Serge Thorimbert

Identification of Polyoxometalates as Nanomolar Noncompetitive Inhibitors of Protein Kinase CK2

Protein kinase CK2 is a multifunctional kinase of medical importance that is dysregulated in many cancers. In this study, polyoxometalates were identified as original CK2 inhibitors. [P2Mo18O62](6-) has the most potent activity. It inhibits the kinase in the nanomolar range by targeting key structural elements located outside the ATP- and peptide substrate-binding sites. Several polyoxometalate derivatives exhibit strong inhibitory efficiency, with IC50 values < or = 10 nM. Furthermore, these inorganic compounds show a striking specificity for CK2 when tested in a panel of 29 kinases. Therefore, polyoxometalates are effective CK2 inhibitors in terms of both efficiency and selectivity and represent nonclassical kinase inhibitors that interact with CK2 in a unique way. This binding mode may provide an exploitable mechanism for developing potent drugs with desirable properties, such as enhanced selectivity relative to ATP-mimetic inhibitors.

Chiral Recognition of Hybrid Metal Oxide by Peptides

Resolution of gram quantities of a subtly chiral polyoxometalate (POM; the chirality originates from substitution of one metal in the nanosized framework) is possible by reaction with small peptides. Functionalizable acyl polyoxotungstate (TBA)(6)[alpha(1)-P(2)W(17)O(61){SnCH(2)CH(2)C(=O)}] (see picture) can be resolved by kinetic resolution. This approach paves the way for applications of chiral POMs ranging from asymmetric catalysis to their bioactivity.

Chemoselective Catalysis with Organosoluble Lewis Acidic Polyoxotungstates

The preparation of new organosoluble Lewis acidic polyoxometalates (POMs) is reported. These complexes were prepared by the incorporation of Zr, Sc, and Y atoms into the corresponding monolacunary Dawson [P(2)W(17)O(61)](10-) and Keggin [PW(11)O(39)](7-) polyoxotungstates. The catalytic activity of these compounds was evaluated for C-C bond formation in the Diels-Alder, Mannich, and Mukaiyama-type reactions. Comparisons with previously described Lewis acidic POMs are reported. Competitive reactions between imines and aldehydes or between various imines demonstrated that fine tuning of the reactivity could be reached by varying the metal atom incorporated into the polyanionic framework. A series of experiments that employed pyridine derivatives allowed us to distinguish between the Lewis and induced Brønsted acidity of the POMs. These catalysts activate imines in a Lewis acidic way, whereas aldehydes are activated by indirect Brønsted catalysis.

Regioselective Activation of Oxo Ligands in Functionalized Dawson Polyoxotungstates

The organic side chain of tin-substituted Dawson polyoxotungstates alpha1- and alpha2-[P2W17O61{SnCH2CH2COOH}]7- can be used to direct regioselective acylations of oxo ligands in the inorganic backbone, which was examined both experimentally and computationally. Acylation of the oxo ligand gave exalted electrophilicity to the acyl moiety, and the compounds that were obtained led to direct ligation of POMs to complex organic molecules.

Insertion of Amides into a Polyoxometalate

POM alert: The incorporation of an amide oxygen atom into the framework of the Dawson-type polyoxometalate (POM) cluster [P(2)V(3)W(15)O(62)](9-) (see picture) allows the communication of electronic effects between the organic and the inorganic parts of the molecule, including fine-tuning of the redox properties of the entire hybrid POM by the organic components, and transmission of the POMs electron-attracting properties to the organic moiety.

Lanthanide Polyoxocationic Complexes: Experimental and Theoretical Stability Studies and Lewis Acid Catalysis

The [ε-PMo(V)(8)Mo(VI)(4)O(36)(OH)(4){Ln(III)(H(2)O)}(4)](5+) (Ln=La, Ce, Nd, Sm) polyoxocations, called εLn(4), have been synthesized at room temperature as chloride salts soluble in water, MeOH, EtOH, and DMF. Rare-earth metals can be exchanged, and (31)P NMR spectroscopic studies have allowed a comparison of the affinity of the reduced {ε-PMo(12)} core, thus showing that the La(III) ions have the highest affinity and that rare earths heavier than Eu(III) do not react with the ε-Keggin polyoxometalate. DFT calculations provide a deeper insight into the geometries of the systems studied, thereby giving more accurate information on those compounds that suffer from disorder in crystalline form. It has also been confirmed by the hypothetical La→Gd substitution reaction energy that Ln ions beyond Eu cannot compete with La in coordinating the surface of the ε-Keggin molybdate. Two of these clusters (Ln=La, Ce) have been tested to evidence that such systems are representative of a new efficient Lewis acid catalyst family. This is the first time that the catalytic activity of polyoxocations has been evaluated.

Self-Buffering Hybrid Gold-Polyoxometalate Catalysts for the Catalytic Cyclization of Acid-Sensitive Substrates

Grafting of a gold complex to an organo-polyoxometalate delivers catalytically active bitopic hybrids. The gold end activates allenes, while the metal-oxide surface can capture protons (see scheme). The scope of the gold-catalyzed oxacyclization of allenols is expanded to highly sensitive tertiary benzylic alcohols.

Carbonyl-Inserted Organo-Hybrids of a Dawson-Type Phosphovanadotungstate: Scope and Chemoselective Oxidation Catalysis

The Dawson-type polyoxometalate (POM) [P(2)V(3)W(15)O(62)](9-) is a prototype for inclusion of carbonyls of amides, ureas, carbamates, and thiocarbamates into polyoxometallic structures. The carbonyl-inserted POMs catalyze the oxidation of sulfides. Chemoselectivity depends primarily on the proton content of the POM, but it is also influenced by the organic substituent.

Unusual reactivity of acetate versus carbonate in palladium-catalyzed nucleophilic substitutions: A strong silicon effect

Abstract The presence of a silicon group reverses the relative reactivity of carbonate and acetate in palladium-catalyzed nucleophilic substitutions.

Water Dissociation on α1-Hafnium and Ytterbium Substituted Dawson Polyoxotungstates: A Density Functional Theory Study†

Density functional theory (DFT) calculations were devised to get insight into Lewis acidic catalysis by POMs, especially on the intriguing activation of complexed water molecules that was observed in some experimental cases. Computationally, it appears that deprotonation is feasible with [alpha(1)-Hf(H(2)O)P(2)W(17)O(61)](6-), but not with [alpha(1)-Yb(H(2)O)P(2)W(17)O(61)](7-). This reflects the difference of the electronic structures (diamagnetic for hafnium POM, paramagnetic for ytterbium POM). From a mechanistical point of view, indirect Brønsted catalysis cannot be excluded in the hafnium case, especially for Mannich reactions. But our calculations show that catalysis by [alpha(1)-Yb(H(2)O)P(2)W(17)O(61)](7-) (and presumably all the lanthanide series) proceeds through direct complexation of the substrates to the POM.