Discovery of 4-aminoquinazoline--urea derivatives as Aurora kinase inhibitors with antiproliferative activity

Jin Cai; Lili Li; Kwon Ho Hong; Xiaoqing Wu; Junqing Chen; Peng Wang; Meng Cao; Xi Zong; Min Ji

doi:10.1016/j.bmc.2014.09.029

Discovery of 4-aminoquinazoline--urea derivatives as Aurora kinase inhibitors with antiproliferative activity

Bioorg Med Chem. 2014 Nov 1;22(21):5813-23. doi: 10.1016/j.bmc.2014.09.029. Epub 2014 Sep 19.

Authors

Jin Cai¹, Lili Li¹, Kwon Ho Hong², Xiaoqing Wu³, Junqing Chen¹, Peng Wang⁴, Meng Cao⁴, Xi Zong¹, Min Ji⁵

Affiliations

¹ School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China.
² Department of Medicinal Chemistry and The Institute for Therapeutics Discovery and Development, University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, USA.
³ Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA.
⁴ School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China.
⁵ School of Chemistry and Chemical Engineering, Institute of Pharmaceutical Engineering, Southeast University, 87 Dingjiaqiao, Nanjing, Jiangsu 210096, PR China; School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, PR China. Electronic address: jimin@seu.edu.cn.

PMID: 25270403
DOI: 10.1016/j.bmc.2014.09.029

Abstract

Two series of 20 novel 4-aminoquinazoline-urea derivatives have been designed and synthesized. The entire target compounds were investigated for their in vitro antiproliferative activity against six human cancer cell lines (K562, U937, A549, NCI-H661, HT29 and LoVo) using the MTT-based assay. Most compounds showed significant antiproliferative activities against four solid tumor cell lines, but no or poor activities against two leukemia cell lines. Furthermore, the target compounds were screened for Aurora A/B kinases inhibitory activity. Among them, 7c, 7d, 8c, and 8d are more potent against Aurora A kinase than ZM447439. Docking study of compounds 7d and ZM447439 revealed that they bound strongly to the ATP-binding sites of Aurora A and B. Thus, they may be promising lead compounds for the development of novel anti-tumor drug potentially via inhibiting Aurora kinases.

Keywords: Antiproliferative activity; Aurora kinase; Cancer cell; Docking simulation; Quinazolines; ZM447439.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Aurora Kinase A / antagonists & inhibitors*
Aurora Kinase A / metabolism
Aurora Kinase B / antagonists & inhibitors*
Aurora Kinase B / metabolism
Benzamides / chemistry
Binding Sites
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Drug Evaluation, Preclinical
Enzyme Activation / drug effects
Humans
Molecular Docking Simulation
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Structure, Tertiary
Quinazolines / chemistry*
Structure-Activity Relationship
Urea / analogs & derivatives*

Substances

4-(4-(N-benzoylamino)anilino)-6-methoxy-7-(3-(1-morpholino)propoxy)quinazoline
4-aminoquinazoline
Antineoplastic Agents
Benzamides
Protein Kinase Inhibitors
Quinazolines
Urea
Aurora Kinase A
Aurora Kinase B