Optically pure, water-stable metallo-helical ‘flexicate’ assemblies with antibiotic activity

The helicates—chiral assemblies of two or more metal atoms linked by short or relatively rigid multidentate organic ligands—may be regarded as non-peptide mimetics of α-helices because they are of comparable size and have shown some relevant biological activity. Unfortunately, these beautiful helical compounds have remained difficult to use in the medicinal arena because they contain mixtures of isomers, cannot be optimized for specific purposes, are insoluble, or are too difficult to synthesize. Instead, we have now prepared thermodynamically stable single enantiomers of monometallic units connected by organic linkers. Our highly adaptable self-assembly approach enables the rapid preparation of ranges of water-stable, helicate-like compounds with high stereochemical purity. One such iron(II) ‘flexicate’ system exhibits specific interactions with DNA, promising antimicrobial activity against a Gram-positive bacterium (methicillin-resistant Staphylococcus aureus, MRSA252), but also, unusually, a Gram-negative bacterium (Escherichia coli, MC4100), as well as low toxicity towards a non-mammalian model organism (Caenorhabditis elegans)

MALDI imaging mass spectrometry for direct tissue analysis: a new frontier for molecular histology

Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) is a powerful tool for investigating the distribution of proteins and small molecules within biological systems through the in situ analysis of tissue sections. MALDI-IMS can determine the distribution of hundreds of unknown compounds in a single measurement and enables the acquisition of cellular expression profiles while maintaining the cellular and molecular integrity. In recent years, a great many advances in the practice of imaging mass spectrometry have taken place, making the technique more sensitive, robust, and ultimately useful. In this review, we focus on the current state of the art of MALDI-IMS, describe basic technological developments for MALDI-IMS of animal and human tissues, and discuss some recent applications in basic research and in clinical settings

Paper: a cheap yet effective chiral stationary phase for chromatographic resolution of metallo-supramolecular helicates

Simple paper chromatography using brine as an eluent affords the two enantiomers of metallo-supramolecular triple-helicates. The technique may be scaled up for preparative resolution by using cellulose columns in conventional column chromatography

Revolutionizing resin handling for combinatorial synthesis

Without the stereodirecting ability of 2-substituents, strategies to prepare 2-deoxyglycosides selectively in high alpha- or beta-anomeric forms rely heavily on indirect sequences from glycals or latent 2-deoxysugars. As such, these require a subsequent reductive step that would be unsuitable for many complex natural products and for any viable total synthesis program. A case in point is that of the kedarcidin chromophore and its alpha-linked 2,6-dideoxysugars, L-mycarose and L-kedarosamine. In particular, direct and efficient alpha-selective methods for allo-configured systems are especially difficult to realise. Herein we describe a direct, potent, and mild protocol to efficiently generate alpha-L-mycarosides from thioglycosides by using AgPF6, which is exemplified by the alpha-mycosylation of an advanced kedarcidin substructure. Although the present method is applicable to other 2-deoxy systems, such as the synthesis of alpha-L-kedarosaminides, normal 2-oxythioglycosides remain inert to AgPF6 and can be used as acceptors armed with strategic anomeric linkages

Intramolecular DNA coiling mediated by metallo-supramolecular cylinders: Differential binding of P and M helical enantiomers

We have designed a synthetic tetracationic metallo-supramolecular cylinder that targets the major groove of DNA with a binding constant in excess of 10(7) M(−1) and induces DNA bending and intramolecular coiling. The two enantiomers of the helical molecule bind differently to DNA and have different structural effects. We report the characterization of the interactions by a range of biophysical techniques. The M helical cylinder binds to the major groove and induces dramatic intramolecular coiling. The DNA bending is less dramatic for the P enantiomer

MALDI-In Source Decay Applied to Mass Spectrometry Imaging: A New Tool for Protein Identification.

Matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS) imaging is a powerful technique giving access to the distribution of a large range of biomolecules directly from a tissue section, allowing, for example, the discovery of new pathological biomarkers. Nevertheless, one main difficulty lies in the identification of the detected species, especially proteins. MALDI-in source decay (ISD) is used to fragment ions directly in the mass spectrometer ion source. This technique does not require any special sample treatment but only the use of a specific MALDI matrix such as 2,5-dihydroxybenzoic acid or 1,5-diaminonaphthalene. MALDI-ISD is generally employed on classical, purified samples, but here we demonstrate that ISD can also be performed directly on mixtures and on a tissue slice leading to fragment ions, allowing the identification of major proteins without any further treatment. On a porcine eye lens slice, de novo sequencing was even performed. Crystallins not yet referenced in databases were identified by sequence homology with other mammalian species. On a mouse brain slice, we demonstrate that results obtained with ISD are comparable and even better than those obtained with a classical in situ digestion