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

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.

• Authors: Xiaoling Hu, Junfang Li, Honghua Zhang, Quanwei Yu, Yuying Wang, Xuelin Li, Lin Long, Weifan Jiang, Zhen Wang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 240 Pg. 114560 (Oct 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 35777102 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Topoisomerase I Inhibitors
• Topoisomerase Inhibitors
• Cyclooxygenase 2
• DNA Topoisomerases, Type I

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms (drug therapy)
• Cyclooxygenase 2 (metabolism)
• DNA Topoisomerases, Type I (metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Humans
• Molecular Structure
• Structure-Activity Relationship
• Topoisomerase I Inhibitors (chemistry, pharmacology, therapeutic use)
• Topoisomerase Inhibitors (pharmacology)