Synthesis and identification of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl as potential Aurora A inhibitors

Chun-Yan Sang; Wen-Wen Qin; Xiu-Juan Zhang; Yu Xu; You-Zhen Ma; Xing-Rong Wang; Ling Hui; Shi-Wu Chen

doi:10.1016/j.bmc.2018.11.006

Synthesis and identification of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl as potential Aurora A inhibitors

Bioorg Med Chem. 2019 Jan 1;27(1):65-78. doi: 10.1016/j.bmc.2018.11.006. Epub 2018 Nov 7.

Authors

Chun-Yan Sang¹, Wen-Wen Qin¹, Xiu-Juan Zhang¹, Yu Xu¹, You-Zhen Ma¹, Xing-Rong Wang¹, Ling Hui², Shi-Wu Chen³

Affiliations

¹ School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
² Experimental Center of Medicine, General Hospital of Lanzhou Military Command, Lanzhou 730050, China.
³ School of Pharmacy, Lanzhou University, Lanzhou 730000, China. Electronic address: chenshw@lzu.edu.cn.

PMID: 30502115
DOI: 10.1016/j.bmc.2018.11.006

Abstract

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.

Keywords: Anticancer agents; Aurora kinases; Pyrimidine; Stable nitroxides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry
Aniline Compounds / pharmacology*
Apoptosis / drug effects
Aurora Kinase A / chemistry
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclic N-Oxides / chemical synthesis
Cyclic N-Oxides / chemistry
Cyclic N-Oxides / pharmacology*
G2 Phase Cell Cycle Checkpoints / drug effects
Humans
Molecular Docking Simulation
Piperidines / chemical synthesis
Piperidines / chemistry
Piperidines / pharmacology*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Spindle Apparatus / drug effects

Substances

Aniline Compounds
Cyclic N-Oxides
Piperidines
Protein Kinase Inhibitors
Pyrimidines
Aurora Kinase A