Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile
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- 作者：Chao-Cheng Chiang ; Yu-Hsiang Lin ; Shu Fu Lin ; Chun-Liang Lai ; Chiawei Liu ; Win-Yin Wei ; Sheng-chuan Yang ; Ru-Wen Wang ; Li-Wei Teng ; Shih-Hsien Chuang ; Jia-Ming Chang ; Ta-Tung Yuan ; Ying-Shuen Lee ; Pao
- 刊名：Journal of Medicinal Chemistry
- 出版年：2010
- 出版时间：August 26, 2010
- 年：2010
- 卷：53
- 期：16
- 页码：5929-5941
- 全文大小：1165K
- 年卷期：v.53,no.16(August 26, 2010)
- ISSN：1520-4804
文摘
A series of pyrrole−indolin-2-ones were synthesized, and their inhibition profile for Aurora kinases was studied. The potent compound 33 with phenylsulfonamido at the C-5 position and a carboxyethyl group at the C-3′ position selectively inhibited Aurora A over Aurora B with IC50 values of 12 and 156 nM, respectively. Replacement of the carboxyl group with an amino group led to compound 47, which retained the activity for Aurora B and lost activity for Aurora A (IC50 = 2.19 μM). Computation modeling was used to address the different inhibition profiles of 33 and 47. Compounds 47 and 36 (the ethyl ester analogue of 33) inhibited the proliferation of HCT-116 and HT-29 cells and suppressed levels of the phosphorylated substrates of Aurora A and Aurora B in the Western blots.