Synthesis, in vitro and in vivo evaluation of novel substituted N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N-methyl-quinazolin-4-amines as potent antitumor agents

Dong Cao; Xiaoyan Wang; Lei Lei; Liang Ma; Fang Wang; Chunyu Wang; Minghai Tang; Wei Xiang; Taijin Wang; Hongyang Li; Lijuan Chen

doi:10.1016/j.bmcl.2016.03.016

Synthesis, in vitro and in vivo evaluation of novel substituted N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N-methyl-quinazolin-4-amines as potent antitumor agents

Bioorg Med Chem Lett. 2016 Apr 15;26(8):1931-5. doi: 10.1016/j.bmcl.2016.03.016. Epub 2016 Mar 7.

Authors

Dong Cao¹, Xiaoyan Wang¹, Lei Lei¹, Liang Ma², Fang Wang¹, Chunyu Wang¹, Minghai Tang¹, Wei Xiang¹, Taijin Wang¹, Hongyang Li¹, Lijuan Chen³

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
² Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China.
³ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China. Electronic address: chenlijuan125@163.com.

PMID: 26979159
DOI: 10.1016/j.bmcl.2016.03.016

Abstract

A novel series of substituted N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N-methylquinazolin-4-amines were synthesized and evaluated for their in vitro antiproliferative activity. Among them, compound 7a exhibited the best potency, with IC50 values of 0.029-0.147 μM against four types of cancer cell lines. In addition, 7a was confirmed that it could arrest the cell cycle at G2/M phase and trigger apoptosis. Indirect immunofluorescence staining revealed its anti-tubulin property. Importantly, 7a significantly inhibited tumor growths in HepG2 xenograft models without causing significant loss of body weight, suggesting that 7a is a promising new anticancer agent to be developed.

Keywords: 4-Anilinoquinazoline derivatives; Anti-proliferation; G(2)/M arrest.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Liver Neoplasms, Experimental / drug therapy
Liver Neoplasms, Experimental / pathology
Mice
Mice, Nude
Molecular Docking Simulation
Molecular Structure
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology*
Quinazolines / chemical synthesis*
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N-methyl-quinazolin-4-amine
Piperazines
Quinazolines