Analogues and derivatives of oncrasin-1, a novel inhibitor of the C-terminal domain of RNA polymerase II and their antitumor activities.
Analogues and derivatives of oncrasin-1, a novel inhibitor of the C-terminal domain of RNA polymerase II and their antitumor activities.
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DOI：
10.1021/jm101417n
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发表时间：
2011-04-28
影响因子：
7.3
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Wu S;Wang L;Guo W;Liu X;Liu J;Wei X;Fang B
为了优化小分子RNA聚合酶II抑制剂oncrasin-1的抗肿瘤活性，我们评估了69种oncrasin-1类似物对正常人上皮细胞和K-Ras突变肿瘤细胞的细胞毒活性。这些化合物中约有40种在肿瘤细胞中与促红素-1一样或更有效，而对正常细胞的细胞毒性作用最小。构效关系分析表明，大多数活性化合物在吲哚的3位上含有一个羟基甲基或一个乙基代替物。苯环上的供电子和吸电子基团均具有良好的耐受性。羟基甲基化合物的效力范围从同等到100倍于相应的醛类化合物。我们测试了3种活性类似物对RNA聚合酶磷酸化的影响，发现它们都抑制了RNA聚合酶II c端结构域的磷酸化，这表明活性化合物可能通过与oncrasin-1相同的机制起作用。
To optimize the antitumor activity of oncrasin-1, a small molecule RNA polymerase II inhibitor, we evaluated 69 oncrasin-1 analogues for their cytotoxic activity against normal human epithelial cells and K-Ras mutant tumor cells. About 40 of those compounds were as potent as or more potent than oncrasin-1 in tumor cells and had minimal cytotoxic effect on normal cells. Structure-activity relationship analysis revealed that most of the active compounds contained either a hydroxymethyl group or an aldehyde group as a substitute at the 3-position of the indole. Both electron-donating and electron-withdrawing groups in the benzene ring were well tolerated. The hydroxymethyl compounds ranged from equipotent with to 100 times as potent as the corresponding aldehyde compounds. We tested 3 active analogues’ effect on RNA polymerase phosphorylation and found that they all inhibited phosphorylation of the C-terminal domain of RNA polymerase II, suggesting that the active compounds might act through the same mechanisms as oncrasin-1.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
影响因子：
10.5
作者：
Hirose, Y;Tacke, R;Manley, JL
通讯作者：
Manley, JL
影响因子：
11.4
作者：
Baumli, Sonja;Lolli, Graziano;Johnson, Louise N.
通讯作者：
Johnson, Louise N.
影响因子：
8
作者：
Chinni, SR;Li, YW;Sarkar, FH
通讯作者：
Sarkar, FH
DOI：
10.1073/pnas.94.26.14300
发表时间：
1997-12-23
影响因子：
11.1
作者：
Archambault, J;Chambers, RS;Greenblatt, J
通讯作者：
Greenblatt, J