Eric Meggers

Asymmetric photoredox transition-metal catalysis activated by visible light

Asymmetric catalysis is seen as one of the most economical strategies to satisfy the growing demand for enantiomerically pure small molecules in the fine chemical and pharmaceutical industries. And visible light has been recognized as an environmentally friendly and sustainable form of energy for triggering chemical transformations and catalytic chemical processes. For these reasons, visible-light-driven catalytic asymmetric chemistry is a subject of enormous current interest. Photoredox catalysis provides the opportunity to generate highly reactive radical ion intermediates with often unusual or unconventional reactivities under surprisingly mild reaction conditions. In such systems, photoactivated sensitizers initiate a single electron transfer from (or to) a closed-shell organic molecule to produce radical cations or radical anions whose reactivities are then exploited for interesting or unusual chemical transformations. However, the high reactivity of photoexcited substrates, intermediate radical ions or radicals, and the low activation barriers for follow-up reactions provide significant hurdles for the development of efficient catalytic photochemical processes that work under stereochemical control and provide chiral molecules in an asymmetric fashion. Here we report a highly efficient asymmetric catalyst that uses visible light for the necessary molecular activation, thereby combining asymmetric catalysis and photocatalysis. We show that a chiral iridium complex can serve as a sensitizer for photoredox catalysis and at the same time provide very effective asymmetric induction for the enantioselective alkylation of 2-acyl imidazoles. This new asymmetric photoredox catalyst, in which the metal centre simultaneously serves as the exclusive source of chirality, the catalytically active Lewis acid centre, and the photoredox centre, offers new opportunities for the ‘green’ synthesis of non-racemic chiral molecules.

An Organometallic Protein Kinase Inhibitor Pharmacologically Activates p53 and Induces Apoptosis in Human Melanoma Cells

Unlike other tumors, melanomas harbor wild-type (WT) p53 but exhibit impaired p53-dependent apoptosis. The mechanisms for the impaired p53 activation are poorly understood but may be linked to the high expression of the p53 suppressor Mdm2, which is found in >50% of melanoma lesions. Here, we describe an organometallic glycogen synthase kinase 3beta (GSK3beta) inhibitor (DW1/2) as a potent activator of p53 and inducer of cell death in otherwise highly chemoresistant melanoma cells. Using RNA interference and pharmacologic approaches, we show that p53 is required for the cytotoxic effects of this organometallic inhibitor. The DW1/2 compound was barely able to induce cell death in melanoma cells with p53 mutations, further confirming the requirement for p53-WT in the cytotoxic effects of the GSK3beta inhibition. Mechanistic analysis of the p53-dependent cell death indicated an apoptotic mechanism involving depolarization of mitochondrial membrane potential, caspase cleavage, and elevated NOXA expression. The effect of p53 was not simply due to passive up-regulation of protein expression as adenoviral-mediated overexpression of p53 was not able to induce cell death. Treatment of melanoma cells with DW1/2 was instead found to decrease levels of Mdm2 and Mdm4. The importance of Mdm2 down-regulation in DW1/2-induced apoptosis was confirmed by treating the p53-WT cells with the p53/Mdm2 antagonist Nutlin-3. Taken together, our data provide a new strategy for the pharmacologic activation of p53 in melanoma, which may be a viable approach for overcoming apoptotic resistance in melanoma and offer new hope for rational melanoma therapy.

Targeting large kinase active site with rigid, bulky octahedral ruthenium complexes.

A strategy for targeting protein kinases with large ATP-binding sites by using bulky and rigid octahedral ruthenium complexes as structural scaffolds is presented. A highly potent and selective GSK3 and Pim1 half-sandwich complex NP309 was successfully converted into a PAK1 inhibitor by making use of the large octahedral compounds Lambda-FL172 and Lambda-FL411 in which the cyclopentadienyl moiety of NP309 is replaced by a chloride and sterically demanding diimine ligands. A 1.65 A cocrystal structure of PAK1 with Lambda-FL172 reveals how the large coordination sphere of the ruthenium complex matches the size of the active site and serves as a yardstick to discriminate between otherwise closely related binding sites.

On the Mechanism of Long-Range Electron Transfer through DNA

Hopping between bases of similar redox potentials is the mechanism by which charge transport occurs through DNA. This was shown by rate measurements performed with double strands 1-3. This mechanism explains why hole transfer displays a strong sequence dependence, and postulates that electron transfer in unperturbed DNA should not be dependent on the sequence.

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

From Conventional to Unusual Enzyme Inhibitor Scaffolds: The Quest for Target Specificity

The tremendous challenge presented by the specific molecular recognition of single biomacromolecular targets within complex biological systems demands novel and creative design strategies. This Minireview discusses some conventional and unusual approaches for the design of target-selective enzyme inhibitors with a focus on the underlying chemical scaffolds. These include complicated natural-product-like organic molecules, stable octahedral metal complexes, fullerenes, carboranes, polymetallic clusters, and even polymers. Thus the whole repertoire of organic, inorganic, and macromolecular chemistry can be applied to tackle the problem of target-specific enzyme inhibition.

Asymmetric Radical–Radical Cross‐Coupling through Visible‐Light‐Activated Iridium Catalysis

Combining single electron transfer between a donor substrate and a catalyst-activated acceptor substrate with a stereocontrolled radical-radical recombination enables the visible-light-driven catalytic enantio- and diastereoselective synthesis of 1,2-amino alcohols from trifluoromethyl ketones and tertiary amines. With a chiral iridium complex acting as both a Lewis acid and a photoredox catalyst, enantioselectivities of up to 99% ee were achieved. A quantum yield of <1 supports the proposed catalytic cycle in which at least one photon is needed for each asymmetric C-C bond formation mediated by single electron transfer.

Organometallic Compounds with Biological Activity: A Very Selective and Highly Potent Cellular Inhibitor for Glycogen Synthase Kinase 3

A chiral second‐generation organoruthenium half‐sandwich compound is disclosed that shows a remarkable selectivity and cellular potency for the inhibition of glycogen synthase kinase 3 (GSK‐3). The selectivity was evaluated against a panel of 57 protein kinases, in which no other kinase was inhibited to the same extent, with a selectivity window of at least tenfold to more than 1000‐fold at 100 μM ATP. Furthermore, a comparison with organic GSK‐3 inhibitors demonstrated the superior cellular activity of this ruthenium compound: wnt signaling was fully induced at concentrations down to 30 nM. For comparison, the well‐established organic GSK‐3 inhibitors 6‐bromoindirubin‐3′‐oxime (BIO) and kenpaullone activate the wnt pathway at concentrations that are higher by around 30‐fold and 100‐fold, respectively. The treatment of zebrafish embryos with the organometallic inhibitor resulted in a phenotype that is typical for the inhibition of GSK‐3. No phenotypic change was observed with the mirror‐imaged ruthenium complex. The latter does not, in fact, show any of the pharmacological properties for the inhibition of GSK‐3. Overall, these results demonstrate the potential usefulness of organometallic compounds as molecular probes in cultured cells and whole organisms.

Electron Transfer through DNA in the Course of Radical‐Induced Strand Cleavage

No benefit from base stacking is observed for rates of electron transfer in DNA. This conclusion was drawn from experiments with a new DNA assay in which a radical cationic site, generated by strand cleavage, can be reduced by the guanine bases in the same DNA (the electron transfer is indicated by arrows in the diagram). The distance dependence of this electron transfer step is determined by the chemical yield of the reduction product.

Asymmetric Catalysis with Substitutionally Labile yet Stereochemically Stable Chiral-at-Metal Iridium(III) Complex

A metal-coordination-based high performance asymmetric catalyst utilizing metal centrochirality as the sole element of chirality is reported. The introduced substitutionally labile chiral-at-metal octahedral iridium(III) complex exclusively bears achiral ligands and effectively catalyzes the enantioselective Friedel-Crafts addition of indoles to α,β-unsaturated 2-acyl imidazoles (19 examples) with high yields (75%-99%) and high enantioselectivities (90-98% ee) at low catalyst loadings (0.25-2 mol %). Counterintuitively, despite its substitutional lability, which is mechanistically required for coordination to the 2-acyl imidazole substrate, the metal-centered chirality is maintained throughout the catalysis. This novel class of reactive chiral-at-metal complexes will likely be of high value for a large variety of asymmetric transformations.