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).
Copyright and reuse:The Warwick Research Archive Portal (WRAP) makes this work of researchers of the University of Warwick available open access under the following conditions. Copyright © and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable the material made available in WRAP has been checked for eligibility before being made available.Copies of full items can be used for personal research or study, educational, or not-forprofit purposes without prior permission or charge. Provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. Publisher's statement:This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/ja502789eThe version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP url' above for details on accessing the published version and note that access may require a subscription. ABSTRACT: Stereochemistry is a very important issue for pharmaceutical industry and can determine drug efficacy. Design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid (Aβ) aggregation represent valid therapeutic strategies for treatment of Alzheimer's disease (AD). Herein we report that two triple-helical dinuclear metallo-supramolecular complexes can act as a novel class of chiral amyloid-β inhibitors. Through targeting α/β-discordant stretches at the early steps of aggregation, these metal complexes can enantioselectively inhibit Aβ aggregation, which are demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, there is no report to show that a chiral compound can enantioselectively inhibit Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier (BBB) and have SOD activity. Previous studies have demonstrated that chiral discrimination between enantiomers is extremely important, as stereopure drugs can often reduce the total dose of drug given and minimize any toxicity resulting from the inactive enantiomer. And this is also a critical factor which should be carefully considered in AD treatment. Our work provides new insights into chiral inhibition of Aβ aggregation and opens a new avenue for design and screening of chiral agents as Aβ inhibitors against AD.
Optically pure, single diastereomer fac-tris(diimine) complexes of Fe(II) are available from a remarkably facile one-pot procedure using a range of readily available (R)-2-phenylglycinol derivatives.
These authors contributed equally to this work An antiparallel strand arrangement in water-soluble helicates creates an amphipathic functional topology akin to that of host-defence peptides. High and selective cancer cell line toxicity is exhibited, causing dramatic changes in the cell cycle without DNA damage, and remarkably there is no significant toxicity to MRSA and E. coli.
One-pot reactions of 2-pyridinecarboxaldehyde, chiral phenylethanamines and Fe(II) give single diastereomer fac diimine complexes at thermodynamic equilibrium so that no chiral separations are required (d.r. > 200 : 1). The origins of this stereoselectivity are partly steric and partly a result of the presence of three sets of inter-ligand parallel-offset π-stacking interactions. Mn(II), Co(II), Co(III), Ni(II) and Zn(II) give similar fac structures, alongside the imidazole analogues for Fe(II). While most of the complexes are paramagnetic, the series of molecular structures allows us to assess the influence of the π-stacking present, and there is a strong correlation between this and the M-N bond length. Fe(II) is close to optimal. For the larger Zn(II) ion, very weak π-stacking leads to poorer measured stereoselectivity (NMR) but this is improved with increased solvent polarity. The mechanism of stereoselection is further investigated via DFT calculations, chiroptical spectroscopy and the use of synthetic probes.
Methods by which helical bimetallic assemblies may be accessed as single isomers are described and reviewed. While there are a number of notable successes, the conclusion is made that no existing approach satisfies the criteria which will allow these fascinating compounds to emerge from the synthetic research laboratory environment to practical application in e.g. healthcare. For this to be achieved the compounds must be optically pure and non-racemising, soluble and chemically stable in water, readily available on a large scale, chemically diverse and synthetically robust.
YesEnantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that\ud of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian\ud carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line\ud HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower\ud than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is\ud probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and\ud intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy\ud and supported by circular/linear dichroism in solution. Selectivity for 50-CACATA and 50-CACTAT\ud segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are\ud stabilised, and remarkably only the L metallo-helix enantiomer stabilizes T-shaped 3WJs during gel\ud electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide\ud duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the\ud number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible\ud metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the\ud cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all\ud compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage\ud occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase,\ud and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together\ud these screening and mechanistic results are consistent with the more rigid helices acting via a DNA\ud binding mechanism while the flexible assemblies do not
The design and synthesis of metal complexes that can specifically target DNA secondary structure has attracted considerable attention. Chiral metallosupramolecular complexes (e.g. helicates) in particular display unique DNA-binding behavior, however until recently few examples which are both water-compatible and enantiomerically pure have been reported. Herein we report that one metallohelix enantiomer Δ1a, available from a diastereoselective synthesis with no need for resolution, can enantioselectively stabilize human telomeric hybrid G-quadruplex and strongly inhibit telomerase activity with IC50 of 600 nM. In contrast, no such a preference is observed for the mirror image complex Λ1a. More intriguingly, neither of the two enantiomers binds specifically to human telomeric antiparallel G-quadruplex. To the best of our knowledge, this is the first example of one pair of enantiomers with contrasting selectivity for human telomeric hybrid G-quadruplex. Further studies show that Δ1a can discriminate human telomeric G-quadruplex from other telomeric G-quadruplexes.
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