Anion receptor chemistry

This review covers advances in anion complexation in the year 2013, 2014 and 2015. The review focuses on the applications of anion receptor chemistry including sensing, self-assembly, extraction, transport, catalysis, as well as fundamental advances in the area. <br/

On the continued fraction expansion of certain Engel series

An Engel series is a sum of the reciprocals of an increasing sequence of positive integers, which is such that each term is divisible by the previous one. Here we consider a particular class of Engel series, for which each term of the sequence is divisible by the square of the preceding one, and find an explicit expression for the continued fraction expansion of the sum of a generic series of this kind. As a special case, this includes certain series whose continued fraction expansion was found by Shallit. A family of examples generated by nonlinear recurrences with the Laurent property is considered in detail, along with some associated transcendental numbers

Ab Initio Calculation of the Lattice Distortions induced by Substitutional Ag- and Cu- Impurities in Alkali Halide Crystals

An ab initio study of the doping of alkali halide crystals (AX: A = Li, Na, K, Rb; X = F, Cl, Br, I) by ns2 anions (Ag- and Cu-) is presented. Large active clusters with 179 ions embedded in the surrounding crystalline lattice are considered in order to describe properly the lattice relaxation induced by the introduction of substitutional impurities. In all the cases considered, the lattice distortions imply the concerted movement of several shells of neighbors. The shell displacements are smaller for the smaller anion Cu-, as expected. The study of the family of rock-salt alkali halides (excepting CsF) allows us to extract trends that might be useful at a predictive level in the study of other impurity systems. Those trends are presented and discussed in terms of simple geometric arguments.Comment: LaTeX file. 8 pages, 3 EPS pictures. New version contains calculations of the energy of formation of the defects with model clusters of different size

Fluorinated synthetic anion carriers:experimental and computational insights into transmembrane chloride transport

A series of fluorinated tripodal tris-thioureas function as highly active anion transporters across lipid bilayers and cell membranes. Here, we investigate their mechanism of action using anion transport assays in cells and synthetic vesicles and molecular modelling of transporter–lipid interactions. When compared with non-fluorinated analogues, fluorinated compounds demonstrate a different mechanism of membrane transport because the free transporter cannot effectively diffuse through the membrane. As a result, in H+/Cl cotransport assays, fluorinated transporters require the presence of oleic acid to form anionic oleate complexes for recycling of the transporter, whereas non-fluorinated analogues readily diffuse through the membrane as free transporters and show synergistic transport with the proton transporter gramicidin. Molecular dynamics simulations revealed markedly stronger transporter–lipid interactions for fluorinated compounds compared with non-fluorinated analogues and hence, higher energy barriers for fluorinated compounds to cross the membrane as free transporters. With use of appropriate proton transporters to ensure measurement of the correct rate-limiting steps, the transport rates determined in synthetic vesicle assays show excellent agreement with the anion transport rates determined in cell- based assays. We conclude that integration of computational and experimental methods provides a strategy to optimise transmembrane anion transporter design for biomedical applications.ARC, EPSRC, FCT, CICEC

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer : long-term survival results from the STAMPEDE trial

Background STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. Methods We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. Results Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P  0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). Conclusions The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden

Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial

Background STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL). Methods and findings Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively. Conclusions Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC. Trial registration ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544

Fatty Acid Fueled Transmembrane Chloride Transport

We report an example of the use of fatty acids to drive chloride transport by creating a pH gradient across a vesicular lipid bilayer membrane. Addition of an unselective squaramide-based chloride transporter (which transports both H+and Cl-) facilitates the transport of HCl from the vesicle (driven by the pH gradient) so creating a chloride gradient. Addition of further aliquots of fatty acid ‘fuel’ can initiate further transport of chloride out of the vesicle by re-establishing the pH gradient. This is an example of a prototypical chloride pumping system

Fatty Acid Fueled Transmembrane Chloride Transport

Generation of chemical gradients across biological membranes of cellular compartments is a hallmark of all living systems. Here we report a proof-of-concept prototype transmembrane pumping system in liposomes. The pump uses fatty acid to fuel chloride transport, thus generating a transmembranechloride gradient. Addition of fatty acid to phospholipid vesicles generates a transmembrane pH gradient (pHin < pHout), and this electrochemical H+ potential is harnessed by an anionophore to drive chloride efflux via H+/Cl− cotransport. Further addition of fatty acid efficiently fuels the system to continuously drive chloride transport against the concentration gradient, up to [Cl−] 65 mM | [Cl−] 100 mM, and is 1400 times more efficient than using an in out +− external fuel. Based on our findings from dissecting the H /Cl flux process with the use of different liposomal fluorescence assays, and supported by additional liposome-based 13C NMR and DLS studies; we proposed that the presence of an anionophore can induce asymmetric distribution of fatty acid, and contribute to another Cl− flux mechanism in this system.AR

Fatty Acid Fueled Transmembrane Chloride Transport

We report an example of the use of fatty acids to drive chloride transport by creating a pH gradient across a vesicular lipid bilayer membrane. Addition of an unselective squaramide-based chloride transporter (which transports both H⁺and Cl^-) facilitates the transport of HCl from the vesicle (driven by the pH gradient) so creating a chloride gradient. Addition of further aliquots of fatty acid ‘fuel’ can initiate further transport of chloride out of the vesicle by re-establishing the pH gradient. This is an example of a prototypical chloride pumping system

Supramolecular transmembrane anion transport: new assays and insights

Transmembrane anion transport has been the focus of a number of supramolecular chemistry research groups for a number of years. Much of this research is driven by the biological relevance of anion transport and the search to find new treatments for diseases such as cystic fibrosis which is caused by genetic problems leading to faulty cystic fibrosis transmembrane conductance regulator (CFTR) channels leading to reduced chloride and bicarbonate transport through epithelial cell membranes. Considerable effort has been devoted to the development of new transporters and our group along with others have been searching for combinations of organic scaffolds and anion binding groups that produce highly effective transporters which work at low concentration. These compounds may be used in the future as ‘channel replacement therapies’ restoring the flux of anions through epithelial cell membranes and ameliorating the symptoms of cystic fibrosis. Less effort has been put into gaining a fundamental understanding of anion transport processes. Over the last three years, our group has developed a number of new transport assays that allow anion transport mechanisms to be determined. This account covers the latest developments in this area providing a concise review of the new techniques we can use to study anion transport processes individually without resorting to measuring exchange processes and the new insights that these assays provide. The account provides an overview of the effects of anions transporters on cells and an explanation of why many systems perturb pH gradients within cells in addition to transporting chloride. We discuss assays to determine whether anionophores are facilitating chloride or HCl transport and how this latter assay can be modified to determine chloride vs. proton selectivity in small molecule anion receptors. We show how molecular design can be used to produce receptors that are capable of transporting chloride but not perturb pH gradients. We cover the role that anion transporters in the presence of fatty acids play in dissipating pH gradients across lipid bilayer membranes and the effect that this process has on chloride selective transport. We also discuss how coupling of anion transport to cation transport by natural cationophores can be used to determine whether anion transport is electrogenic or electroneutral. In addition, we compare these new assays to the previously used chloride/nitrate exchange assay and show how that this exchange assay can underestimate the chloride transport ability of certain receptors that are rate limited by nitrate transport