Suzanne E. Howson
University of Warwick
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Featured researches published by Suzanne E. Howson.
Chemical Communications | 2009
Suzanne E. Howson; Laura E. N. Allan; Nikola Paul Chmel; Guy J. Clarkson; Remy van Gorkum; Peter Scott
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.
Dalton Transactions | 2011
Suzanne E. Howson; Laura E. N. Allan; Nikola Paul Chmel; Guy J. Clarkson; Robert J. Deeth; Alan D. Faulkner; Daniel Simpson; Peter Scott
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.
Journal of the American Chemical Society | 2014
Meng Li; Suzanne E. Howson; Kai Dong; Nan Gao; Jinsong Ren; Peter Scott; Xiaogang Qu
Stereochemistry is a very important issue for the pharmaceutical industry and can determine drug efficacy. The design and synthesis of small molecules, especially chiral molecules, which selectively target and inhibit amyloid-β (Aβ) aggregation, represent valid therapeutic strategies for treatment of Alzheimers disease (AD). Herein we report that two triple-helical dinuclear metallosupramolecular 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 is demonstrated using fluorescent living cell-based screening and multiple biophysical and biochemical approaches. To the best of our knowledge, this is the first report of enantioselective inhibition of Aβ aggregation. Intriguingly, as a promising candidate for AD treatment, the chiral metal complex can cross the blood-brain barrier and have superoxide dismutase activity. It is well-known that chiral discrimination is important for understanding chiral drug action. Generally, one enantiomer is pharmaceutically active while the other is inactive or exerts severe side effects. Chiral discrimination should be important for 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.
Chemical Science | 2013
Viktor Brabec; Suzanne E. Howson; Rebecca A. Kaner; Rianne M. Lord; Jaroslav Malina; Roger M. Phillips; Qasem M. A. Abdallah; Patrick C. McGowan; Alison Rodger; Peter Scott
Enantiomers of a relatively rigid DNA-binding metallo-helix are shown to have comparable activity to that of cisplatin against the cell lines MCF7 (human breast adenocarcinoma) and A2780 (human ovarian carcinoma) but are ca five times more active against the cisplatin-resistant A2780cis. The cell-line HCT116 p53+/+ (human colon carcinoma) is highly sensitive giving IC50 values in the nM range, far lower than the cisplatin control. The hypothesis that the biological target of such metallohelices is DNA is probed by various techniques. Tertiary structure changes in ct-DNA (formation of loops and intramolecular coiling) on exposure to the compounds are demonstrated by atomic force microscopy and supported by circular/linear dichroism in solution. Selectivity for 5′-CACATA and 5′-CACTAT segments is shown by DNase I footprinting. Various three- and four-way oligonucleotide junctions are stabilised, and remarkably only the Λ metallo-helix enantiomer stabilizes T-shaped 3WJs during gel electrophoresis; this is despite the lack of a known helix binding site. In studies with oligonucleotide duplexes with bulges it is also shown for the first time that the metallo-helix binding strength and the number of binding sites are dependent on the size of the bulge. In contrast to all the above, flexible metallo-helices show little propensity for structured or selective DNA binding, and while for A2780 the cancer cell line cytotoxicity is retained the A2780cis strain shows significant resistance. For all compounds in the study, H2AX FACS assays on HCT116 p53+/+ showed that no significant DNA damage occurs. In contrast, cell cycle analysis shows that the DNA binders arrest cells in the G2/mitosis phase, and while all compounds cause apoptosis, the DNA binders have the greater effect. Taken together these screening and mechanistic results are consistent with the more rigid helices acting via a DNA binding mechanism while the flexible assemblies do not.
Chirality | 2008
Angeliki Damianoglou; Edward J. Crust; Matthew R. Hicks; Suzanne E. Howson; Alex E. Knight; Jascindra Ravi; Peter Scott; Alison Rodger
To obtain accurate and consistent measurements from circular dichroism (CD) instruments over time and from different laboratories, it is important that they are properly calibrated. The characteristics of the available reference materials are not ideal to ensure proper calibration as they typically only give peaks in one or two spectral regions, and often have issues concerning purity and stability. Currently either camphor sulfonic acid or ammonium camphor sulfonate are used. The latter can be an unstable, slightly hygroscopic secondary standard compound with only one characterized CD band. The former is the very hygroscopic primary standard for which only one enantiomer is readily available. We have synthesized a new reference material for CD, Na[Co(EDDS)].H(2)O (EDDS = N,N-ethylenediaminedisuccinic acid) which addresses these problems. It is extremely stable and available in both enantiomeric forms. The CD spectrum of Na[Co(EDDS)].H(2)O has nine distinct peaks between 180 and 599 nm. It thus fulfils the principal requirements for CD calibration chemical standards and has the potential to be used to ensure good practice in the measurement of CD data, providing two spectra of equal magnitude and opposite sign for a given concentration and path length. We have carried out an interlaboratory comparison using this material and show how it can be used to improve CD comparability between laboratories. A fitting algorithm has been developed to assess CD spectropolarimeter performance between 750 and 178 nm. This could be the basis of a formal quality control process once criteria for performance have been decided.
Dalton Transactions | 2010
Nikola Paul Chmel; Suzanne E. Howson; Laura E. N. Allan; Jim Barker; Guy J. Clarkson; Scott S. Turner; Peter Scott
The first organic-soluble, optically and diastereomerically pure EDDS metal complexes have been synthesised. A number of synthetic approaches were attempted, but finally the tetraphenylphosphonium series emerged as providing readily accessible compounds of trivalent Cr, Fe and Co in reasonable yields via the silver salts without the need to perform ion-exchange chromatography. The species PPh(4)[M(III)(S,S-EDDS)] are very soluble in methanol, acetonitrile and even THF but isolation was facilitated by addition of stoichiometric water giving the highly crystalline but still conveniently soluble title compounds. The structures of the three isomorphous crystals comprise H(2)O-bridged extended hydrogen bonded structures with large channels occupied by the counterion molecules. The magnetic properties and circular dichroism spectra are reported along with comparative data for water-soluble NH(4)[Fe(III)(S,S-EDDS)]. Phase purity (and hence diastereomeric purity) in the paramagnetic systems is assessed through powder XRD. The practical utility of this type of compound was confirmed by optical resolution of (+/-)-[Ru(II)(bpy)(3)]Cl(2).
Dalton Transactions | 2012
Suzanne E. Howson; Nikola Paul Chmel; Guy J. Clarkson; Robert J. Deeth; Daniel Simpson; Peter Scott
Optically pure phenylethaniminopyridine (S(C)-L) tris-chelates of Fe(II) and other first row transition metal systems have previously been shown to give exclusively the fac structures in the solid state. Here it is shown by powder X-ray diffraction that the complex [CuL(3)][ClO(4)](2) crystallises exclusively as the mer isomer, although--for a given absolute configuration of the ligand--of the same helicity (Δ/Λ) as that displayed by the other metal complexes. The similar ligand R(C)-L(F), which contains a peripheral (19)F spin label, gave [CuL(F)(3)][ClO(4)](2) which also adopts exclusively the mer structure in the crystal, but is shown by NMR spectroscopy to have a fac:mer ratio of 1:6 in solution at low temperature. Molecular mechanics calculations for a number of isomers and conformers are consistent with the presence of such a mixture of isomers in solution for both complexes. The origin of the difference in behaviour between Fe(II) and Cu(II) is the presence of a Jahn-Teller distortion (and the generally longer M-N bonds) in the Cu(II) complexes. This disturbs intra-ligand π-stacking, leading to the poor fac/mer stereoselectivity while leaving enantioselectivity Δ/Λ apparently unaffected.
Dalton Transactions | 2011
Suzanne E. Howson; Peter Scott
Intramolecular π-stacking plays a role in diastereomerically pure Fe(II) complexes of certain pyridine/imines, but contrary to a recent report, no such interaction is present in the Cu(II) analogues and the stereoselectivity is as yet unknown.
Nucleic Acids Research | 2017
Andong Zhao; Suzanne E. Howson; Chuanqi Zhao; Jinsong Ren; Peter Scott; Chunyu Wang; Xiaogang Qu
Abstract 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.
Dalton Transactions | 2013
Suzanne E. Howson; Guy J. Clarkson; Alan D. Faulkner; Rebecca A. Kaner; Michael J. Whitmore; Peter Scott
Single diastereomer, diamagnetic, octahedral Fe(II) tris chelate complexes are synthesised that contain three pendant pyridine proligands pre-organised for coordination to a second metal. They bind Cu(I) and Ag(I) with coordination geometry depending on the identity of the metal and the detail of the ligand structure, but for example homohelical (ΔFe,ΔCu) configured systems with unusual trigonal planar Cu cations are formed exclusively in solution as shown by VT-NMR and supported by DFT calculations. Similar heterobimetallic tris(triazole) complexes are synthesised via clean CuAAC reactions at a tris(alkynyl) complex, although here the configurations of the two metals differ (ΔFe,ΛCu), leading to the first optically pure heterohelicates. A second series of Fe complexes perform less well in either strategy as a result of lack of preorganisation.