Steven J. Langford

Spectroscopy of Naphthalene Diimides and Their Anion Radicals

Naphthalene diimides 1–4 having different N,N-disubstitution undergo single electron reduction processes either chemically or electrochemically to yield the corresponding radical anion in high yield. This study concentrates on 1, bearing pentyl side chains connected through the diimide nitrogens, and compares the results obtained against those bearing isopropyl, propargyl, and phenylalanyl side chains. Compound 1 exhibits mirror image absorption and fluorescence in the near-UV region in CH2Cl2 and dimethylformamide that is typical of monomeric N,N-dialkyl-substituted naphthalene diimides. In toluene, excimer-like emission is observed, which suggests ground-state complexes involving 1 are formed. X-Ray crystallography has been used to characterize 1 in the solid state. Cyclic voltammetry enables the reversible potentials for [NDI]0/– and [NDI]−/2– type processes to be measured. Bulk one-electron reduction of 1–4 is characterized by dramatic changes in the absorption and emission spectra. Additionally, highly structured EPR (electron paramagnetic resonance) signals from dimethylformamide solutions of the radical anions of 1–3 have been obtained and are consistent with coupling between the unpaired electron and the naphthalene diimide nitrogens and hydrogens and the NCH hydrogens of the appropriate side chains. The overall structure of the EPR spectrum is substituent-dependent. These changes in spectroscopic output upon an electronic input may be described as a simple ‘on/off’ switching mechanism with which to apply a ‘bottom-up’ approach to molecular device manufacture.

Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice.

Re‐expression of the death‐signalling p75 neurotrophin receptor (p75NTR) is associated with injury and neurodegeneration in the adult nervous system. The induction of p75NTR expression in mature degenerating spinal motor neurons of humans and transgenic mice with amyotrophic lateral sclerosis (ALS) suggests a role of p75NTR in the progression of motor neuron disease (MND). In this study, we designed, synthesized and evaluated novel antisense peptide nucleic acid (PNA) constructs targeting p75NTR as a potential gene knockdown therapeutic strategy for ALS. An 11‐mer antisense PNA directed at the initiation codon, but not downstream gene sequences, dose‐dependently inhibited p75NTR expression and death‐signalling by nerve growth factor (NGF) in Schwann cell cultures. Antisense phosphorothioate oligonucleotide (PS‐ODN) sequences used for comparison failed to confer such inhibitory activity. Systemic intraperitoneal administration of this antisense PNA to mutant superoxide dismutase 1 (SOD1G93A) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75NTR expression and subsequent caspase‐3 activation in spinal cords were consistent with increased survival in antisense PNA‐treated mice. The uptake of fluorescent‐labelled antisense PNA in the nervous system of transgenic mice was also confirmed. This study suggests that p75NTR may be a promising antisense target in the treatment of ALS.

RuII-Polypyridine Complexes Covalently Linked to Electron Acceptors as Wires for Light-Driven Pseudorotaxane-Type Molecular Machines

The photophysical properties of wire-type compounds based on a photosensitizing RuII complex linked to an electron-accepting bipyridinium or diazapyrenium group have been studied with the aim of designing light-driven molecular machines based on pseudorotaxanes (shown schematically). As an outcome, the photoinduced dethreading of a pseudorotaxane formed by a crown ether ring and one of the investigated wire-type compounds has been realized.

Antisense peptide nucleic acid targeting GluR3 delays disease onset and progression in the SOD1 G93A mouse model of familial ALS

Glutamate excitotoxicity is strongly implicated as a major contributing factor in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Excitotoxicity results from elevated intracellular calcium ion (Ca2+) levels, which in turn recruit cell death signaling pathways. Recent evidence suggests that α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionic acid (AMPA) receptor subunit (GluR) stoichiometry is a dominant factor leading to excess Ca2+ loading in neurodegeneration. In particular, the Ca2+ permeable glutamate receptor subunit 3 (GluR3) has been implicated in several neurologic conditions such as bipolar disorder and epilepsy. Recent proteomic analysis within our group on the copper zinc superoxide dismutase (SOD1)G93A transgenic mouse model of familial ALS (FALS) reveals a potentially deleterious upregulation of GluR3 in spinal cord compared to that in wild‐type littermates. Based on this finding we designed a 12mer antisense peptide nucleic acid (PNA) directed against GluR3. This sequence significantly reduced levels of GluR3 protein and protected neuroblastoma × spinal cord (NSC‐34) cells against death induced by the AMPA receptor‐specific agonist (S)‐5‐fluorowillardiine. We subsequently treated SOD1G93A mice thrice weekly with intraperitoneal injections of the antisense PNA (2.5 mg/kg) commencing at postnatal day 50. Mice treated with the antisense sequence had significantly extended survival compared to mice injected with a nonsense sequence. Western blot analysis, however, did not reveal a significant reduction in GluR3 protein levels in whole extracts of the lumbar spinal cord. These results suggest that interference with the GluR3 component of the AMPA receptor assembly may be a novel strategy for controlling excitotoxic destruction of motor neurons and may lead to new therapeutic opportunities for the treatment of human ALS.

Simple molecular-level machines. Interchange between different threads in pseudorotaxanes

In suitably designed supramolecular systems, composed of a macrocycle and two different thread-like compounds, it is possible to choose, by means of chemical inputs, which thread enters the macrocycles cavity, and it is also possible to cause reversible interchange between the two threads. Two such systems are described. In one of them, the macrocyclic component is 1,5-dinaphtho-38-crown-10, the potential threads are 1,1′-dibenzyl-4,4′-bipyridinium and 2,7-dibenzyldiazapyrenium dications, and the chemical input used is amine/acid. In the other system, the macrocyclic component is the tetracationic cyclophane, cyclobis(paraquat-p-phenylene), the potential threads are tetrathiafulvalene and a 1,5-dioxynaphthalene derivative, and the input is reduction/oxidation. These systems are examples of chemically driven molecular-level mechanical machines.

Self-assembling mixed porphyrin trimers – the use of diaxial Sn(IV)porphyrin phenolates as an organising precept

Abstract Tin(IV)porphyrin phenolates are the stable product of the equilibrium-based condensation reaction of phenols with tin(IV)porphyrin dihydroxide in an organic medium. Their formation is characterised by significant shifts (1–5 ppm) of the phenolic protons within the recorded 1 H NMR spectra. To demonstrate the inherent simplicity of their formation and the flexibility in choice of phenolic ligand towards the design and fabrication of more elaborate assemblies and arrays we have constructed two different mixed porphyrin trimer families in which the porphyrin units differ in their orientation to the central porphyrin unit using Sn–O, Ru(III)–N and Zn(II)–N interactions. In one of these cases, 5 molecular components are self-assembled in one-pot to form a cofacially stacked mixed porphyrin trimer with high yield.

Efficient Photoinduced Electron Transfer in a Rigid U-Shaped Tetrad Bearing Terminal Porphyrin and Viologen Units

Apparently solvent-mediated and not through-bond photoinduced electron transfer (ET) takes place from the porphyrin (P) unit to the methylviologen (MV2+ ) unit in the rigid U-shaped molecules 1 (i.e., kTSET >kTBET ; TS=through-solvent, TB=through-bond). The ratio of the rates of charge separation to charge recombination is greater than 1400:1.

A New Class of Giant Tetrads for Studying Aspects of Long-Range Intramolecular Electron Transfer Processes: Synthesis and Computational Studies

Theroleofsolvent-mediatedelectrontransfer can be studied in multichromophoric systems that possess “U-shaped” cavities (see scheme). One approach to building these geometries is through the use of Diels–Alder chemistry on norbornylogous scaffolds. 1H NMR and computational AMu20091 and HF/3–21G studies indicate that the major isomer formed within this sequence has a “U-shape”. This conclusion is consistent with recently reported photophysical studies on the U-shaped system.

Spectroscopic and Electrochemical Properties of Catenanes Containing the 2,7-Diazapyrenium Unit

Abstract The spectroscopic and electrochemical properties of two cyclophanes containing one and, respectively, two 2,7-diazapyrenium electron-acceptor units, and of their [2]catenanes with macrocycles containing two dioxybenzene or dioxynaphthalene electrondonor units have been investigated. The absorption spectra of the catenanes show weak and broad bands in the visible region, assigned to charge-transfer (CT) interactions. The very strong and structured fluorescence (298 K) and the structured fluorescence and phosphorescence (77 K) of the diazapyrenium unit are maintained in the two cyclophanes, but they are no longer present in the [2]catenanes, presumably because of a quenching process caused by the lower energy CT excited states. Each diazapyrenium unit undergoes two distinct reduction processes - only the first one of which is fully reversible - that are hardly affected at all when the diazapyrenium units are incorporated in a cyclophane. In the [2]catenanes, the CT interaction displaces the reduction processes of the diazapyrenium units toward more negative potentials. The results obtained for the diazapyrenium and previously investigated 4,4′-bipyridinium salts, selected cyclophane derivatives, and some [2]catenanes obtained by interlocking the cyclophanes with macrocycles containing two dioxyaromatic electron-donor units are compared and discussed.

Concept Transfer—From Genetic Instruction to Molecular Logic

This review describes the advances made in utilizing the unique recognition and structural characteristics of DNA to perform Boolean algebra using complex logic functions such as AND, XOR, NAND and INHIBIT based on chemical or photonic inputs. A comparison of these results to the action of novel 12-mer antisense peptide nucleic acid (PNA) constructs targeting the AMPA receptor in live motor neuron hybrids (NSC34) is made. In this case, a NOT function is displayed through downregulation of the GluR3 subunit, a result that impedes other cellular chemical processes. The consequence of cellular logic based on chemical inputs such as PNAs and their utilization as whole-cell machines whose biological output is chemical input-dependent is discussed briefly.