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Design, synthesis and preliminary biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids as antiproliferative agents
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2017-08-31 , DOI: 10.1016/j.ejmech.2017.08.042
Zhong-Hua Li , Xue-Qi Liu , Tao-Qian Zhao , Peng-Fei Geng , Wen-Ge Guo , Bin Yu , Hong-Min Liu

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.



中文翻译:

新的[1,2,3]三唑并[4,5- d ]嘧啶/硫脲杂化物作为抗增殖剂的设计,合成和初步生物学评估

通过支架置换/环裂解策略设计并合成了一系列新的[1,2,3]三唑并[4,5- d ]嘧啶/硫脲杂化物。SARs研究表明,对于R 2取代基,与硫脲连接的N-杂芳基部分比苯环更可取,而疏水性芳香族基团对于改善活性是有利的。在这些化合物中,化合物5r显着抑制肺癌细胞株H1650和A549的细胞生长(分别为IC 50  = 1.91、3.28μM ),但对正常细胞系GES-1的毒性较小(IC 50  = 27.43μM)。机理研究表明,化合物5r可以显着抑制H1650细胞的集落形成,可能通过内在的凋亡途径诱导细胞凋亡,并使细胞周期停滞在G2 / M期。我们的研究表明,[1,2,3]三唑并[4,5- d ]嘧啶/硫脲杂种是一类新型的化学型,对肺癌细胞具有有趣的抗增殖活性,可潜在地用于设计新的抗肿瘤药。

更新日期:2017-08-31
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