Details

Autor(en) / Beteiligte

• Cheng, Xinlai
• Merz, Karl-Heinz
• Vatter, Sandra
• Zeller, Jochen
• Muehlbeyer, Stephan
• Thommet, Andrea
• Christ, Jochen
• Wölfl, Stefan
• Eisenbrand, Gerhard

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2017-06, Vol.60 (12), p.4949-4962

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.