Anion receptor chemistry: highlights from 2011 and 2012

This review covers advances in anion complexation in the years 2011 and 2012. The review covers both organic and inorganic systems and also highlights the applications to which anion receptors can be applied such as self-assembly and molecular architecture, sensing, catalysis and anion transport

Highly effective yet simple transmembrane anion transporters based upon ortho-phenylenediamine bis-ureas

Simple, highly fluorinated receptors are shown to function as highly effective transmembrane anion antiporters with the most active transporters rivalling the transport efficacy of natural anion transporter prodigiosin for bicarbonate

Hydrated Lanthanoid Complexes of 5-(2'-Pyridyl)tetrazole Formed in the Presence of Dimethyl Sulfoxide

Reaction of DMSO solvates of lanthanoid nitrates or perchlorates with 5-(2'-pyridyl)tetrazole (pytz) and triethylamine in organic solvents resulted in the unexpected crystallization of hydrates, rather than DMSO solvates. This was confirmed by the structural characterization of [Eu(pytz)3(H2O)3]. Decreasing the metal:ligand ratio in the reaction mixture resulted in the crystallization of a complex salt formulated as [Y(pytz)2(H2O)4](pytz).(Hpytz).4H2O; once again DMSO was absent from the product. Interestingly, the omission of base from one reaction resulted in the serendipitous crystallization of Hpytz in a zwitterionic form, unlike the neutral ligand structure reported previously

A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations

Perturbations in cellular chloride concentrations can affect cellular pH, autophagy and lead to the onset of apoptosis. With this in mind synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in the lysosomal pH which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Neutral receptors for the transport of anions across lipid membranes

This report describes a novel method, using 33S NMR techniques, for the detection of sulfate transport across synthetic lipid membranes comprised of 1-palmitoyl-2 oleoylphosphatidylcholine. With this method it was possible to verify that tris(2 aminoethyl)amine based (thio)ureas and cyclic peptide based cryptands can promote the transmembrane transport of sulfate anions. This is a particularly notable accomplishment due to the highly hydrophilic nature of the sulfate anion, and the associated challenges with partitioning such a species into a hydrophobic lipid membrane. Furthermore, a series of bis(thio)urea compounds, based on the 1,2- bisaminocyclohexane scaffold are reported as ion transporters, capable of facilitating both chloride/nitrate and chloride/bicarbonate antiport transport processes. They have also been investigated for binding properties with a variety of anions, using 1H NMR techniques. The influence of stereochemistry on the anion binding and transport ability of the receptors is discussed in detail, with cis-stereoisomers being superior anion transporters to the transanalogues. Receptors based on the ortho-phenylenediamine bis-urea motif have been demonstrated as highly effective anion transporters and function by an antiport mechanism of anion transport. Modification of existing transporters, by adding fluorination at the central phenyl ring or by increasing fluorination at the peripheral phenyl groups, yielded highly potent anion transporters capable of surpassing the activity of the natural anion transporter prodigiosin, for chloride/bicarbonate exchange

The influence of stereochemistry on anion binding and transport

Bis(thio)urea receptors (1–4) based on 1,2-bisaminocyclohexane are shown to function as transmembrane anion antiporters. The results show that cis-receptors have a greater propensity for anion transport than analogous trans-receptors. Stability constants using 1H NMR techniques highlight the significance of stereoisomerism on anion binding in solution, as cis-receptors bind anions more strongly than trans-receptors

Further insight into the coordination of 2,5-dicarbothioamidopyrroles: the case of Cu and Co complexes

The coordination chemistry of 2,5-dicarbothioamidopyrrole ligands, namely N2,N5-dibutyl-3,4-diphenyl-1H-pyrrole-2,5-bis(carbothioamide) and N2,N5,3,4-tetraphenyl-1H-pyrrole-2,5-bis(carbothioamide), has been investigated with Cu(II) metal centres by means of X-ray crystallography. This resulted in the formation of the expected planar S,N,S? coordinated complex for the former ligand and unexpected ring-closure reactions, with formation of benzothiazole sidearms, for the latter. Both Cu(II) and Cu(I), used in large excess, were found to favour the ring-closure reaction, although the structural characterisation of the resulting complexes contained only Cu(II) cations, with varying coordination geometries ranging from square planar and square-based pyramidal to tetrahedral. By repeating the reaction using a slight excess of Cu(II) (2 : 1) two more different structures were obtained where the metal was coordinated to the original ligand, N2,N5,3,4-tetraphenyl-1H-pyrrole-2,5-bis(carbothioamide), or to the mixed ligand where only one of the thioamide substituents had converted to a benzothiazole. The essential role of Cu for the ring closure reaction was also established by comparing its complex with structural features of the analogous Co(II) complex, the latter revealing no ring closure to give benzothiazole substituents and co-crystallisation of a mixed Co(II)/Co(III) complex. Finally, the structure and photophysical properties of the corresponding 3,4-diphenyl-2,5-bis(benzothiozol-5-yl)-pyrrole ligand, obtained via treatment of the thioamide with K3[Fe(CN)6], were also investigated revealing a blue-centered emissio

Synthetic transporters for sulfate: a new method for the direct detection of lipid bilayer sulfate transport

he transmembrane transport of anions by small synthetic molecules is a growing field in supramolecular chemistry and has focussed mainly on the transmembrane transport of chloride. On the other hand, the transport of the highly hydrophilic sulfate anion across lipid bilayers is much less developed, even though the inability to transport sulfate across cellular membranes has been linked to a variety of genetic diseases. Tris-thioureas possess high sulfate affinities and have been shown to be excellent chloride and bicarbonate transporters. Herein we report the sulfate transport abilities of a series of tris-ureas and tris- thioureas based on a tris(2-aminoethyl)amine or cyclopeptide scaffold. We have developed a new technique based on 33S NMR that can be used to monitor sulfate transport, using 33S-labelled sulfate and paramagnetic agents such as Mn2+ and Fe3+ to discriminate between intra- and extravesicular sulfate. Reasonable sulfate transport abilities were found for the reported tris-ureas and tris-thioureas, providing a starting point for the development of more powerful synthetic sulfate transporters that can be used in the treatment of certain channelopathies or as a model for biological sulfate transporter