Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer

Lijuan Ding; Feng Wei; Nanya Wang; Yue Sun; Qiang Wang; Xia Fan; Ling Qi; Shudong Wang

doi:10.1080/14756366.2021.1917564

Tertiary sulphonamide derivatives as dual acting small molecules that inhibit LSD1 and suppress tubulin polymerisation against liver cancer

J Enzyme Inhib Med Chem. 2021 Dec;36(1):1563-1572. doi: 10.1080/14756366.2021.1917564.

Authors

Lijuan Ding¹, Feng Wei¹, Nanya Wang¹, Yue Sun¹, Qiang Wang¹, Xia Fan¹, Ling Qi², Shudong Wang¹

Affiliations

¹ The First Hospital of Jilin University, Changchun, China.
² The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China.

Abstract

A series of tertiary sulphonamide derivatives were synthesised and evaluated for their antiproliferative activity against liver cancer cell lines (SNU-475, HepG-2, and Bel-7402). Among these tertiary sulphonamides, compound 17a displayed the best anti-liver cancer activity against Bel-7402 cells with an IC₅₀ value of 0.32 μM. Compound 17a could effectively inhibit tubulin polymerisation with an IC₅₀ value of 1.27 μM. Meanwhile, it selectively suppressed LSD1 with an IC₅₀ value of 63 nM. It also concentration-dependently inhibited migration against Bel-7402 cells. Importantly, tertiary sulphonamide 17a exhibited the potent antitumor activity in vivo. All these findings revealed that compound 17a might be a tertiary sulphonamide-based dual inhibitor of tubulin polymerisation and LSD1 to treat liver cancer.

Keywords: Bel-7402 cells; LSD1; Tertiary sulphonamide; liver cancer; tubulin polymerisation.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone Demethylases / antagonists & inhibitors*
Histone Demethylases / metabolism
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Molecular Structure
Polymerization / drug effects
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
Tubulin / metabolism
Tubulin Modulators / chemical synthesis
Tubulin Modulators / chemistry
Tubulin Modulators / pharmacology*

Substances

Antineoplastic Agents
Enzyme Inhibitors
Small Molecule Libraries
Sulfonamides
Tubulin
Tubulin Modulators
Histone Demethylases
KDM1A protein, human

Grants and funding

This work was supported by the National Natural Science Foundation of China [Grant No.81770375], and Foundation of Science and Technology Department of Jilin Province [Grant No. 20200801061GH, 20190101006JH].