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Issue 31, 2012
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Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition

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Abstract

The regioselective cyclometalation of 4-(pyridin-2-yl)phthalimide was exploited for the economical design of organometallic protein kinase inhibitors. 4-(Pyridin-2-yl)phthalimide can be prepared from inexpensive 4-bromophthalimide in just three steps including one Pd-catalyzed Stille cross-coupling. The versatility of this new ligand was demonstrated with the synthesis of ruthenium(II) half-sandwich as well as octahedral ruthenium(II) and iridium(III) complexes. The regioselectivity of the C–H activation in the course of the cyclometalation can be influenced by the reaction conditions and the steric demand of the introduced metal complex fragment. The biological activity of this new class of metalated phthalimides was evaluated by profiling two representative members against a large panel of human protein kinases. A cocrystal structure of one metallo-phthalimide with the protein kinase Pim1 confirmed an ATP-competitive binding with the intended hydrogen bonding between the phthalimide moiety and the hinge region of the ATP-binding site.

Graphical abstract: Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition

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Publication details

The article was received on 30 Apr 2012, accepted on 07 Jun 2012 and first published on 11 Jun 2012


Article type: Paper
DOI: 10.1039/C2DT30940H
Citation: Dalton Trans., 2012,41, 9337-9348
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    Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition

    S. Blanck, Y. Geisselbrecht, K. Kräling, S. Middel, T. Mietke, K. Harms, L. Essen and E. Meggers, Dalton Trans., 2012, 41, 9337
    DOI: 10.1039/C2DT30940H

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