Philip Alan Gale

• MA DPhil DSc
• Professor at University of Technology Sydney

New approaches to the transmembrane transport of anions are discussed in this review. Advances in the design of small molecule anion carriers are reviewed in addition to advances in the design of synthetic anion channels. The application of anion transporters to the potential future treatment of disease is discussed in the context of recent finding...

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. Anion receptor chemistry concerns the design of molecules that recognize, respond to,...

Synthetic transmembrane anion transporters (anionophores) have potential as tools for biomedical research and as therapeutic agents for diseases associated with anion-channel dysfunction. However, the possibility of H+ or OH� transport by anionophores has received little attention, and an anionophore selective for Cl� over H+/OH� is currently unava...

A series of fluorescent anion transporters consisting of a urea or thiourea group linked to a naphthalimide fluorophore have been synthesised and their anion transport properties studied. The compounds possess similar anion transport properties to (thio)urea-based anionophores that have previously been reported. Fluorescence studies in cells show a...

Fluoride has been overlooked as a target in the development of synthetic anion transporters despite natural fluoride transport channels being recently discovered. In this paper we report the direct measurement of fluoride transport across lipid bilayers facilitated by a series of strapped calix[4]pyrroles and show that these compounds facilitate tr...

The global challenge of antibiotic resistance necessitates innovative approaches to improving the efficacy of existing therapeutics while mitigating their environmental impact. This study investigates the role of saponins derived from Glycyrrhiza glabra root extract in modulating interactions of tobramycin, a broad-spectrum aminoglycoside antibioti...

A potent squaramide-based anion transporter was used to evaluate how vesicles prepared with tailored lipid compositions, which mimic organelle membranes, can impact transmembrane transport.

Designing molecular receptors that bind anions in water is a significant challenge, and an even greater difficulty lies in using these receptors to remove anions from water without resorting to the hazardous liquid–liquid extraction approach. We here demonstrate an effective and synthetically simple strategy toward these goals by exploiting ion-pai...

Mitochondrial uncoupling by small molecule protonophores is a promising strategy for developing novel anticancer agents. Recently, aryl urea substituted fatty acids (aryl ureas) were identified as a new class of protonophoric anticancer agents. To mediate proton transport these molecules self‐assemble into membrane‐permeable anionic dimers in which...

In this paper we demonstrate that Pt(ii) complexes can function as efficient transmembrane chloride transporters. A series of Pt(ii) metal complexes with urea-appended isoquinoline ligands were synthesised and operate via classical hydrogen bonding interactions rather than ligand exchange. A number of the complexes exhibited potent transmembrane ch...

The conformational change accompanying the N , N ′-dimethylation of a diphenylsquaramide has been exploited to form a series of potent anionophores with convergent anion binding sites. The compounds were demonstrated to transport H ⁺ /Cl ⁻ across lipid bilayers in model vesicles and dissipate a pH gradient.

Synthetic anion transporters that mediate electroneutral (H+/Cl–) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostatic environments. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralize lysosomal pH gradients and inhibit autophagy. However, their effect on other...

A five-membered central scaffold was used to develop a series of anion receptors. The library perturbed liposomal pH gradients through H ⁺ /Cl ⁻ transmembrane transport and elicited a variety of cytotoxicities against normal and cancerous cell lines.

In respiring mitochondria, the proton gradient across the inner mitochondrial membrane is used to drive ATP production. Mitochondrial uncouplers, which are typically weak acid protonophores, can disrupt this process to induce mitochondrial dysfunction and apoptosis in cancer cells. We have shown that bisaryl urea-based anion transporters can also m...

A series of Pt(II) metal complexes with urea-appended isoquinoline ligands act as efficient transmembrane chloride transporters and operate via classical hydrogen bonding interactions rather than ligand exchange. A number of the complexes exhibited potent transmembrane chloride transport activity.

Synthetic anion transporters that mediate electroneutral (H+/Cl-) transport have demonstrated anti-cancer activity due to their ability to disrupt subcellular homeostasis. Elucidation of the cell death mechanism revealed the transporters’ ability to neutralise lysosomal pH gradients and inhibit autophagy. However, their effect on other subcellular...

A series of fluorescent coumarin bis-ureas 1-4 have been synthesised, and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes. Single crystal X-ray diffraction of compound 1 showed antiparallel stacking of the coumarin rings, stabilised by hydrogen bonds. Binding studi...

Synthetic anion transporters show potential in treating life-threatening diseases like cystic fibrosis and cancer. However, with increasingly complex transporter architectures designed to control anion binding and transport, it is important to consider solubility and deliverability during transporter design. The fluorination of synthetic anion tran...

Aryl-urea substituted fatty acids are protonophores and mitochondrial uncouplers that utilise a urea-based synthetic anion transport moiety to carry out the protonophoric cycle. Herein we show that replacement of the urea group with carbamate, a functional group not previously reported to possess anion transport activity, produces analogues that re...

The quantification of anion binding by molecular receptors within lipid bilayers remains challenging. Here we measure anion binding in lipid bilayers by creating a fluorescent macrocycle featuring a strong sulfate affinity. We find the determinants of anion binding in lipid bilayers to be different from those expected that govern anion binding in s...

Targeting the cancer cell mitochondrion is a promising approach for developing novel anticancer agents. The experimental anticancer agent N,N'-bis(3,5-dichlorophenyl)urea (SR4) induces apoptotic cell death in several cancer cell lines by uncoupling mitochondrial oxidative phosphorylation (OxPhos) using a protein-free mechanism. However, the precise...

Highly selective anion recognition and extraction is challenging and yet critical for removal of pollutants from the environment and the effective recovery of valuable chemicals from low-content (at sub-ppm or ppb level) sources. In this paper, we detail the gram-scale synthesis of a superphane 2, an anion receptor that selectively binds ReO4⁻. Sup...

Active transport of ions uphill, creating a concentration gradient across a cell membrane, is essential for life. It remains a significant challenge to develop synthetic systems that allow active uphill transport. Here, a transport process fuelled by organometallic compounds is reported that creates a pH gradient. The hydrolysis reaction of PtII co...

In the February issue of Chem, Hu, Wang, and coworkers synthesized a Janus metal-organic layer that can be embedded into lipid bilayer membranes, undergoes photo-induced charge transfer, and facilitates active H⁺ transport and subsequent ATP synthesis by CF0F1-ATP synthase in liposomes.

Active transport of ions uphill against a concentration gradient across a cell membrane is essential for life. It remains a significant challenge to develop synthetic systems that allow active uphill transport. Here an uphill transport phenomenon fuelled by organometallic compounds is reported that creates a pH gradient. The hydrolysis reaction of...

To celebrate Prof. Jonathan Sessler’s 65th birthday, this Backstory on his life and career follows his path to success. We begin with his early days as an independent researcher and then show how his Texas-sized chemistry has molded over the years with the help of the “Crown and Anchor approach.” We hope this article will inspire readers to pursue...

Using the chemical versatility of the benzo[b]thiophene motif, an extensive library of 24 (thio)urea receptors, with different binding properties and lipophilicities, was prepared and included α,α‐, α,β‐, β,β‐, β,γ‐, α,γ‐, and γ,γ‐benzo[b]thiophene positional isomers, as well as β‐ or γ‐benzo[b]thiophene‐based molecules decorated with aliphatic cha...

Guest editors Katrina Jolliffe and Philip Gale introduce the Organic & Biomolecular Chemistry themed collection on the supramolecular chemistry of anions.

Understanding non-covalent molecular recognition events at biomembrane interfaces is important in biological, medicinal, and materials chemistry research.1 Despite the crucial regulatory roles of anion binding/transport processes at biomembranes, no information is available regarding how strongly anions can bind to naturally occurring or synthetic...

This review covers advances made in anion complexation in the years 2019 and 2020. Included here are developments in self-assembly, sensing, anion separation, transport, catalysis, and fundamental advances in anion recognition systems.

Understanding non-covalent molecular recognition events at biomembrane interfaces is important in biological, medicinal, and materials chemistry research.1 Despite the crucial regulatory roles of anion binding/transport processes at biomembranes, no information is available regarding how strongly anions can bind to naturally occurring or synthetic...

Membrane transport proteins fulfill important regulatory functions in biology with a common trait being their ability to respond to stimuli in the environment. Various small-molecule receptors, capable of mediating transmembrane transport, have been successfully developed. However, to confer stimuli-responsiveness on them poses a fundamental challe...

Understanding non-covalent molecular recognition events at biomembrane interfaces is important in biological, medicinal, and materials chemistry research.1 Despite the crucial regulatory roles of anion binding/transport processes at biomembranes, no information is available regarding how strongly anions can bind to naturally occurring or synthetic...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

Inspired by the reported antiviral activity of pyrimidines and triazolopyrimidines, two series of 2-anilinopyrimidines (5a-e) and 1-aryl-[1,2,4]triazolo[4,3-a]pyrimidines (14a-k) were designed and synthesized as potential antiviral agents. X-ray crystallographic study of compounds (14d) and (14k) confirmed the structure of the desired isomer and re...

The liposomal membrane transport assay, which uses 8-hydroxypyrene-1,3,6-trisulfonic acid to monitor the internal pH of the vesicles (the HPTS assay), is a widely used technique for analysing the activity of anionophore-facilitated transport across a phospholipid membrane. This paper describes the stepwise technique to conduct this transport assay,...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

Various artificial transmembrane transporters, designed to function through mobile carrier or channel mechanisms, have been developed in the past decade. With the aid of structural manipulation and by employing either discrete chemical entities or self-assembled nanostructures, progress has been made in achieving the selective recognition and trans...

Cyclodextrins have been employed as delivery agents for lipophilic anion transporters, which allow their incorporation into lipid bilayers without using an organic solvent or pre-incorporation.

The vesicular anion transport activity assay, which uses 8-hydroxypyrene-1,3,6-trisulfonic acid to monitor the internal pH of the vesicles (the HPTS assay), is a widely used technique for analysing the activity of anionophore facilitated transport across a phospholipid membrane. This methods paper describes the stepwise technique to conduct this tr...

The vesicular anion transport activity assay, which uses 8-hydroxypyrene-1,3,6-trisulfonic acid to monitor the internal pH of the vesicles (the HPTS assay), is a widely used technique for analysing the activity of anionophore facilitated transport across a phospholipid membrane. This methods paper describes the stepwise technique to conduct this tr...

CYCLODEXTRINS HAVE BEEN EMPLOYED AS DELIVERY AGENTS FOR LIPOPHILIC ANION TRANSPORTERS, WHICH ALLOW THEIR INCORPORATION INTO LIPID BILAYERS WITHOUT USING AN ORGANIC SOLVENT OR PRE-INCORPORATION.

CYCLODEXTRINS HAVE BEEN EMPLOYED AS DELIVERY AGENTS FOR LIPOPHILIC ANION TRANSPORTERS, WHICH ALLOW THEIR INCORPORATION INTO LIPID BILAYERS WITHOUT USING AN ORGANIC SOLVENT OR PRE-INCORPORATION.

A series of fluorescent coumarin bis-ureas have been synthesised and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes.

A series of fluorescent coumarin bis-ureas have been synthesised and their anion transport properties studied. The compounds function as highly potent HCl co-transport agents in lipid bilayer membranes.

CYCLODEXTRINS HAVE BEEN EMPLOYED AS DELIVERY AGENTS FOR LIPOPHILIC ANION TRANSPORTERS, WHICH ALLOW THEIR INCORPORATION INTO LIPID BILAYERS WITHOUT USING AN ORGANIC SOLVENT OR PRE-INCORPORATION.

CYCLODEXTRINS HAVE BEEN EMPLOYED AS DELIVERY AGENTS FOR LIPOPHILIC ANION TRANSPORTERS, WHICH ALLOW THEIR INCORPORATION INTO LIPID BILAYERS WITHOUT USING AN ORGANIC SOLVENT OR PRE-INCORPORATION.

The arrangement of hydrogen bond donors around a central lipophilic scaffold has proven to be a successful strategy in the development of potent chloride transporters. In this work, we revisit an acridinone 1,9-bis(thio)urea motif which had previously shown promise as an anion sensor and expand the series of compounds by appending a variety of elec...

A number of artificial cation ionophores (or transporters) have been developed for basic research and biomedical applications. However, their mechanisms of action and the putative correlations between changes in intracellular cation concentrations and induced cell death remain poorly understood. Here, we show that three hemispherand-strapped calix[...

The arrangement of hydrogen bond donors around a central lipophilic scaffold has proven a successful strategy in the development of potent chloride transporters. In this work, we revisit an acridinone 1,9-bis(thio)urea motif which had previously shown promise as an anion sensor and expand the series of compounds by appending a variety of electron-w...

The arrangement of hydrogen bond donors around a central lipophilic scaffold has proven a successful strategy in the development of potent chloride transporters. In this work, we revisit an acridinone 1,9-bis(thio)urea motif which had previously shown promise as an anion sensor and expand the series of compounds by appending a variety of electron-w...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

Phenylthiosemicarbazones (PTSCs) are proton-coupled anion transporters with pH-switchable behaviour known to be regulated by an imine protonation equilibrium. Previously, chloride/nitrate exchange by PTSCs was found to be inactive at pH 7.2 due to locking of the thiourea anion binding site by an intramolecular hydrogen bond, and switched ON upon im...

The vesicular anion transport activity assay, which uses 8-hydroxypyrene-1,3,6-trisulfonic acid to monitor the internal pH of the vesicles (the HPTS assay), is a widely used technique for analysing the activity of anionophore facilitated transport across a phospholipid membrane. This methods paper describes the stepwise technique to conduct this tr...

The vesicular anion transport activity assay, which uses 8-hydroxypyrene-1,3,6-trisulfonic acid to monitor the internal pH of the vesicles (the HPTS assay), is a widely used technique for analysing the activity of anionophore facilitated transport across a phospholipid membrane. This methods paper describes the stepwise technique to conduct this tr...

The arrangement of hydrogen bond donors around a central lipophilic scaffold has proven a successful strategy in the development of potent chloride transporters. In this work, we revisit an acridinone 1,9-bis(thio)urea motif which had previously shown promise as an anion sensor and expand the series of compounds by appending a variety of electron-w...

The arrangement of hydrogen bond donors around a central lipophilic scaffold has proven a successful strategy in the development of potent chloride transporters. In this work, we revisit an acridinone 1,9-bis(thio)urea motif which had previously shown promise as an anion sensor and expand the series of compounds by appending a variety of electron-w...

We report a series of easily accessible carbazole-based bis-ureas and thioureas as effective anion receptors and transporters. The compounds exhibit moderate Cl⁻ binding affinity in wet DMSO and Cl⁻ transport capabilities in phospholipid membranes predominantly through an electroneutral H⁺/Cl⁻ and anion exchange mechanisms.

The selective and efficient capture of phosphopeptides is critical for comprehensive and in-depth phosphoproteome analysis. Here we report a new switchable two-dimensional (2D) supramolecular polymer that serves as an ideal platform for the enrichment of phosphopeptides. A well-defined, positively charged metallacycle incorporated into the polymer...

Na+, Cl− and K+ are the most abundant electrolytes present in biological fluids that are essential to the regulation of pH homeostasis, membrane potential and cell volume in living organisms. Herein, we report synthetic crown ether-thiourea conjugates as a cation/anion symporter, which can transport both Na+ and Cl− across lipid bilayers with relat...

pH-dependent liposomal assays are often used to determine anion selectivity in transmembrane anion transport experiments. In this communication, we discuss the validity and limitations of these assays, and provide guidelines for their use to avoid misleading results.

Supramolecular chemistry is a comparatively young field that to date has mainly been focused on building a foundation of fundamental understanding. With much progress in this area, researchers are seeking to apply this knowledge to the development of commercially viable products. In this review we seek to outline historical and recent developments...

Despite commonly being used as the hosts for gases, solvents and other neutral molecules, metal-organic frameworks (MOFs) have received recent attention as supramolecular anion binding hosts with a broad range of environmental and biological applications. The review summarizes the development of this area, with the anion-binding MOFs categorized ba...

Synthetic anion transporters that facilitate chloride transport are promising candidates for channelopathy treatments. However, most anion transporters exhibit an undesired side effect of facilitating proton transport via interacting with fatty acids present in the membrane. To address the limitation, we here report the use of a new tetrapodal scaf...

In this issue of Chem, Palacín, Ballester, and co-workers discuss the properties of a calix[4]pyrrole cavitand capable of facilitiating the selective transport of L-proline across liposomal membranes and which can contribute to the uptake of this amino acid in cells.

In this review we cover recent developments in fluorescent and colorimetric anion sensors. These systems employ a range of different non-covalent interactions including hydrogen- and halogen-bonding, Lewis acidic boron-based sensors, metal-based sensors, charged systems, compounds that use anion-pi interactions to stabilise complexes, photoswitchab...

Respiring mitochondria establish a proton gradient across the mitochondrial inner membrane (MIM) that is used to generate ATP. Protein-independent mitochondrial uncouplers collapse the proton gradient and disrupt ATP production by shuttling protons back across the MIM in a protonophoric cycle. Continued cycling relies on the formation of MIM-permea...

Anion transporters have shown potential application as anti‐cancer agents that function by disrupting homeostasis and triggering cell death. In this research article we report switchable anion transport by gold complexes of anion transporters that are “switched on” in situ in the presence of the reducing agent GSH by decomplexation of gold. GSH is...

The development of discrete molecular carriers for anions and supramolecular anion channels are reviewed followed by an overview of the use of these systems in biological systems as putative treatments for diseases such as cystic fibrosis and cancer.

Bis‐imidazole‐based anion transporters have been complexed to AuIII to switch off their anion transport properties. In the presence of reducing agents such as GSH the gold is sequestered from the transporter and transport is switched on. This provides a method of targeting anion transporters to tissue with higher concentrations of GSH including tum...

Anion transporters have shown potential application as anti-cancer agents that function by disrupting homeostasis and triggering cell death. In this research article we report switchable anion transport by gold complexes of anion transporters that are ‘switched on’ in the presence of the reducing agent GSH by decomplexation of gold. GSH is found in...

The genesis of anion receptor chemistry can be traced back to the late 1960s with the work of Shriver and Biallas on chelating Lewis acids and Park and Simmons on ammonium-containing cryptand-like halide receptors. Despite pioneering work in the 1970s and 1980s from the groups of Lehn and Schmidtchen, the area did not attract significant interest u...

This review covers advances in anion complexation in the years 2017 and 2018. The review focuses on the applications of anion receptor chemistry, including sensing, self-assembly, extraction, transport, catalysis, and fundamental advances in the area.

The anion‐binding and transport properties of an extensive library of thiophene‐based molecules are reported. Seventeen bis‐urea positional isomers, with different binding conformations and lipophilicities, have been synthesized by appending α‐ or β‐thiophene or α‐, β‐, or γ‐benzo[b]thiophene moieties to an ortho‐phenylenediamine central core, yiel...

The selective and efficient capture of phosphopeptides is critical for comprehensive and in-depth phosphoproteome analysis. However, this remains a significant challenge due to the inherently low abundance of these species in complex bio-samples. In this paper, we report a switchable two-dimensional (2D) supramolecular polymer that can serve as an...

Synthetic anion receptors that facilitate transmembrane chloride transport are of interest as potential therapeutic agents for cancer and cystic fibrosis. Transporters selective for chloride over protons are desired for therapeutic applications to avoid autophagy inhibition and cytotoxicity. Examples of such compounds are rare because the majority...

Many synthetic and supramolecular chiral polymeric systems are known to exhibit the “majority rules effect” (MRE), a positive non-linear response in which a small enantiomeric excess (ee) of the chiral building blocks lead to unproportionally large chiroptical signals near zero ee. In contrast, the opposite “racemate rules effect” (RRE), a negative...

Defective anion transport is a hallmark of the genetic disease cystic fibrosis (CF). One approach to restore anion transport to CF cells utilises alternative pathways for transmembrane anion transport, including artificial anion carriers (anionophores). Here, we screened 22 anionophores for biological activity using fluorescence emission from the h...

Ein Tetraharnstoff‐Makrocyclus und andere synthetische Anionentransporter erleichtern den H+/Cl−‐Symport und zeigen abgeschwächte Transportraten in Gegenwart eines Membranpotentials, wie P. A Gale und Mitarbeiter in ihrem Forschungsartikel (DOI: 10.1002/ange.201907466) beschreiben. Diese spannungsabhängige Eigenschaft, die an spannungsgesteuerte Io...

A tetraurea macrocycle and other synthetic anion transporters facilitate transmembrane H+/Cl− symport and show attenuated transport rates in the presence of a membrane potential, as described by P. A. Gale et al. in their Research Article on page 15142 ff. This voltage‐dependent property, reminiscent of voltage‐gated ion channels, is related to the...

Synthetic anion transporters that facilitate transmembrane H⁺/Cl⁻ symport (cotransport) have anti‐cancer potential due to their ability to neutralize pH gradients and inhibit autophagy in cells. However, compared to the natural product prodigiosin, synthetic anion transporters have low‐to‐modest H⁺/Cl⁻ symport activity and their mechanism of action...

Spannungsabhängiger Ionentransport: Eine Gruppe von synthetischen Anionentransportern mit einem Tetraharnstoff‐Makrocyclus erleichtert den HCl‐Transport, der durch Anlegen eines Membranpotentials abgeschaltet werden kann. Diese Eigenschaft steht im Zusammenhang mit der starken Lipidphosphat‐Kopfgruppenbindung und dem Fehlen von Chlorid‐Uniport‐Akti...

A series of chloride receptors has been synthesized containing an amide hydrogen bonding site and a hydroquinone motif. It was anticipated that oxidation of the hydroquinone unit to quinone would greatly the diminish chloride binding affinity of these receptors. A conformational switch is promoted in the quinone form through the formation of an int...

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 transmembrane chloride gradient. Addition of fatty acid to phospholip...

Anionophores are small synthetic molecules that can bind anions and facilitate their transport across lipid bilayer membranes. There are many different classes of transmembrane anion transporter with a wide range of structures. Developing a method to switch on the anion transport function under specific conditions would dramatically widen the scope...