Identification of a water-soluble indirubin derivative as potent inhibitor of insulin-like growth factor 1 receptor through structural modification of the parent natural molecule
Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new indirubin 3′- an...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
May 30, 2017
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| In: |
Journal of medicinal chemistry
Year: 2017, Volume: 60, Issue: 12, Pages: 4949-4962 |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.7b00324 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1021/acs.jmedchem.7b00324 Verlag, Volltext: https://doi.org/10.1021/acs.jmedchem.7b00324 
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| Author Notes: | Xinlai Cheng, Karl-Heinz Merz, Sandra Vatter, Jochen Zeller, Stephan Muehlbeyer, Andrea Thommet, Jochen Christ, Stefan Wölfl, and Gerhard Eisenbrand |
| Summary: | Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5- and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new indirubin 3′- and 5′-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor. |
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| Item Description: | Gesehen am 04.07.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1520-4804 |
| DOI: | 10.1021/acs.jmedchem.7b00324 |