Anthony D.M. Curtis

Novel calix[4]resorcinarene glycosides

Abstract Calix[4]resorcinarene glycosides may be prepared using mild conditions by condensing the corresponding glycosidic aldehyde with resorcinol in the presence of a Lewis acid. The protected glycosyl moieties confer enhanced solubility in a number of organic solvents whilst deprotection provides resorcinarenes which are water soluble.

Preclinical evaluation of statins as a treatment for ovarian cancer.

OBJECTIVE To evaluate the potential for statins to treat ovarian cancer. METHODS The sensitivity of 7 ovarian cancer cell lines to either statins or statins combined with either carboplatin or paclitaxel was assessed using monolayer cultures. Sensitivity to simvastatin was also evaluated in ovarian cancer spheroids. The kinetics of cell death induced by simvastatin was evaluated by measuring Trypan Blue exclusion. Autophagy induced by simvastatin was assessed by measuring LC3-II, p62 or Rab7 by immunoblotting or immunocytochemistry. RESULTS All statins except pravastatin demonstrated single agent activity against monolayers (IC50=1-35 μM) and spheroids (IC50=1-13 μM). This was mediated by HMG-CoAR inhibition, because either mevalonate or geranylgeraniol prevented the cytotoxic effects of simvastatin. Continuous exposure for 4 days was necessary to cause cell death. Simvastatin caused accumulation of p62 but loss of Rab7, suggesting inhibition of autophagosome trafficking. Accumulation of LC3-II was also observed, even in the presence of bafilomycin, suggesting additional stimulation of an earlier step in autophagy. Knockdown of the key autophagy regulator Atg5 caused a modest increase in the sensitivity of Ovcar-8 cells to simvastatin. Finally, additive or mild antagonist effects were observed when simvastatin was combined simultaneously with either carboplatin or paclitaxel, but when cells were exposed to simvastatin prior to carboplatin, profound antagonism was observed. CONCLUSIONS These observations suggest that clinical trials of statins in ovarian cancer should evaluate high doses and schedules that ensure continual inhibition of HMG-CoAR. Simvastatin has conflicting effects on the autophagy pathway and this may contribute to its cytotoxic activity.

INTERACTION OF A WATER SOLUBLE FULLERENE DERIVATIVE WITH REACTIVE OXYGEN SPECIES AND MODEL ENZYMATIC SYSTEMS

Fullerenes are a new class of compounds with potential uses in biology and medicine but little is known about their interaction with biological systems. Fullerenes were reported to be pro- or anti-oxidants depending on their structure or on experimental conditions. This work presents the effects of dendrofullerene, a water soluble derivative of C60, on model biological systems from both perspectives. The relative importance of type I and type II mechanisms involved in the production of the reactive forms of oxygen leading to inhibition of GST activity was studied using dendrofullerene, white light and the quenching agents. The addition of mannitol or superoxide dismutase, known quenchers of the type I mechanism had no effect on the rate of GST inactivation. Significant inhibition of the inactivation provided by the dendrofullerene was observed on addition of tryptophan, a known quencher of the type II mechanism. Activity towards the basic enzymatic system cytochrome P-450 has also been investigated and at a concentration of 250 μM dendrofullerene exhibits selective inhibition of progesterone metabolism which is attributed to the fullerene moiety rather than the dendritic chain.

The Synthesis of C2-Symmetric and Axially Chiral Compounds for Recognition and Catalysis

Abstract Axially chiral amidines and guanidines, some possessing C2-symmetry, have been targeted as potential chiral catalysts for reactions of α,β-unsaturated carboxylic acids or esters. The key step in each synthesis required the coupling of two sterically demanding aromatic compounds to form atropisomeric biaryl species.

Computer modelling of the adsorption of proteins on solid surfaces under the influence of double layer and van der Waals energy

The study of protein interactions with surfaces is important in many branches of biomedical engineering. A computer model has been set up in order to aid the understanding and prediction of the likelihood of protein adsorption at a surface and of coagulation between two proteins. In this model, a protein is represented as a hard sphere, neglecting conformation changes which may occur during the adsorption process. The sphere is assumed to be in a medium whose properties are described by the ionic strength, the pH and the dielectric permittivity. It is considered to interact both with an infinite plane, representing the surface, and with another sphere, representing another protein. The model focuses on the total interaction energy between a protein and a surface and between two proteins. The energy is expressed according to the DLVO theory of colloidal stability, which assumes that the adsorption behaviour of proteins at a surface depends, first, on the van der Waals interactions energy and, second, on the electrostatic double layer interaction energy. The conditions under which adhesion is prevented correspond to the presence of local extremes of the enegy function, whereas the conditions under which adhesion is likely to take place correspond to absence of local extremes.

Stereoselective aldol reactions of β-boronate carbonyl derivatives.

Abstract Deprotonation of β-boronate carbonyl derivatives can be readily achieved using LDA. Reaction of the resulting enolates with aldehydes gives the corresponding Aldol products, with high syn-selectivity for Z-enolates. This result is consistent with chelation enhanced stabilisation of the enolate geometry via the boronate moiety.

Synthesis and characterization of TPGS–gemcitabine prodrug micelles for pancreatic cancer therapy

The therapeutic potential of a nucleoside analog, gemcitabine, is severely compromised due to its rapid clearance from systemic circulation by enzymatic degradation into an inactive metabolite. In the present investigation, micelles based on polymer–drug conjugate were developed for gemcitabine and investigated for their potential to improve cancer chemotherapy. The tocopherol poly(ethylene glycol) succinate 1000 (TPGS)–gemcitabine prodrug was synthesized via an amide linkage and characterised by analytical methods, including FT-IR, 1H NMR, and MALDI-TOF. The micellar formulation of TPGS–gemcitabine prodrug was developed by a self-assembly technique and evaluated for various physicochemical parameters including particle size, polydispersity, morphology, critical micelle concentration and release profile. It was observed that gemcitabine present in TPGS–gemcitabine micelles was resistant to deamination by crude cytidine deaminase. The improved cytotoxicity of the micellar formulation was observed using TPGS–gemcitabine micelles against pancreatic cancer cells. Further, it was found that, unlike native gemcitabine, nucleoside transporters were not required for TPGS–Gem micelles to demonstrate their anticancer potential. These findings revealed that TPGS–gemcitabine micelles may serve as a promising platform for gemcitabine in order to improve its anticancer efficacy.

The origin of the stereoselectivity in the aldol reactions of β-boronate carbonyl derivatives.

Abstract β-Boronate carbonyl derivatives can be readily deprotonated using LDA and reaction of the resulting enolates with aldehydes gives the corresponding aldol products, with high syn -selectivity for Z -enolates with both benzaldehyde and pivaldehyde. Moderate to good syn -selectivity is observed for E -enolates. These results are consistent with chelation enhanced stabilisation of the enolate geometry via the boronate moiety and chelation enhanced locking of the resulting aldolate stereochemistry.

Application of Nanoparticle Technologies in the Combat against Anti-Microbial Resistance

Anti-microbial resistance is a growing problem that has impacted the world and brought about the beginning of the end for the old generation of antibiotics. Increasingly, more antibiotics are being prescribed unnecessarily and this reckless practice has resulted in increased resistance towards these drugs, rendering them useless against infection. Nanotechnology presents a potential answer to anti-microbial resistance, which could stimulate innovation and create a new generation of antibiotic treatments for future medicines. Preserving existing antibiotic activity through novel formulation into or onto nanotechnologies can increase clinical longevity of action against infection. Additionally, the unique physiochemical properties of nanoparticles can provide new anti-bacterial modes of action which can also be explored. Simply concentrating on antibiotic prescribing habits will not resolve the issue but rather mitigate it. Thus, new scientific approaches through the development of novel antibiotics and formulations is required in order to employ a new generation of therapies to combat anti-microbial resistance.

Heat Dissipation of Hybrid Iron Oxide-Gold Nanoparticles in an Agar Phantom

Hybrid iron oxide-gold nanoparticles (HNPs) have shown potential in cancer therapy as agents for tumour ablation and thermal switches for targeted drug release. Heat generation occurs by exploitation of the surface plasmon resonance of the gold coating, which usually occurs at the maximum UV absorption wavelength. However, lasers at such wavelength are often expensive and highly specialised. Here, we report the heating and monitoring of heat dissipation of HNPs suspended in agar phantoms using a relatively inexpensive Ng: YAG pulsed 1064 nm laser source. The particles experience heating of up to 40°C with a total area of heat dissipation up to 132.73 mm2 from the 1 mm diameter irradiation point after 60 seconds. This work reports the potential and possible drawbacks of these particles for translation into cancer therapy based on our findings.