期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 60, 期 12, 页码 4949-4962出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00324
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资金
- Deutsche Forschungsgemeinschaft [CH 1690/2-1]
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'-oxide 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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