Design, synthesis and preliminary biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids as antiproliferative agents

Eur J Med Chem. 2017 Oct 20:139:741-749. doi: 10.1016/j.ejmech.2017.08.042.

Zhong-Hua Li ¹, Xue-Qi Liu ¹, Tao-Qian Zhao ¹, Peng-Fei Geng ¹, Wen-Ge Guo ¹, Bin Yu ², Hong-Min Liu ³

Affiliations

1 Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China.
2 Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China. Electronic address: zzuyubin@hotmail.com.
3 Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Henan Province for Drug Quality and Evaluation, PR China. Electronic address: liuhm@zzu.edu.cn.

PMID: 28863355 DOI: 10.1016/j.ejmech.2017.08.042

Abstract

A series of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids were designed and synthesized through the scaffold replacement/ring cleavage strategy. SARs studies revealed that the N-heteroarene moiety attached to the thiourea is preferred over the phenyl ring for the R² substituents, while the hydrophobic aromatic group is beneficial for improving the activity. Among these compounds, compound 5r significantly inhibited cell growth of lung Cancer cell lines H1650 and A549 (IC₅₀ = 1.91, 3.28 μM, respectively), but was less toxic against the normal cell line GES-1 (IC₅₀ = 27.43 μM). Mechanistic studies showed that compound 5r could remarkably inhibit the colony formation of H1650 cells, induced Apoptosis possibly through the intrinsic apoptotic pathways, and arrested the cell cycle at G2/M phase. Our studies suggest that the [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids are a new class of chemotypes possessing interesting antiproliferative activity against lung Cancer cells and could be potentially utilized for designing new antitumor agents.

Keywords

Antiproliferative activity; Ring cleavage; Scaffold replacement; Thiourea; [1,2,3]triazolo[4,5-d]pyrimidine.

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