Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile

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 15...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2010-08, Vol.53 (16), p.5929-5941
Main Authors: Chiang, Chao-Cheng, Lin, Yu-Hsiang, Lin, Shu Fu, Lai, Chun-Liang, Liu, Chiawei, Wei, Win-Yin, Yang, Sheng-chuan, Wang, Ru-Wen, Teng, Li-Wei, Chuang, Shih-Hsien, Chang, Jia-Ming, Yuan, Ta-Tung, Lee, Ying-Shuen, Chen, Paonien, Chi, Wei-Kuang, Yang, Ju-Ying, Huang, Hung-Jyun, Liao, Chu-Bin, Huang, Jiann-Jyh
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Aurora Kinase B
Aurora Kinases
Cell Proliferation - drug effects
Drug Screening Assays, Antitumor
HCT116 Cells
HeLa Cells
Histones - metabolism
HT29 Cells
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Models, Molecular
Phosphorylation
Protein Binding
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Pyrroles - chemical synthesis
Pyrroles - chemistry
Pyrroles - pharmacology
Stereoisomerism
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm1001869