James I. Bruce

Experimental assessment of the efficacy of sensitised emission in water from a europium ion, following intramolecular excitation by a phenanthridinyl group

The overall quantum yields for phenanthridinium sensitised emission from a europium ion have been measured in H2O and D2O for a series of five structurally related, octadentate ligands in which the distance from the phenanthridinium chromophore to the Eu ion varies from 2.5 to ca. 8.2 A. Overall quantum yields (pD⩽2) range from 0.25 to 0.012 suggesting that the experimental distance for 50% efficiency of intramolecular energy transfer lies close to 5.5 A for this system.

Antioxidant inhibitors potentiate the cytotoxicity of photodynamic therapy

Photodynamic therapy (PDT) is an increasingly popular anticancer treatment that uses photosensitizer, light and tissue oxygen to generate cytotoxic reactive oxygen species (ROS) within illuminated cells. Acting to counteract ROS‐mediated damage are various cellular antioxidant pathways. In this study, we combined PDT with specific antioxidant inhibitors to potentiate PDT cytotoxicity in MCF‐7 cancer cells. We used disulphonated aluminium phthalocyanine photosensitizer plus various combinations of the antioxidant inhibitors: diethyl‐dithiocarbamate (DDC, a Cu/Zn‐SOD inhibitor), 2‐methoxyestradiol (2‐ME, a Mn‐SOD inhibitor), l‐buthionine sulfoximine (BSO, a glutathione synthesis inhibitor) and 3‐amino‐1,2,4‐triazole (3‐AT, a catalase inhibitor). BSO, singly or in combination with other antioxidant inhibitors, significantly potentiated PDT cytotoxicity, corresponding with increased ROS levels and apoptosis. The greatest potentiation of cell death over PDT alone was seen when cells were preincubated for 24 h with 300 μm BSO plus 10 mm 3‐AT (1.62‐fold potentiation) or 300 μm BSO plus 1 μm 2‐ME (1.52‐fold), or with a combination of all four inhibitors (300 μm BSO, 10 mm 3‐AT, 1 μm 2‐ME and 10 μm DDC: 1.4‐fold). As many of these inhibitors have already been clinically tested, this work facilitates future in vivo studies.

Fully protected glycosylated zinc (II) phthalocyanine shows high uptake and photodynamic cytotoxicity in MCF-7 cancer cells

Phthalocyanine photosensitizers are effective in anticancer photodynamic therapy (PDT) but suffer from limited solubility, limited cellular uptake and limited selectivity for cancer cells. To improve these characteristics, we synthesized isopropylidene‐protected and partially deprotected tetra β‐glycosylated zinc (II) phthalocyanines and compared their uptake and accumulation kinetics, subcellular localization, in vitro photocytotoxicity and reactive oxygen species generation with those of disulfonated aluminum phthalocyanine. In MCF‐7 cancer cells, one of the compounds, zinc phthalocyanine {4}, demonstrated 10‐fold higher uptake, 5‐fold greater PDT‐induced cellular reactive oxygen species concentration and 2‐fold greater phototoxicity than equimolar (9 μm) disulfonated aluminum phthalocyanine. Thus, isopropylidene‐protected β‐glycosylation of phthalocyanines provides a simple method of improving the efficacy of PDT.

Targeting tumour energy metabolism potentiates the cytotoxicity of 5-aminolevulinic acid photodynamic therapy

Background:Cancerous cells usually exhibit increased aerobic glycolysis, compared with normal tissue (the Warburg effect), making this pathway an attractive therapeutic target.Methods:Cell viability, cell number, clonogenic assay, reactive oxygen (ROS), ATP, and apoptosis were assayed in MCF-7 tumour cells and corresponding primary human mammary epithelial cells (HMEC).Results:Combining the glycolysis inhibitors 2-deoxyglucose (2DG; 180 mM) or lonidamine (300 μM) with 10 J cm−2 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) increases MCF-7 cytotoxicity (by 3.5-fold to 70% death after 24 h, and by 10-fold in 9-day clonogenic assays). However, glycolysis inhibition only slightly increases HMEC PDT cytotoxicity (between two-fold and three-fold to a maximum of 9% death after 24 h). The potentiation of PDT cytotoxicity only occurred if the glycolysis inhibitors were added after ALA incubation, as they inhibited intracellular accumulation of photosensitiser if coincubated with ALA.Conclusion:As 2DG and lonidamine are already used as cancer chemotherapeutic agents, our results are directly translatable to combination therapies with existing topical PDT.

Correlation of optical and NMR spectral information with coordination variation for axially symmetric macrocyclic Eu(III) and Yb(III) complexes: axial donor polarisability determines ligand field and cation donor preference

In Bleaneys theory of magnetic anisotropy, the second-order crystal field coefficient, Bo2, is predicted to determine the dipolar NMR shift of paramagnetic lanthanide complexes in solution. This parameter has been measured directly, by analysing the europium emission spectra for a series of eight- and nine-coordinate axially symmetric complexes based on cyclen including aza-carboxylate ligands (e.g. DOTA), phosphonates (DOTP), phosphinates and several carboxamides (e.g. DOTAM). For both Yb and Eu complexes with a common coordination number and geometry (square antiprism (SAP) or twisted square antiprism (TSAP)), the dipolar NMR shift correlates very well with this parameter, which also determines the sign and magnitude of a major CD band in the near-IR CD spectra of a series of enantiopure Yb complexes. Measurements of the free energy change associated with axial ligand exchange in a cationic europium tetraamide complex, [Eu(DOTAMPh)](CF3SO3)3 supported by a simple electrostatic perturbation model, have been interpreted in terms of a predominant donor atom polarisation model which affords a simple assessment of Ln ion donor atom preference and ranks the axial second-order ligand field coefficient.

Modulation of the water exchange rates in [Gd–DO3A] complex by formation of ternary complexes with carboxylate ligands

Ternary complexes of formula [Gd–DO3A–L–(H2O)] (where L is a carboxylate-containing ligand) display exchange lifetimes of the metal-coordinated water that can be modulated as a function of L.

Near IR-emitting DNA-probes exploiting stepwise energy transfer processes

The synthesis and characterisation of two new cyclen-based near IR-emitting lanthanide complexes is reported; the lanthanides are sensitised by rhodamine, which in turn is excited by energy transfer from a coumarin 2 moiety. The three lumophores function as an energy transfer cascade spanning the UV-visible-near IR region of the spectrum, resulting in large Stokes shifts. Double stranded DNA selectively switches one of the two energy transfer processes off, enabling luminescent DNA-sensing in the near IR region. The regioselective di-alkylation of the cyclen scaffold is explained with the help of DFT calculations.

Synthesis, characterisation and application of lanthanide cyclen complexes in organic synthesis

Hexadentate cyclen complexes of Sm(III), Eu(III) and Yb(III) have been prepared from 1,4-bis[(R)-α-methylbenzylaminocarbonylmethyl]-1,4,7,10-tetraazacycldodecane and characterised. The crystal structures of the isomorphous complexes of Eu(III) and Sm (III) have been determined. These may be electrochemically reduced to the +II oxidation state and employed in organic synthesis. However, no asymmetric induction was observed and this can be attributed to the fluxional nature of these complexes in solution and the limited asymmetric influence imparted by the N-(α-methylbenzyl)acetamide chiral auxiliary.

Direct NMR and luminescence observation of water exchange at cationic ytterbium and europium centres

Cationic chiral Yb and Eu tetra-amide complexes, have been studied by VT NMR, luminescence and crystallography: the rate of dissociation of water is about 500 times faster at Yb than at the square antiprismatic Eu centre.

Synthesis of a linear bis-porphyrin with a Ru(phen)22+-complexed 2,2′-bipyridine spacer

A linear bis-porphyrin bridged by a 5,5′-diphenyl-2,2′-bipyridine rod-like spacer complexing a [Ru(phen)2]2+ fragment has been synthesized in 7.4% yield by one-pot condensation of 3,5-di-tert-butylbenzaldehyde, 4,4′-dimethyl-3,3′-dihexyl-2,2′-methylenedipyrrole and the [Ru(phen)2]2+ complex of 5,5′-bis(p-formylphenyl)-2,2′-bipyridine, followed by chloranil oxidation. The protected dialdehyde (5,5′-bis[(5,5-dimethyl-1,3-dioxan-2-yl)phenyl]-2,2′-bipyridine) was obtained in 80% yield by Suzuki coupling of 2-[4-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl]-4,4,5,5-tetramethyl-1,3-dioxaborolane and 5,5′-dibromo-2,2′-bipyridine, using [Pd(PPh3)4] as catalyst. A new procedure is reported for the preparation of 5,5′-dibromo-2,2′-bipyridine, which is obtained in 80% yield by Stille homocoupling of 2,5-dibromopyridine in the presence of hexamethylditin.