2. Academic Validation
  3. Rational design and synthesis of flavonolactam derivatives as potent topo I inhibitors with antitumor activity

Rational design and synthesis of flavonolactam derivatives as potent topo I inhibitors with antitumor activity

  • Eur J Med Chem. 2026 Jul 5:311:118804. doi: 10.1016/j.ejmech.2026.118804.
Xiaoyu Shi 1,  Yaoguang Huang 1,  Xupeng Yang 1,  Mingyu Wang 1,  Xu Han 1,  Shengnan Yang 1,  Wenjing Li 1,  Jingming Jia 2,  Anhua Wang 3,  Shaohui Huang 4
Affiliations

Affiliations

  • 1 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
  • 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: [email protected].
  • 3 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China. Electronic address: [email protected].
  • 4 Department of Head and Neck Surgery, Stomatological Hospital of China Medical University, Shenyang, 110002, People's Republic of China. Electronic address: [email protected].
PMID: 41934689 DOI: 10.1016/j.ejmech.2026.118804
Abstract

Targeting Topoisomerase I (Topo I) remains a pivotal strategy for the treatment of colorectal Cancer (CRC). In this study, we rationally designed and synthesized a series of flavonolactam derivatives and systematically evaluated their biological activities and mechanisms of action. Among these, compounds NL-26 and NL-28 exhibited potent inhibitory effects on Topo I activity, arresting the cell cycle at the G2/M phase and inducing Apoptosis to suppress tumor cell proliferation. Notably, NL-26 displayed the most potent Topo I inhibitory activity, which was comparable to that of the reference inhibitor camptothecin (CPT). In vivo pharmacokinetic studies revealed that NL-26 possesses a desirable profile, characterized by an AUC0-t of 1979.7 h ng/mL and a t1/2 of 3.7 h. Furthermore, NL-26 demonstrated robust antitumor efficacy in HCT116 xenograft models, achieving a tumor growth inhibition (TGI) of 55.1%. Collectively, these findings identify NL-26 as a promising lead compound and validate the flavonolactam scaffold as a privileged template for the development of next-generation Topo I-targeting therapeutics.

Keywords

CPT; CRC; Flavonolactam derivatives; Topo I.

Figures
Products