Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 139, Issue -, Pages 741-749Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2017.08.042
Keywords
Thiourea; [1,2,3]triazolo[4,5-d]pyrimidine; Antiproliferative activity; Scaffold replacement; Ring cleavage
Categories
Funding
- National Natural Science Foundation of China [81430085, 21372206, 81703326, 81773562]
- National Key Research Programs of Proteins [2016YFA0501800]
- Key Research Program of Henan Province [1611003110100]
- Zhengzhou University [32210533]
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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 R-2 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 mu M, respectively), but was less toxic against the normal cell line GES-1 (IC50 = 27.43 mu M). 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. (C) 2017 Elsevier Masson SAS. All rights reserved.
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