Design, synthesis, and biological evaluation of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives as TRPM4 inhibitors for the treatment of prostate cancer

Le Niu; Huina Liu; Xiaomei Li; Lin Wang; Hui Hua; Qiaofeng Cao; Qiuping Xiang; Ting Cai; Dongsheng Zhu

doi:10.1016/j.bmc.2023.117584

Design, synthesis, and biological evaluation of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives as TRPM4 inhibitors for the treatment of prostate cancer

Bioorg Med Chem. 2024 Jan 15:98:117584. doi: 10.1016/j.bmc.2023.117584. Epub 2023 Dec 28.

Authors

Le Niu¹, Huina Liu², Xiaomei Li², Lin Wang³, Hui Hua², Qiaofeng Cao³, Qiuping Xiang², Ting Cai⁴, Dongsheng Zhu⁵

Affiliations

¹ Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo No.2 Hospital, Ningbo, 315010, China; Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, and Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
² Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo No.2 Hospital, Ningbo, 315010, China.
³ Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, and Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
⁴ Guoke Ningbo Life Science and Health Industry Research Institute, Ningbo No.2 Hospital, Ningbo, 315010, China. Electronic address: tingcai@ucas.ac.cn.
⁵ Department of Urology, the Second Affiliated Hospital of Nanjing Medical University, and Department of Medicinal Chemistry, School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China. Electronic address: zhuds@njmu.edu.cn.

PMID: 38168629
DOI: 10.1016/j.bmc.2023.117584

Abstract

Transient receptor potential melastatin 4 (TRPM4) is considered to be a potential target for cancer and other human diseases. Herein, a series of 2-(naphthalen-1-yloxy)-N-phenylacetamide derivatives were designed and synthesized as new TRPM4 inhibitors, aiming to improve cellular potency. One of the most promising compounds, 7d (ZX08903), displayed promising antiproliferative activity against prostate cancer cell lines. 7d also suppressed colony formation and the expression of androgen receptor (AR) protein in prostate cancer cells. Furthermore, 7d can concentration-dependently induce cell apoptosis in prostate cancer cells. Collectively, these findings indicated that compound 7d may serve as a promising lead compound for further anticancer drug development.

Keywords: Cellular potency; Drug design; Prostate cancer; TRPM4.

MeSH terms

Antineoplastic Agents*
Cell Line, Tumor
Cell Proliferation
Drug Design
Drug Screening Assays, Antitumor
Humans
Male
Molecular Structure
Prostatic Neoplasms* / drug therapy
Prostatic Neoplasms* / metabolism
Structure-Activity Relationship
TRPM Cation Channels*

Substances

Antineoplastic Agents
TRPM4 protein, human
TRPM Cation Channels