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

Abstract

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).

The antimicrobial and antibiofilm activities of copper(II) complexes

“…This has been found to be an important component of the extracellular matrix of biofilms, and for instance DNAse treatment significantly reduces the biomass of biofilms of S. aureus and other bacteria [28]. However, a number of other DNAbinding metallo-complexes that we tested have no or barely any activity on biofilms, including the aforementioned compounds 10 and 11, as well as other compounds such as major groove-binding complexes of iron [22] or ruthenium [23] (data not shown). It is well known that many coordination complexes with copper, but not those with platinum or palladium, are redox active and can mediate DNA cleavage [17].…”

“…In recent years we have investigated the antimicrobial activity of compounds containing iron, ruthenium, copper and palladium [16,[21][22][23][24]. All of these compounds have been reported to bind DNA, either through groove binding or intercalation.…”

“…All of these compounds have been reported to bind DNA, either through groove binding or intercalation. Several compounds showed good antimicrobial activity on both Gramnegative and Gram-positive bacteria, albeit that the latter are generally more sensitive to metal complexes [16,[21][22][23][24]. These complexes have only been tested on planktonic cells, and we therefore sought to investigate the activity of a panel of copper(II) complexes against biofilms, and focussed this specifically on a clinical isolate of meticillin-resistant Staphylococcus aureus (MRSA) that is capable of forming stable 5 biofilms.…”

Accelerated single photon emission from dye molecule-driven nanoantennas assembled on DNA

“…As mentioned earlier, cationic dyes tend to bind to DNA, hindering their rotational degrees of freedom 23 . In practice, large dye molecules typically interact with the DNA grooves, favouring a π/4 molecular orientation 27 . For θ = π/4, Γ/Γ 0 decreases nearly exponentially with d in the 4-10 nm range for both dimers and single gold particles (see Fig.…”

Asymmetric triplex metallohelices with high and selective activity against cancer cells

“…32,33 These compounds are highly symmetrical, with the general structure of Fig1(a). We previously established that the very high stereoselection ( v. ) in the monometallics arises largely from steric effects, while the arene -interactions shown are principally responsible for fac/mer selectivity and the unusual stability of flexicates in water.…”