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

Xiaoling Hu; Junfang Li; Honghua Zhang; Quanwei Yu; Yuying Wang; Xuelin Li; Lin Long; Weifan Jiang; Zhen Wang

doi:10.1016/j.ejmech.2022.114560

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. Epub 2022 Jun 23.

Authors

Xiaoling Hu¹, Junfang Li¹, Honghua Zhang¹, Quanwei Yu², Yuying Wang³, Xuelin Li⁴, Lin Long⁴, Weifan Jiang⁵, Zhen Wang⁶

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: jiangwf@usc.edu.cn.
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: zhenw@lzu.edu.cn.

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.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / 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
Topoisomerase I Inhibitors / pharmacology
Topoisomerase I Inhibitors / therapeutic use
Topoisomerase Inhibitors / pharmacology

Substances

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