Caroline M. R. Low

Substituent effects on aromatic stacking interactions

Synthetic supramolecular zipper complexes have been used to quantify substituent effects on the free energies of aromatic stacking interactions. The conformational properties of the complexes have been characterised using NMR spectroscopy in CDCl(3), and by comparison with the solid state structures of model compounds. The structural similarity of the complexes makes it possible to apply the double mutant cycle method to evaluate the magnitudes of 24 different aromatic stacking interactions. The major trends in the interaction energy can be rationalised using a simple model based on electrostatic interactions between the pi-faces of the two aromatic rings. However, electrostatic interactions between the substituents of one ring and the pi-face of the other make an additional contribution, due to the slight offset in the stacking geometry. This property makes aromatic stacking interactions particularly sensitive to changes in orientation as well as the nature and location of substituents.

Substituent effects on cation–π interactions: A quantitative study

A synthetic supramolecular complex has been adapted to quantify cation–π interactions in chloroform by using chemical double-mutant cycles. The interaction of a pyridinium cation with the π-face of an aromatic ring is found to be very sensitive to the π-electron density. Electron-donating substituents lead to a strong attractive interaction (−8 kJ/mol−1), but electron-withdrawing groups lead to a repulsive interaction (+2 kJ/mol−1).

Noncovalent Assembly of [2]Rotaxane Architectures

Reversible zinc-pyridine coordination and hydrogen-bonding interactions have been used to assemble a [2]rotaxane from three components. Cooperativity in the macrocyclization process that results in the porphyrin dimer makes the system exceptionally stable. However, the kinetic lability of the zinc-porphyrin interaction means the dimer is in dynamic equilibrium with its monomer, and this has been exploited in the construction of a [2]rotaxane.

An evaluation of force-field treatments of aromatic interactions

Experimental measurements of edge-to-face aromatic interactions have been used to test a series of molecular mechanics force fields. The experimental data were determined for a range of differently substituted aromatic rings using chemical double mutant cycles on hydrogen-bonded zipper complexes. These complexes were truncated for the purposes of the molecular mechanics calculations so that problems of conformational searching and the optimisation of large structures could be avoided. Double-mutant cycles were then carried out in silico using these truncated systems. Comparison of the experimental aromatic interaction energies and the X-ray crystal structures of these truncated complexes with the calculated data show that conventional molecular mechanics force fields (MM2, MM3, AMBER and OPLS) do not perform well. However, the XED force field which explicitly represents electron anisotropy as an expansion of point charges around each atom reproduces the trends in interaction energy and the three-dimensional structures exceedingly well. Collapsing the XED charges onto atom centres or the use of semi-empirical atom-centred charges within the XED force field gives poor results. Thus the success of XED is not related to the methods used to assign the atomic charge distribution but can be directly attributed to the use of off-atom centre charges.

Quantitative determination of intermolecular interactions with fluorinated aromatic rings.

The chemical double mutant cycle approach has been used to investigate substituent effects on intermolecular interactions between aromatic rings and pentafluorophenyl pi-systems. The complexes have been characterised using 1H and 19F NMR titrations, X-ray crystal structures of model compounds and molecular mechanics calculations. In the molecular zipper system used for these experiments, H-bonds and the geometries of the interacting surfaces favour the approach of the edge of the aromatic ring with the face of the pentafluorophenyl pi-system. The interactions are generally repulsive and this repulsion increases with more electron-withdrawing substituents up to a limit of +2.2 kJ mol(-1), when the complex distorts to minimise the unfavourable interaction. Strongly electron-donating groups cause a change in the geometry of the aromatic interaction and attractive stacking interactions are found (-1.6 kJ mol(-1) for NMe2). These results are generally consistent with an electrostatic model: the polarisation of the pentafluorophenyl ring leads to a partial positive charge located at the centre and this leads to repulsive interactions with the positive charges on the protons on the edge of the aromatic ring; when the aromatic ring has a high pi-electron density there is a large electrostatic driving force in favour of the stacked geometry which places this pi-electron density over the centre of the positive charge on the pentafluorophenyl group.

Cancer-Selective Targeting of the Nf-ΚB Survival Pathway With Gadd45Β/Mkk7 Inhibitors

Summary Constitutive NF-κB signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-κB-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug-discovery strategy, we developed DTP3, a D-tripeptide, which disrupts the GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard, bortezomib, but more than 100-fold higher cancer cell specificity in vitro. Notably, DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.

Preferential Solvation and Hydrogen Bonding in Mixed Solvents

The molecular-recognition events that underpin many processes in chemistry and biology are intimately linked to accompanying changes in solvation. The subtle interplay of the different factors that contribute to these changes in solvation gives rise to phenomena that are difficult to interpret at the molecular level. However, a detailed understanding of these effects is essential for the development of quantitative approaches to the analysis of noncovalent molecular interactions in solution. We recently introduced the 1:1 complex formed between tri-n-butylphosphine oxide (1) and perfluoro-tert-butanol (2 ; Scheme 1) as a

Ultrasonic formation and reactions of sodium phenylselenide

Abstract Treatment of diphenyldiselenide with sodium metal in tetrahydrofuran under ultrasonic conditions conveniently gave a suspension of sodium phenylselenide which could be transferred by syringe or cannula and reacted with sulphonates, halides and epoxides.

UK academic drug discovery

Tralau-Stewart and colleagues present a survey of the academic drug discovery environment in the United Kingdom in 2013, and discuss the major trends in comparison with the United States.

Influence of solvent polarity on preferential solvation of molecular recognition probes in solvent mixtures.

The association constants for formation of 1:1 complexes between a H-bond acceptor, tri-n-butylphosphine oxide, and a H-bond donor, 4-phenylazophenol, have been measured in a range of different solvent mixtures. Binary mixtures of n-octane and a more polar solvent (ether, ester, ketone, nitrile, sulfoxide, tertiary amide, and halogenated and aromatic solvents) have been investigated. Similar behavior was observed in all cases. When the concentration of the more polar solvent is low, the association constant is identical to that observed in pure n-octane. Once a threshold concentration of the more polar solvent in reached, the logarithm of the association constant decreases in direct proportion to the logarithm of the concentration of the more polar solvent. This indicates that one of the two solutes is preferentially solvated by the more polar solvent, and it is competition with this solvation equilibrium that determines the observed association constant. The concentration of the more polar solvent at which the onset of preferential solvation takes place depends on solvent polarity: 700 mM for toluene, 60 mM for 1,1,2,2-tetrachloroethane, 20 mM for the ether, ester, ketone, and nitrile, 0.2 mM for the tertiary amide, and 0.1 mM for the sulfoxide solvents. The results can be explained by a simple model that considers only pairwise interactions between specific sites on the surfaces of the solutes and solvents, which implies that the bulk properties of the solvent have little impact on solvation thermodynamics.