. A total of 45 derivatives were synthesized and evaluated for their antiproliferative activity against three human cancer cell lines (A549, HCT116, HepG2). Structure-activity relationship (SAR) studies demonstrated that the carbonylmethylene linker and 3-methoxy-4-methylphenyl substitution afforded optimal potency. The most promising compound C6 showed exceptional cytotoxicity against HCT116 cells with an IC50 value of 0.001 μM, 16-fold more potent than that of compound SN-38. Mechanistic studies confirmed that C6 induced S-phase cell cycle arrest and apoptosis in HCT116 cells, suppressed cell migration and invasion, and downregulated Topo I protein expression in a concentration-dependent fashion. Furthermore, compound C6 exhibited significant in vivo antitumor efficacy in an HCT116 xenograft model with a favorable safety profile. Pharmacokinetic evaluation in rats confirmed moderate absolute bioavailability and a reasonable half-life. Collectively, compound C6 was identified as a potent Topo I inhibitor with promising antitumor activity.
PMID:
42497470
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.
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