2. Academic Validation
  3. Discovery of dual inhibitors of topoisomerase I and Cyclooxygenase-2 for colon cancer therapy

Discovery of dual inhibitors of topoisomerase I and Cyclooxygenase-2 for colon cancer therapy

  • Eur J Med Chem. 2022 Oct 5;240:114560. doi: 10.1016/j.ejmech.2022.114560.
Xiaoling Hu 1,  Junfang Li 1,  Honghua Zhang 1,  Quanwei Yu 2,  Yuying Wang 3,  Xuelin Li 4,  Lin Long 4,  Weifan Jiang 5,  Zhen Wang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China.
  • 2 Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan, 610093, China.
  • 3 State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China.
  • 4 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 5 School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 6 School of Pharmacy, Lanzhou University, Lanzhou, 730000, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China. Electronic address: [email protected].
PMID: 35777102 DOI: 10.1016/j.ejmech.2022.114560
Abstract

Novel tolfenamic acid derivatives based on the structure of I-1 were designed and synthesized to improve its poor target inhibition and solubility. Among them, W10 was identified as a potent dual-target inhibitor of Topo I (IC50 = 0.90 ± 0.17 μM) and COX-2 (IC50 = 2.31 ± 0.07 μM) with improved water solubility (32.33 μg/mL). Moreover, W10 also exhibited fairly potent anti-proliferative and pro-apoptosis activity via the mitochondrial pathway, as well as suppressed aberrant NF-κB/IκB activation in colon Cancer cells in vitro. Additionally, W10 possessed favorable pharmacokinetic properties and excellent antitumor effects in vivo. In general, our study has demonstrated the potency of a novel Topo I/COX-2 dual inhibitor, which can potentially be developed into a chemotherapeutic candidate for colon Cancer.

Keywords

Colon cancer; Cyclooxygenase-2; Dual inhibitor; Topoisomerase I; Water solubility.

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