Katja Kräling

Iridium Complex with Antiangiogenic Properties

Substitutionally inert metal complexes are promising emerging scaffolds for targeting enzyme active sites. Over the last several years, our research group has demonstrated that inert ruthenium(II) complexes can serve as highly selective nanomolar and even picomolar inhibitors of protein kinases. Octahedral metal coordination geometries in particular offer new gateways to design rigid, globular molecules with defined shapes that can fill protein pockets such as enzyme active sites in a unique fashion (Figure 1). However, the

An Organometallic Inhibitor for the Human Repair Enzyme 7,8-Dihydro-8-oxoguanosine Triphosphatase.

The probe-based discovery of the first small-molecule inhibitor of the repair enzyme 8-oxo-dGTPase (MTH1) is presented, which is an unconventional cyclometalated ruthenium half-sandwich complex. The organometallic inhibitor with low-nanomolar activity displays astonishing specificity, as verified in tests with an extended panel of protein kinases and other ATP binding proteins. The binding of the organometallic inhibitor to MTH1 is investigated by protein crystallography.

Bioactive cyclometalated phthalimides: design, synthesis and kinase inhibition

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.

Bioorthogonal Enzymatic Activation of Caged Compounds

Engineered cytochrome P450 monooxygenase variants are reported as highly active and selective catalysts for the bioorthogonal uncaging of propargylic and benzylic ether protected substrates, including uncaging in living E. coli. observed selectivity is supported by induced-fit docking and molecular dynamics simulations. This proof-of-principle study points towards the utility of bioorthogonal enzyme/protecting group pairs for applications in the life sciences.

Unusual η2-Allene Osmacycle with Apoptotic Properties

Screening of a library of structurally unusual osmacyclic complexes for their antiproliferate properties in HeLa cells led to the discovery of a highly cytotoxic η2‐allene osmacycle. In this remarkably stable complex, osmium constitutes part of a metallacycle through the formation of a σ‐bond to a carbon in combination with coordination to an allene moiety. The osmacycle strongly induces apoptosis in Burkitt‐like lymphoma cells at submicromolar concentrations. The reduction of the mitochondrial membrane potential, the induction of DNA fragmentation, and the activation of caspases‐9 and ‐3 reveal that programmed cell death occurs through the intrinsic mitochondrial pathway. From the lipophilic and cationic nature of the osmacycle, in addition to a low oxidation potential (E1/2=+0.27 V vs. Fc/Fc+, Fc=ferrocene) it is proposed that mitochondria are the cellular target where oxidative decomposition initiates apoptosis.

Non-ATP-Mimetic Organometallic Protein Kinase Inhibitor

US National Institutes of Health [CA114046]; German Research Foundation [ME 1805/9-1]; Helmholtz Zentrum Berlin (HZB)