Sofia I. Pascu

Cellular confocal fluorescence studies and cytotoxic activity of new Zn(II) bis(thiosemicarbazonato) complexes

We report the synthesis and characterisation of new, highly fluorescent, zinc complexes of bis(thiosemicarbazone) ligands incorporating extended aromatic backbones which are cytotoxic at levels comparable to cisplatin; cellular fluorescence imaging studies suggest these cause cell death by disruption of mitochondria.

Probing flexibility in porphyrin-based molecular wires using double electron electron resonance.

A series of butadiyne-linked zinc porphyrin oligomers, with one, two, three, and four porphyrin units and lengths of up to 75 A, have been spin-labeled at both ends with stable nitroxide TEMPO radicals. The pulsed EPR technique of double electron electron resonance (DEER) was used to probe the distribution of intramolecular end-to-end distances, under a range of conditions. DEER measurements were carried out at 50 K in two types of dilute solution glasses: deutero-toluene (with 10% deutero-pyridine) and deutero-o-terphenyl (with 5% 4-benzyl pyridine). The complexes of the porphyrin oligomers with monodentate ligands (pyridine or 4-benzyl pyridine) principally adopt linear conformations. Nonlinear conformations are less populated in the lower glass-transition temperature solvent. When the oligomers bind star-shaped multidentate ligands, they are forced to bend into nonlinear geometries, and the experimental end-to-end distances for these complexes match those from molecular mechanics calculations. Our results show that porphyrin-based molecular wires are shape-persistent, and yet that their shapes can deformed by binding to multivalent ligands. Self-assembled ladder-shaped 2:2 complexes were also investigated to illustrate the scope of DEER measurements for providing structural information on synthetic noncovalent nanostructures.

Interlocked Host Anion Recognition by an Indolocarbazole-Containing [2]Rotaxane

The design, synthesis, structure, and anion-binding properties of the first indolocarbazole-containing interlocked structure are described. The novel [2]rotaxane molecular structure incorporates a neutral indolocarbazole-containing axle component which is encircled by a tetracationic macrocycle functionalized with an isophthalamide anion recognition motif. (1)H NMR and UV-visible spectroscopies and X-ray crystallography demonstrated the importance of pi-donor-acceptor, CH...pi, and electrostatic interactions in the assembly of pseudorotaxanes between the electron-deficient tetracationic macrocycle and a series of pi-electron-rich indolocarbazole derivatives. Subsequent urethane stoppering of one of these complexes afforded a [2]rotaxane, which was shown by (1)H NMR spectroscopic titration experiments to exhibit enhanced chloride and bromide anion recognition compared to its non-interlocked components. Computational molecular dynamics simulations provide further insight into the mechanism and structural nature of the anion recognition process, confirming it to involve cooperative hydrogen-bond donation from both macrocycle and indolocarbazole components of the rotaxane. The observed selectivity of the [2]rotaxane for chloride is interpreted in terms of its unique interlocked binding cavity, defined by the macrocycle isophthalamide and indolocarbazole N-H protons, which is complementary in size and shape to this halide guest.

Stabilisation of a heptamethine cyanine dye by rotaxane encapsulation

The crystal structure of a cyanine dye rotaxane shows that the cyclodextrin is tightly threaded round the polymethine bridge of the dye; encapsulation dramatically increases the kinetic chemical stability of the radicals formed on oxidation and reduction of the dye, making it possible to observe the rotaxane radical dication by ESR and UV-vis-NIR spectroscopy.

The Development of Boronic Acids as Sensors and Separation Tools

Synthetic receptors for diols that incorporate boronic acid motifs have been developed as new sensors and separation tools. Utilizing the reversible interactions of diols with boronic acids to form boronic esters under new binding regimes has provided new hydrogel constructs that have found use as dye-displacement sensors and electrophoretic separation tools; similarly, molecular boronic-acid-containing chemosensors were constructed that offer applications in the sensing of diols. This review provides a somewhat-personal perspective of developments in boronic-acid-mediated sensing and separation, placed in the context of the seminal works of others in the area, as well as offering a concise summary of the contributions of the co-authors in the area.

Engineering conjugation in para-phenylene-bridged porphyrin tapes

We report the synthesis of 7 new para-phenylene-bridged zinc porphyrin dimers, five of which were characterized by single-crystal X-ray analysis. A variety of links were tested for holding the para-phenylene bridges in π-conjugation with the porphyrins, and the natures of these restraining links strongly influence the properties of the porphyrin dimers. The keto-linked dimer exhibits a long-lived singlet excited state and strong fluorescence at 960 nm (1.7% quantum yield) in contrast to most previously reported conjugated porphyrin tapes, which are essentially non-emissive. Replacement of the cross-conjugated keto links by directly conjugated C–C bonds eradicates the fluorescence and shifts the absorption maximum to 1077 nm. On the other hand, replacement of the keto links with non-conjugated CPh2 links confers fluorescence at 736 nm (10% quantum yield) and results in remarkably similar one- and two-photon absorption behavior to that of meso–meso ethynylene-bridged porphyrin dimers (peak two-photon cross section: 7,300 GM at 878 nm). Cross-conjugated keto links do more than just hold the para-phenylene bridge coplanar with the porphyrins; they reduce the HOMO–LUMO gap, although to a lesser extent than direct π-conjugated links. Planarized para-phenylene-bridged porphyrin dimers provide insights into the relationship between previously investigated classes of conjugated porphyrin oligomers, and they open up possibilities for the synthesis of new types of near-IR two-photon absorbing dyes.

Fluorescent copper(II) bis(thiosemicarbazonates): synthesis, structures, electron paramagnetic resonance, radiolabeling, in vitro cytotoxicity and confocal fluorescence microscopy studies.

Copper bis(4-ethyl-3-thiosemicarbazonato) acenaphthenequinone (1) and copper bis(4-methyl-3-thiosemicarbazonato) acenaphthenequinone (2) are synthesized and characterized in solution, in the solid state, and radiolabeled. Serum-protein binding radioassays show good stability in solution and about 25 % binding to protein over 1 h, which is comparable with the hypoxia selective tracer [(64)Cu(ATSM)]. Cyclic voltammetry shows fast and reversible reduction at redox potentials similar to the values known for hypoxia-selective copper compounds. However, despite this, complex 1 does not show any hypoxic-selective uptake in HeLa cells over 1-h standard assays. Possible reasons for this are studied by using the intrinsic fluorescence of the Cu(II) complexes to determine the cellular distributions and uptake mechanism by confocal microscopy. The complexes are found to bind to the external cell membrane and disperse evenly in the cytoplasm only after a very slow cell internalization (>1 h). No significant changes in distribution are observed by fluorescence imaging under hypoxic conditions. The rate of localization in the cytoplasm contrasts with their Zn(II) analogues, which are known to have fast cell uptake (up to 20 min) and a clear localization in lysosomes and mitochondria. The cytotoxicity mechanism of 1 over 24 h against a number of adherent cell lines is seen to be by membrane disruption and is of a comparable magnitude to that of [Cu(ATSM)], as demonstrated by methyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays.

The effect of fluorinated aryl substituents on the crystal structures of 1,2,3,5-dithiadiazolyl radicals

The crystal structures of six new partially fluorinated aryl 1,2,3,5-dithiadiazolyls [ArCNSSN]˙ are reported [Ar = 2,6-F2C6H3 (4); Ar = 3,4-F2C6H3 (5); Ar = 3,5-F2C6H3 (6); Ar = 2,3,6-F3C6H2 (9); Ar = 2,4,6-F3C6H2 (11); and Ar = 3,4,5-F3C6H2 (12)] and compared with three previously reported structures in this series (Ar = 2,3-F2C6H3 (1); Ar = 2,5-F2C6H3 (3); Ar = 2,3,4-F3C6H2 (7)]. Radical 4 is shown to be polymorphic. Molecular electrostatic potential maps have been used to rationalise these structures. These reveal that whilst single F atoms appear to have little structure-directing influence, combinations of an ortho-F on the phenyl ring and a heterocyclic ring N, or several F atoms located in mutually ortho positions with respect to each other, generate significant regions of negative charge which have a substantial structure-directing influence.

Synthesis and evaluation of a boronate-tagged 1,8-naphthalimide probe for fluoride recognition

A biocompatible fluoride receptor has been developed where the interaction between the boronic acid ester and amine (NH) results in fluoride ion selectivity and enhanced fluorescence quenching.

Fluorescent gallium and indium bis(thiosemicarbazonates) and their radiolabelled analogues: Synthesis, structures and cellular confocal fluorescence imaging investigations

New fluorescent and biocompatible aromatic Ga(III)- and In(III)-bis(thiosemicarbazonato) complexes for dual mode optical and PET or SPECT molecular imaging have been synthesised via a synthetic method based on transmetallation reactions from Zn(II) precursors. Complexes have been fully characterised in the solid state by single crystal X-ray diffraction and in solution by spectroscopic methods (UV/Vis, fluorescence, (1)H and (13)C{(1)H} NMR). The bis(thiosemicarbazones) radiolabelled rapidly in high yields under mild conditions with (111)In (a gamma and Auger emitter for SPECT imaging and radiotherapy with t(1/2) = 2.8 d) and (68)Ga (a generator-available positron emitter for PET imaging with t(1/2) = 68 min). Cytotoxicity and biolocalisation studies using confocal fluorescence imaging and fluorescence lifetime imaging (FLIM) techniques have been used to study their in vitro activities and stabilities in HeLa and PC-3 cells to ascertain their suitability as synthetic scaffolds for future multimodality molecular imaging in cancer diagnosis and therapy. The observation that the indium complexes show certain nuclear uptake could be of relevance towards developing (111)In therapeutic agents based on Auger electron emission to induce DNA damage.