Evaluation of Two Models for Human Topoisomerase I Interaction with dsDNA and Camptothecin Derivatives

Human topoisomerase I (Top1) relaxes supercoiled DNA during cell division. Camptothecin stabilizes Top1/dsDNA covalent complexes which ultimately results in cell death, and this makes Top1 an anti-cancer target. There are two current models for how camptothecin and derivatives bind to Top1/dsDNA covalent complexes (Staker, et al., 2002, Proc Natl Acad Sci USA 99: 15387–15392; and Laco, et al., 2004, Bioorg Med Chem 12: 5225–5235). The interaction energies between bound camptothecin, and derivatives, and Top1/dsDNA in the two models were calculated. The published structure-activity-relationships for camptothecin and derivatives correlated with the interaction energies for camptothecin and derivatives in the Laco et al. model, however, this was not the case for several camptothecin derivatives in the Stacker et al. model. By defining the binding orientation of camptothecin and derivatives in the Top1/dsDNA active-site these results allow for the rational design of potentially more efficacious camptothecin derivatives

All-cis 1,2,3,4,5,6-hexafluorocyclohexane is a facially polarized cyclohexane

This work was generously supported by the Engineering and Physical Sciences Research Council (EPSRC) and the European Research Council (ERC).The highest-energy stereoisomer of 1,2,3,4,5,6-hexafluorocyclohexane, in which all of the fluorines are ‘up’, is prepared in a 12-step protocol. The molecule adopts a classic chair conformation with alternate C–F bonds aligned triaxially, clustering three highly electronegative fluorine atoms in close proximity. This generates a cyclohexane with a high molecular dipole (μ = 6.2 D), unusual in an otherwise aliphatic compound. X-ray analysis indicates that the intramolecular Fax···Fax distances (∼2.77 Å) are longer than the vicinal Fax···Feq­ distances (∼2.73 Å) suggesting a tension stabilizing the chair conformation. In the solid state the molecules pack in an orientation consistent with electrostatic ordering. Our synthesis of this highest-energy isomer demonstrates the properties that accompany the placement of axial fluorines on a cyclohexane and the unusual property of a facially polarized ring in organic chemistry. Derivatives have potential as new motifs for the design of functional organic molecules or for applications in supramolecular chemistry design.PostprintPeer reviewe

Biodegradation and proton exchange using natural rubber in microbial fuel cells

Microbial fuel cells (MFCs) generate electricity from waste but to date the technology's development and scale-up has been held-up by the need to incorporate expensive materials. A costly but vital component is the ion exchange membrane (IEM) which conducts protons between the anode and cathode electrodes. The current study compares natural rubber as an alternative material to two commercially available IEMs. Initially, the material proved impermeable to protons, but gradually a working voltage was generated that improved with time. After 6 months, MFCs with natural rubber membrane outperformed those with anion exchange membrane (AEM) but cation exchange membrane (CEM) produced 109 % higher power and 16 % higher current. After 11 months, polarisation experiments showed a decline in performance for both commercially available membranes while natural rubber continued to improve and generated 12 % higher power and 54 % higher current than CEM MFC. Scanning electron microscope images revealed distinct structural changes and the formation of micropores in natural latex samples that had been employed as IEM for 9 months. It is proposed that the channels and micropores formed as a result of biodegradation were providing pathways for proton transfer, reflected by the steady increase in power generation over time. These improvements may also be aided by the establishment of biofilms that, in contrast, caused declining performance in the CEM. The research demonstrates for the first time that the biodegradation of a ubiquitous waste material operating as IEM can benefit MFC performance while also improving the reactor's lifetime compared to commercially available membranes. © 2013 Springer Science+Business Media Dordrecht