Entasis through hook-and-loop fastening in a glycoligand with cumulative weak forces stabilizing Cu(I).

The idea of a possible control of metal ion properties by constraining the coordination sphere geometry was introduced by Vallee and Williams with the concept of entasis, which is frequently postulated to be at stake in metallobiomolecules. However, the interactions controlling the geometry at metal centers remain often elusive. In this study, the coordination properties toward copper ions­Cu(II) or Cu(I)­of a geometrically constrained glycoligand centered on a sugar scaffold were compared with those of an analogous ligand built on an unconstrained alkyl chain. The sugar-centered ligand was shown to be more preorganized for Cu(II) coordination than its open-chain analogue, with an unusual additional stabilization of the Cu(I) redox state. This preference for Cu(I) was suggested to arise from geometric constraints favoring an optimized folding of the glycoligand minimizing steric repulsions. In other words, the Cu(I) d(10) species is stabilized by valence shell electron pair repulsion (VSEPR). This idea was rationalized by a theoretical noncovalent interactions (NCI) analysis. The cumulative effects of weak forces were shown to create an efficient buckle as in a hook-and-loop fastener, and fine structural features within the glycoligand reduce repulsive interactions for the Cu(I) state. This study emphasizes that monosaccharide platforms are appropriate ligand backbones for a delicate geometric control at the metal center, with a network of weak interactions within the ligand. This structuration availing in glycoligands makes them attractive for metallic entasis.

'Auto-click' functionalization for diversified copper(I) and gold(I) NHCs.

Azide-tagged Cu(I)-NHC reacts in an 'auto-click' process to furnish complexes functionalized by 1,2,3-triazoles bearing diverse substituents. The resulting Cu(I) complexes are amenable to further transmetallation to Au(I). The whole strategy proceeds with mild conditions and constitutes an efficient entry to functionalised metal-NHCs with biorelevant moieties.

Use of copper(I) catalyzed azide alkyne cycloaddition (CuAAC) for the preparation of conjugated pyrrolo[2,3-a]carbazole Pim kinase inhibitors.

We have previously demonstrated that pyrrolo[2,3-a]carbazole-3-carbaldehydes are potent Pim kinase inhibitors with in vitro antiproliferative activities. In the present study, we report the synthesis of new pyrrolocarbazoles substituted at the N-10 position. When their ability to inhibit Pim kinase activities were evaluated in in vitro assays, we observed that this nitrogen atom can be substituted without loss of Pim-1 and Pim-3 inhibitory potencies. Moreover, when we added a fluorescent dansyl group (compound 13), we were able to show that 13 penetrates the plasma membrane and enters the cytoplasm.

Lanthanide-binding peptides with two pendant aminodiacetate arms: impact of the sequence on chelation.

Lanthanide complexes with a series of hexapeptides-incorporating two unnatural chelating amino acids with aminodiacetate groups, Ada(1) and Ada(2)-have been examined in terms of their speciation, structure, stability and luminescence properties. Whereas Ada(2) acts as a tridentate donor in all cases, Ada(1) may act as a tetradentate donor thanks to the coordination of the amide carbonyl function assisted by the formation of a six-membered chelate ring. The position of the Ada(1) residue in the sequence is demonstrated to be critical for the lanthanide complex speciation and structure. Ada(1) promotes the coordination of the backbone amide function to afford a highly dehydrated Ln complex and an S-shape structure of the peptide backbone, only when found in position 2.

Advances in metal-carbene complexes as potent anti-cancer agents.

This critical review is an updated survey of metal-carbenes as potential anticancer chemotherapeutics. We report on the recent advances in the discovery of N-heterocyclic carbenes, acyclic diamino carbenes and abnormal NHCs associated with metals from groups 10 and 11 that displayed antiproliferative activity and emphasize, when possible, their molecular target(s) and their mechanism of action.

A platinum Chugaev carbene complex as a potent anticancer agent.

A platinum Chugaev complex was synthesised and fully characterized by multinuclear NMR spectroscopy and X-ray crystallography. This cis bis acyclic diamino carbene complex acts as a cytotoxic compound and behaves as a cisplatin equivalent by interacting with supercoiled DNA and thiols. Stability of the ligand is also discussed.

A lanthanide binding peptide with short chelating side-chains: structural impact of the backbone coordination.

A lanthanide-binding hexapeptide containing two short aminodiacetate side-chains favours the coordination of a backbone carbonyl, which determines the secondary structure of the complex and illustrates the interplay between complex formation and secondary peptide structures.

Lanthanide(III) complexes with two hexapeptides incorporating unnatural chelating amino acids: secondary structure and stability.

Unnatural metal-chelating amino acids bearing aminodiacetate side-chains have been introduced into two hexapeptides to obtain efficient lanthanide-binding peptides. The synthesis of the enantiopure Fmoc-Ada(n)(tBu)2-OH synthons is described with overall yields of 32 and 50% for n=2 and n=3 side-chain carbon atoms, respectively. The two peptides AcWAda(n)PGAda(n)GNH2 (Pn) were synthesized from the protected synthons by standard solid-phase peptide synthesis. Studies of the lanthanide complexes of the two peptides Pn by luminescence titrations, mass spectrometry, circular dichroism, and solution NMR spectroscopy demonstrate that the Ada(n) chain length has a dramatic effect on the complexation properties. Indeed, the flexible compound P3 forms a mononuclear complex of moderate stability (beta11=10(9.9)), which tends to transform into a binuclear species in the presence of excess of the metal ion. Interestingly, the more compact peptide P2 provides stable Ln3+ complexes with the exclusive formation of the mononuclear LnP2 adduct. The stability constant of TbP2 is two orders of magnitude higher (beta11=10(12.1)) than that measured for P3. The 800 MHz NMR spectrum of the La3+ complex of P2 evidences a well-defined type II beta-turn as well as a hydrophobic Trp(indole)-Pro interaction. These interactions exemplify the non-innocent character of the peptide spacer in the complex LaP2 as well as the role of a peptide secondary structure in the stabilization of metal complexes.

Determination of chemical shift anisotropy tensors of carbonyl nuclei in proteins through cross-correlated relaxation in NMR.

The principal components and orientations of the chemical shift anisotropy (CSA) tensors of nearly all 13C carbonyl nuclei in a small protein have been determined in isotropic solution by a combination of three complementary cross-correlation measurements.