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Synthesis and Antiproliferative Activity of 7-Azaindirubin-3′-oxime, a 7-Aza Isostere of the Natural Indirubin Pharmacophore

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journal contribution
posted on 28.12.2009, 00:00 authored by Marina Kritsanida, Prokopios Magiatis, Alexios-Leandros Skaltsounis, Youyi Peng, Peng Li, Lawrence P. Wennogle
The bis-indole alkaloid indirubin and its analogues bear a very interesting natural pharmacophore. They are recognized mainly as kinase inhibitors, but several other activities make them possible candidates for preclinical studies. Based on the previously reported activity of 7-bromoindirubin-3′-oxime and its derivatives, the synthesis of indirubins bearing a heterocyclic nitrogen atom at position 7 was carried out. Herein, we report the first synthesis of 7-azaindirubin-3′-oxime (12) as well as its antiproliferative activity against 57 cancer cell lines and its inhibitory activity against a series of kinases. 7-Azaindirubin (10) and its 3′-oxime derivative (12) showed reduced activity as kinase inhibitors in comparison with other known indirubin derivatives, but antiproliferative activity with a best GI50 value of 0.77 μM.