Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition
| Autor: | Sebastian Blanck, Thomas Mietke, Stephen Middel, Lars-Oliver Essen, Katja Kräling, Klaus Harms, Eric Meggers, Yann Geisselbrecht |
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| Rok vydání: | 2012 |
| Předmět: |
Steric effects
Phthalimides Chemistry Stereochemistry Regioselectivity chemistry.chemical_element Cocrystal Article Stille reaction Ruthenium Inorganic Chemistry Phthalimide chemistry.chemical_compound Proto-Oncogene Proteins c-pim-1 Coordination Complexes Metals Humans Moiety Protein Kinase Inhibitors |
| Zdroj: | Dalton Transactions. 41:9337 |
| ISSN: | 1477-9234 1477-9226 |
| DOI: | 10.1039/c2dt30940h |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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