In vitro inhibition of translation initiation by N,N'-diarylureas--potential anti-cancer agents.
In vitro inhibition of translation initiation by N,N'-diarylureas--potential anti-cancer agents.
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DOI：
10.1016/j.bmcl.2011.10.126
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发表时间：
2012-01-01
影响因子：
2.7
通讯作者：
Chorev, Michael
中科院分区：
文献类型：
--
作者：
Denoyelle, Severine;Chen, Ting;Chen, Limo;Wang, Yibo;Klosi, Edvin;Halperin, Jose A.;Aktas, Bertal H.;Chorev, Michael
关键词：
对称性N，N‘-二芳基脲：1，3-二(3，4-二氯苯基)-1，3-二[4-氯-3(三氟甲基)苯基]和1，3-双[3，5-二(三氟甲基)苯基]脲是eIF2α激酶血红素调节抑制剂的有效激活剂。它们降低eIF2·GTP·tRNAiMet三元复合体的丰度，抑制癌细胞增殖。在保持其生物活性的同时，对其进行了优化处理以提高其溶解性。非对称杂化尿素是通过将对称尿素中的一个疏水苯基部分与极性的3-羟基-甲苯基部分相结合而生成的。随后添加的潜在增溶荷电基团的O-烷基化。新的非对称N，N‘-二芳基脲通过三元报告基因和细胞增殖实验进行了表征，显示了良好的生物活性。这些化合物的代表性样本有效地诱导了eIF2mRNA的磷酸化和CHOP在蛋白质和α水平的表达。这些翻译起始抑制物可能成为开发有效、无毒和靶向特异性抗癌药物的先导。
Symmetrical N,N’-diarylureas: 1,3-bis(3,4-dichlorophenyl)-, 1,3-bis[4-chloro-3(trifluoromethyl) phenyl]- and 1,3-bis[3,5-bis(trifluoromethyl)phenyl]urea, were identified as potent activators of the eIF2α kinase heme regulated inhibitor. They reduce the abundance of the eIF2·GTP·tRNAiMet ternary complex and inhibit cancer cell proliferation. An optimization process was undertaken to improve their solubility while preserving their biological activity. Non-symmetrical hybrid ureas were generated by combining one of the hydrophobic phenyl moieties present in the symmetrical ureas with the polar 3-hydroxy-tolyl moiety. O-alkylation of the later added potentially solubilizing charge bearing groups. The new non-symmetrical N,N’-diarylureas were characterized by ternary complex reporter gene and cell proliferation assays, demonstrating good bioactivities. A representative sample of these compounds potently induced phosphorylation of eIF2α and expression of CHOP at the protein and mRNA levels. These inhibitors of translation initiation may become leads for the development of potent, non-toxic, and target specific anti-cancer agents.
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DOI：
10.1083/jcb.115.4.887
发表时间：
1991-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kozak M
通讯作者：
Kozak M
影响因子：
2.9
作者：
Davidson, W;Frego, L;Werneburg, BG
通讯作者：
Werneburg, BG
影响因子：
11.4
作者：
Cohen, N;Sharma, M;Borden, KLB
通讯作者：
Borden, KLB
DOI：
10.1073/pnas.0805299105
发表时间：
2008-10-07
影响因子：
11.1
作者：
Marshall, R. Andrew;Dorywalska, Magdalena;Puglisi, Joseph D.
通讯作者：
Puglisi, Joseph D.
影响因子：
2.7
作者：
Miyazaki, Yasushi;Tang, Jun;Ozawa, Kazunori
通讯作者：
Ozawa, Kazunori