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J Med Chem. 2017 Jun 22;60(12):4949-4962. doi: 10.1021/acs.jmedchem.7b00324. Epub 2017 Jun 6.

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.

Author information

1
Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern , Erwin-Schrödinger-Strasse 52, D-67663 Kaiserslautern, Germany.
2
Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg , Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany.

Abstract

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.

PMID:
28557430
DOI:
10.1021/acs.jmedchem.7b00324
[Indexed for MEDLINE]

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