[Fe?L?]?? cylinders derived from bis(bidentate) 2-pyridyl-1,2,3-triazole "click" ligands: synthesis, structures and exploration of biological activity.
ABSTRACT: A series of metallosupramolecular [Fe?L?](BF?)? "click" cylinders have been synthesized in excellent yields (90%-95%) from [Fe(H?O)?](BF?)? and bis(bidentate) pyridyl-1,2,3-triazole ligands. All complexes were characterized by elemental analysis, IR, UV-vis, ¹H-, ¹³C- and DOSY-NMR spectroscopies and, in four cases, the structures confirmed by X-ray crystallography. Molecular modeling indicated that some of these "click" complexes were of similar size and shape to related biologically active pyridylimine-based iron(II) helicates and suggested that the "click" complexes may bind both duplex and triplex DNA. Cell-based agarose diffusion assays showed that the metallosupramolecular [Fe?L?](BF?)? "click" cylinders display no antifungal activity against S. cerevisiae. This observed lack of antifungal activity appears to be due to the poor stability of the "click" complexes in DMSO and biological media.
Project description:Two new di(2,2'-bipyridine) ligands, 2,6-bis([2,2'-bipyridin]-5-ylethynyl)pyridine (<b>L1</b>) and bis(4-([2,2'-bipyridin]-5-ylethynyl)phenyl)methane (<b>L2</b>) were synthesized and used to generate two metallosupramolecular [Fe<sub>2</sub>(<b>L</b>)<sub>3</sub>](BF<sub>4</sub>)<sub>4</sub> cylinders. The ligands and cylinders were characterized using elemental analysis, electrospray ionization mass spectrometry, UV-vis, <sup>1</sup>H-, <sup>13</sup>C and DOSY nuclear magnetic resonance (NMR) spectroscopies. The molecular structures of the [Fe<sub>2</sub>(<b>L</b>)<sub>3</sub>](BF<sub>4</sub>)<sub>4</sub> cylinders were confirmed using X-ray crystallography. Both the [Fe<sub>2</sub>(<b>L1</b>)<sub>3</sub>](BF<sub>4</sub>)<sub>4</sub> and [Fe<sub>2</sub>(<b>L2</b>)<sub>3</sub>](BF<sub>4</sub>)<sub>4</sub> complexes crystallized as racemic (<i>rac</i>) mixtures of the ΔΔ (P) and ΛΛ (M) helicates. However, <sup>1</sup>H NMR spectra showed that in solution the larger [Fe<sub>2</sub>(<b>L2</b>)<sub>3</sub>](BF<sub>4</sub>)<sub>4</sub> was a mixture of the <i>rac</i>-ΔΔ/ΛΛ and <i>meso</i>-ΔΛ isomers. The host-guest chemistry of the helicates, which both feature a central cavity, was examined with several small drug molecules. However, none of the potential guests were found to bind within the helicates. <i>In vitro</i> cytotoxicity assays demonstrated that both helicates were active against four cancer cell lines. The smaller [Fe<sub>2</sub>(<b>L1</b>)<sub>3</sub>](BF<sub>4</sub>)<sub>4</sub> system displayed low μM activity against the HCT116 (IC<sub>50</sub> = 7.1 ± 0.5 μM) and NCI-H460 (IC<sub>50</sub> = 4.9 ± 0.4 μM) cancer cells. While the antiproliferative effects against all the cell lines examined were less than the well-known anticancer drug cisplatin, their modes of action would be expected to be very different.
Project description:A small family of [Co?(<b>L<sub>pytrz</sub></b>)?]<sup>6+</sup> cylinders was synthesised from bis(bidentate) 2-pyridyl-1,2,3-triazole "click" ligands (<b>L<sub>pytrz</sub></b>) through an "assembly-followed-by-oxidation" method. The cylinders were characterised using ¹H, <sup>13</sup>C, and DOSY NMR, IR, and UV-Vis spectroscopies, along with electrospray ionisation mass spectrometry (ESMS). Stability studies were conducted in dimethyl sulfoxide (DMSO) and D?O. In contrast to similar, previously studied, [Fe?(<b>L<sub>pytrz</sub></b>)?]<sup>4+</sup> helicates the more kinetically inert [Co?(<b>L<sub>pytrz</sub></b>)?]<sup>6+</sup> systems proved stable (over a period of days) when exposed to DMSO and were even more stable in D?O. The triply stranded [Co?(<b>L<sub>pytrz</sub></b>)?]<sup>6+</sup> systems and the corresponding "free" ligands were tested for antimicrobial activity in vitro against both Gram-positive (<i>Staphylococcus aureus</i>) and Gram-negative (<i>Escherichia coli</i>) microorganisms. Agar-based disk diffusion and Mueller-Hinton broth micro-dilution assays showed that the [Co?(<b>L<sub>pytrz</sub></b>)?]<sup>6+</sup> cylinders were not active against either strain of bacteria. It is presumed that a high charge of the [Co?(<b>L<sub>pytrz</sub></b>)?]<sup>6+</sup> cylinders is preventing them from crossing the bacterial cell membranes, rendering the compounds biologically inactive.
Project description:Shape-selective recognition of nucleic acid structures by supramolecular drugs offers the potential to treat disease. The Trans Activation Response (TAR) region is a region of high secondary structure within the human immunodeficiency virus-1 (HIV-1) RNA that complexes with the virus-encoded Transactivator protein (TAT) and regulates viral transcription. Herein, we explore different metallo-supramolecular triple stranded helicates (cylinders) that target the TAR bulge motif and inhibit the formation of TAR-TAT complexes and HIV infection. Cylinders that incorporate Ni(II) and Ru(II) showed the most potent anti-viral activity with limited evidence of cellular cytotoxicity. These metallo-supramolecular compounds provide an exciting avenue for developing a new class of anti-viral agents.
Project description:An enantiomerically pure diamine based on the 4,15-difunctionalized [2.2]paracyclophane scaffold and 2-formylpyridine self-assemble into an optically pure cyclic metallosupramolecular Fe<sub>4</sub> L<sub>6</sub> helicate upon mixing with iron(II) ions in a diastereoselective subcomponent self-assembly process. The cyclic assembly results from steric strain that prevents the formation of a smaller linear dinuclear triple-stranded helicate, and hence, leads to the larger strain-free assembly that fulfils the maximum occupancy rule. Interestingly, use of the racemic diamine also leads to a racemic mixture of the homochiral cyclic helicates as the major product in a highly diastereoselective narcissistic chiral self-sorting manner given the fact that the assembly contains ten stereogenic elements, which can in principle give rise to 149?different diastereomers. The metallosupramolecular aggregates could be characterized by NMR, UV/Vis and CD spectroscopy, mass spectrometry, and X-ray crystallography.
Project description:The interaction between the HIV-1 transactivator protein Tat and TAR (transactivation responsive region) RNA, plays a critical role in HIV-1 transcription. Iron(II) supramolecular helicates were evaluated for their in vitro activity to inhibit Tat-TAR RNA interaction using UV melting studies, electrophoretic mobility shift assay, and RNase A footprinting. The results demonstrate that iron(II) supramolecular helicates inhibit Tat-TAR interaction at nanomolar concentrations by binding to TAR RNA. These studies provide a new insight into the biological potential of metallosupramolecular helicates.
Project description:A new "click" ligand, 2,6-bis(1-(pyridin-4-ylmethyl)-1H-1,2,3-triazol-4-yl)pyridine (L) featuring a tridentate 2,6-bis(1,2,3-triazol-4-yl)pyridine (tripy) pocket and two pyridyl (py) units was synthesized in modest yield (42%) using the copper(I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The coordination chemistry of the ligand with silver(I) and iron(II) ions was examined using a battery of solution (¹H and DOSY (diffusion ordered spectroscopy) nuclear magnetic resonance (NMR), infrared and absorption spectroscopies, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)), and solid state (X-ray crystallography, elemental analysis) techniques. When treated with silver(I) ions, the ligand forms discrete [Ag(L)]? (X-, where X- = BF?-, NO?- or SbF?-) complexes in dimethyl sulfoxide (DMSO) solution but these complexes crystallize as coordination polymers. The addition of [Fe(H?O)?](BF?)? to an acetonitrile solution of the ligand forms the expected monomeric octahedral [Fe(L)?]2+ complex and treatment of the iron(II) complex with AgBF? generates a heterometallic linear coordination polymer.
Project description: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.
Project description:Helicates and related metallofoldamers, synthesised by dynamic self-assembly, represent an area of chemical space inaccessible by traditional organic synthesis, and yet with potential for discovery of new classes of drug. Here we report that water-soluble, optically pure Fe(ii)- and even Zn(ii)-based triplex metallohelices are an excellent platform for post-assembly click reactions. By these means, the in vitro anticancer activity and most importantly the selectivity of a triplex metallohelix Fe(ii) system are dramatically improved. For one compound, a remarkable array of mechanistic and pharmacological behaviours is discovered: inhibition of Na+/K+ ATPase with potency comparable to the drug ouabain, antimetastatic properties (including inhibition of cell migration, re-adhesion and invasion), cancer stem cell targeting, and finally colonosphere inhibition competitive with the drug salinomycin.
Project description:The reaction of a series of thiolate-ligated iron(II) complexes [Fe(II)(aneN(4))(SC(6)H(5))]BF(4) (1), [Fe(II)(aneN(4))(SC(6)H(4)-p-Cl)]BF(4) (2), and [Fe(II)(aneN(4))(SC(6)H(4)-p-NO(2))]BF(4) (3) with alkylhydroperoxides at low temperature (-78 °C or -40 °C) leads to the metastable alkylperoxo-iron(III) species [Fe(III)(aneN(4))(SC(6)H(5))(OOtBu)]BF(4) (1a), [Fe(III)(aneN(4))(SC(6)H(4)-p-Cl)(OOtBu)]BF(4) (2a), and [Fe(III)(aneN(4))(SC(6)H(4)-p-NO(2))(OOtBu)]BF(4) (3a), respectively. X-ray absorption spectroscopy (XAS) studies were conducted on the Fe(III)-OOR complexes and their iron(II) precursors. The edge energy for the iron(II) complexes (?7118 eV) shifts to higher energy upon oxidation by ROOH, and the resulting edge energies for the Fe(III)-OOR species range from 7121-7125 eV and correlate with the nature of the thiolate donor. Extended X-ray absorption fine structure (EXAFS) analysis of the iron(II) complexes 1-3 in CH(2)Cl(2) show that their solid state structures remain intact in solution. The EXAFS data on 1a-3a confirm their proposed structures as mononuclear, 6-coordinate Fe(III)-OOR complexes with 4N and 1S donors completing the coordination sphere. The Fe-O bond distances obtained from EXAFS for 1a-3a are 1.82-1.85 Å, significantly longer than other low-spin Fe(III)-OOR complexes. The Fe-O distances correlate with the nature of the thiolate donor, in agreement with the previous trends observed for ?(Fe-O) from resonance Raman (RR) spectroscopy, and supported by optimized geometries obtained from density functional theory (DFT) calculations. Reactivity and kinetic studies on 1a- 3a show an important influence of the thiolate donor.
Project description:Considerable attention has been given to deep-learning and machine-learning techniques in an effort to reduce the computational cost of computational fluid dynamics simulation. The present paper addresses the prediction of steady flows passing many fixed cylinders using a deep-learning model and investigates the accuracy of the predicted velocity field. The deep-learning model outputs the x- and y-components of the flow velocity field when the cylinder arrangement is input. The accuracy of the predicted velocity field is investigated, focusing on the velocity profile of the fluid flow and the fluid force acting on the cylinders. The present model accurately predicts the flow when the number of cylinders is equal to or close to that set in the training dataset. The extrapolation of the prediction to a smaller number of cylinders results in error, which can be interpreted as internal friction of the fluid. The results of the fluid force acting on the cylinders suggest that the present deep-learning model has good generalization performance for systems with a larger number of cylinders.