443 results on '"Philip A. Gale"'
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2. Fluorinated tetrapodal anion transporters
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Alexander M. Gilchrist, Xin Wu, Bryson A. Hawkins, David E. Hibbs, and Philip A. Gale
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Chemistry ,Organic chemistry ,Organic synthesis ,Science - Abstract
Summary: 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 transporters has been shown to tune the transporter lipophilicity, transport rates, and binding strength. In this work, we expand on our previously reported tetrapodal (thio)urea transporters with a series of fluorinated tetrapodal anion transporters. The effects of fluorination on tuning the lipophilicity, solubility, deliverability, and anion transport selectivity of the tetrapodal scaffold were investigated using anion-binding and transport assays. The primary mode of anion transport was H+/X− cotransport, with the most fluorinated tetrathiourea (8) displaying the highest transport activity in the 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) assay. Intriguingly, inversion of the transmembrane Cl− vs NO3− transport selectivity compared with previously reported tripodal (thio)urea transporters was observed under a modified HPTS assay.
- Published
- 2023
- Full Text
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3. Fatty Acid-Activated Proton Transport by Bisaryl Anion Transporters Depolarises Mitochondria and Reduces the Viability of MDA-MB-231 Breast Cancer Cells
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Edward York, Daniel A. McNaughton, Meryem-Nur Duman, Philip A. Gale, and Tristan Rawling
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mitochondria ,uncouplers ,anion transporter ,proton transport ,membrane ,anticancer ,Microbiology ,QR1-502 - Abstract
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 mediate mitochondrial uncoupling through a novel fatty acid-activated proton transport mechanism, where the bisaryl urea promotes the transbilayer movement of deprotonated fatty acids and proton transport. In this paper, we investigated the impact of replacing the urea group with squaramide, amide and diurea anion binding motifs. Bisaryl squaramides were found to depolarise mitochondria and reduce MDA-MB-231 breast cancer cell viability to similar extents as their urea counterpart. Bisaryl amides and diureas were less active and required higher concentrations to produce these effects. For all scaffolds, the substitution of the bisaryl rings with lipophilic electron-withdrawing groups was required for activity. An investigation of the proton transport mechanism in vesicles showed that active compounds participate in fatty acid-activated proton transport, except for a squaramide analogue, which was sufficiently acidic to act as a classical protonophore and transport protons in the absence of free fatty acids.
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- 2023
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4. A potent fluorescent transmembrane HCl transporter perturbs cellular pH and promotes cancer cell death
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Mohamed Fares, Xin Wu, Daniel A. McNaughton, Alexander M. Gilchrist, William Lewis, Paul A. Keller, Alain Arias-Betancur, Pere Fontova, Ricardo Pérez-Tomás, and Philip A. Gale
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Organic Chemistry ,Physical and Theoretical Chemistry ,Biochemistry - Abstract
A series of fluorescent coumarin-based bis-ureas have been synthesised. These compounds show strong HCl cotransport properties in model vesicle systems. Cellular localisation studies show that cytotoxic compound 4 localises in lysosomes and perturbs cellular pH.
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- 2023
5. Structure–Activity Relationship and Mechanistic Studies of Bisaryl Urea Anticancer Agents Indicate Mitochondrial Uncoupling by a Fatty Acid-Activated Mechanism
- Author
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Edward York, Daniel A. McNaughton, Ariane Roseblade, Charles G. Cranfield, Philip A. Gale, and Tristan Rawling
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03 Chemical Sciences, 06 Biological Sciences ,Mitochondrial Proteins ,Structure-Activity Relationship ,Organic Chemistry ,Fatty Acids ,Urea ,Molecular Medicine ,Antineoplastic Agents ,General Medicine ,Protons ,Biochemistry ,Mitochondria - Abstract
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 mechanism by which SR4 depolarizes mitochondria is unclear because SR4 lacks an acidic functional group typically found in protein-independent uncouplers. Recently, it was shown that structurally related thioureas can facilitate proton transport across lipid bilayers by a fatty acid-activated mechanism, in which the fatty acid acts as the site of protonation/deprotonation and the thiourea acts as an anion transporter that shuttles deprotonated fatty acids across the phospholipid bilayer to enable proton leak. In this paper, we show that SR4-mediated proton transport is enhanced by the presence of free fatty acids in the lipid bilayer, indicating that SR4 uncouples mitochondria through the fatty acid-activated mechanism. This mechanistic insight was used to develop a library of substituted bisaryl ureas for structure-activity relationship studies and subsequent cell testing. It was found that lipophilic electron-withdrawing groups on bisaryl ureas enhanced electrogenic proton transport via the fatty acid-activated mechanism and had the capacity to depolarize mitochondria and reduce the viability of MDA-MB-231 breast cancer cells. The most active compound in the series reduced cell viability with greater potency than SR4 and was more effective at inhibiting adenosine triphosphate production.
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- 2022
6. Solving world problems with pyrrole: 65th birthday tribute to Prof. Jonathan L. Sessler
- Author
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Calvin V. Chau, Sajal Sen, Adam C. Sedgwick, Philip A. Gale, G. Dan Pantos, Sung Kuk Kim, Jung Su Park, Elisa Tomat, Jonathan F. Arambula, Anne E.V. Gorden, and Hiroyuki Furuta
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General Chemical Engineering ,Biochemistry (medical) ,Materials Chemistry ,Environmental Chemistry ,General Chemistry ,Biochemistry - Published
- 2022
7. Tetrapodal Anion Transporters
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Alexander M. Gilchrist, Lijun Chen, Xin Wu, William Lewis, Ethan N.W. Howe, Lauren K. Macreadie, and Philip A. Gale
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supramolecular chemistry ,lipid bilayer ,anion transport ,anion-selective transport ,Organic chemistry ,QD241-441 - Abstract
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 scaffold to maximize the selective interaction with spherical chloride over binding the carboxylate headgroup of fatty acids. One of the new transporters demonstrated a high selectivity for chloride uniport over fatty acid-induced proton transport while being >10 times more active in chloride uniport than strapped calixpyrroles that were previously the only class of compounds known to possess similar selectivity properties.
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- 2020
- Full Text
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8. Synthetic Na+/K+ exchangers promote apoptosis by disturbing cellular cation homeostasis
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Airlie J. Kinross, Daniel A. McNaughton, Injae Shin, Philip A. Gale, Jonathan L. Sessler, Vincent M. Lynch, Qing He, In Hong Hwang, Martin Drøhse Kilde, Sanghyun Park, Ethan N. W. Howe, and Shenglun Xiong
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Programmed cell death ,Osmotic shock ,General Chemical Engineering ,010402 general chemistry ,01 natural sciences ,Biochemistry ,supramolecular chemistry ,03 medical and health sciences ,0399 Other Chemical Sciences ,Cation homeostasis ,Materials Chemistry ,Environmental Chemistry ,cation transport ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,Reactive oxygen species ,Chemistry ,Endoplasmic reticulum ,Biochemistry (medical) ,Autophagy ,General Chemistry ,0104 chemical sciences ,Biophysics ,Cellular cation homeostasis ,Intracellular - Abstract
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[4]pyrrole based ion pair receptors act as efficient Na+/K+ exchangers in the presence of Cl- in liposomal models, and promote Na+ influx and K+ efflux (Na+/K+ exchange) in cancer cells to induce apoptosis. Mechanistic studies reveal that these cation exchangers induce endoplasmic reticulum (ER) stress in cancer cells by perturbing intracellular cation homeostasis, promote generation of reactive oxygen species, and eventually enhance mitochondria-mediated apoptosis. However, they neither induce osmotic stress nor affect autophagy. The present study provides support for the notion that synthetic receptors which perturb cellular cation homeostasis may provide a new approach to generating agents with potentially useful apoptotic activity.
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- 2021
9. Protonophoric and mitochondrial uncoupling activity of aryl-carbamate substituted fatty acids
- Author
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Hugo MacDermott-Opeskin, Callum Clarke, Xin Wu, Ariane Roseblade, Edward York, Ethan Pacchini, Ritik Roy, Charles Cranfield, Philip A. Gale, Megan L. O'Mara, Michael Murray, and Tristan Rawling
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Organic Chemistry ,Physical and Theoretical Chemistry ,Biochemistry - Abstract
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 retain the activity of their urea counterparts. Thus, the aryl-carbamate substituted fatty acids uncouple oxidative phosphorylation and inhibit ATP production by collapsing the mitochondrial proton gradient. Proton transport proceeds
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- 2022
10. Crown ether-thiourea conjugates as ion transporters
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Bailing Tang, Philip A. Gale, Zhao Li, Xin Wu, Xiao-Sheng Yan, Zhixing Zhao, and Yun-Bao Jiang
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Membrane potential ,chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,General Chemical Engineering ,Vesicle ,0904 Chemical Engineering ,Synthetic membrane ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,ion transport ,symport ,Membrane ,crown ether ,0399 Other Chemical Sciences ,Symporter ,Biophysics ,Lipid bilayer ,thiourea ,Ion transporter ,Crown ether - Abstract
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 relatively high transport activity. Surprisingly, the ion transport activities were diminished when high concentrations of K+ ions were present outside the vesicles. This unusual behavior resulted from the strong affinity of the transporters for K+ ions, which led to predominant partitioning of the transporters as the K+ complexes in the aqueous phase preventing the transporter incorporation into the membrane. Synthetic membrane transporters with Na+, Cl− and K+ transport capabilities may have potential biological and medicinal applications. [Figure not available: see fulltext.]
- Published
- 2021
11. Carbazole-based bis-ureas and thioureas as electroneutral anion transporters
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Philip A. Gale, Patrick Wang, and Xin Wu
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anion transport ,010405 organic chemistry ,Carbazole ,Hydrogen bond ,Supramolecular chemistry ,Transporter ,General Chemistry ,hydrogen bonding ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,3. Good health ,Ion ,chemistry.chemical_compound ,chemistry ,carbazole ,0399 Other Chemical Sciences ,Receptor - Abstract
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.
- Published
- 2021
12. Investigating the Influence of Steric Hindrance on Selective Anion Transport
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Laura A. Jowett, Angela Ricci, Xin Wu, Ethan N. W. Howe, and Philip A. Gale
- Subjects
anion transport ,thioureas ,lipid bilayer ,Organic chemistry ,QD241-441 - Abstract
A series of symmetrical and unsymmetrical alkyl tren based tris-thiourea anion transporters were synthesised and their anion binding and transport properties studied. Overall, increasing the steric bulk of the substituents resulted in improved chloride binding and transport abilities. Including a macrocycle in the scaffold enhanced the selectivity of chloride transport in the presence of fatty acids, by reducing the undesired H+ flux facilitated by fatty acid flip-flop. This study demonstrates the benefit of including enforced steric hindrance and encapsulation in the design of more selective anion receptors.
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- 2019
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13. Janus metal-organic layer functioning as a biomimetic photosynthetic reaction center
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Xin Wu, Alexander M. Gilchrist, and Philip A. Gale
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General Chemical Engineering ,Biochemistry (medical) ,Materials Chemistry ,Environmental Chemistry ,General Chemistry ,0303 Macromolecular and Materials Chemistry ,Biochemistry - Abstract
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.
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- 2022
14. Binding and transport properties of a benzo[b]thiophene‐based mono‐(thio)urea library
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Vasco Cachatra, Li-Jun Chen, Igor Marques, Brian Goodfellow, Cristina Moiteiro, Vítor Félix, Philip Alan Gale, Silvia Carvalho, and William Ryder
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Anion binding ,anion transport ,thiophene ,Channel replacement therapies ,Computational Chemistry ,Ionophores ,Organic Chemistry ,0399 Other Chemical Sciences ,Thio(urea) receptors ,Physical and Theoretical Chemistry ,Supramolecular chemistry ,hydrogen bonding ,0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry - Abstract
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 chains or aryl moieties with different fluorination degrees. 1H NMR titrations, X-ray crystallographic studies, and DFT calculations were used to study the chloride binding affinities between receptors and substrates. Experimental efflux studies suggested that the anion transmembrane transport activity is dependent on the receptors′ lipophilicity and hydrogen bonding ability. Moreover, LUV based assays indicated that anion efflux occurs mainly through an uniport mechanism. Further MD simulations showed that anion transport is highly dependent on the orientation and interactions of the receptors at the water/lipid interface. Graphical Abstract Playing with benzo[b]thiophene-based motifs as Lego bricks, an extensive library of small drug-like synthetic receptors was designed. Their anion binding and transmembrane transport properties were investigated by a combination of experimental and theoretical approaches. The most active transporters recognize chloride using an urea assisted by a C−H binding unit from a single β- or γ-benzo[b]thiophene motif. published
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- 2022
15. The supramolecular chemistry of anions
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Katrina (Kate) A. Jolliffe and Philip A. Gale
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Organic Chemistry ,Physical and Theoretical Chemistry ,Biochemistry - Abstract
Guest editors Katrina Jolliffe and Philip Gale introduce the Organic & Biomolecular Chemistry themed collection on the supramolecular chemistry of anions.
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- 2022
16. Progress in Anion Receptor Chemistry
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Lauren K. Macreadie, Alexander M. Gilchrist, Daniel A. McNaughton, William G. Ryder, Mohamed Fares, and Philip A. Gale
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anion receptor chemistry ,General Chemical Engineering ,Biochemistry (medical) ,0399 Other Chemical Sciences ,Materials Chemistry ,Environmental Chemistry ,General Chemistry ,0303 Macromolecular and Materials Chemistry ,Biochemistry ,supramolecular chemistry - Abstract
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.
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- 2022
17. Stimuli‐Responsive Cycloaurated 'OFF‐ON' Switchable Anion Transporters
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Mohamed Fares, Xin Wu, Deepthi Ramesh, William Lewis, Paul A. Keller, Ethan N. W. Howe, Ricardo Pérez‐Tomás, and Philip A. Gale
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010405 organic chemistry ,General Medicine ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences - Published
- 2020
18. Prospects and Challenges in Anion Recognition and Transport
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Alexander M. Gilchrist, Philip A. Gale, and Xin Wu
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Chemistry ,General Chemical Engineering ,Anion receptor chemistry ,Biochemistry (medical) ,Supramolecular chemistry ,0303 Macromolecular and Materials Chemistry ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Molecular recognition ,Materials Chemistry ,Environmental Chemistry ,0210 nano-technology ,Anion receptor - Abstract
Summary 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 until the 1990s, when the field of anion receptor chemistry—which includes molecular recognition, sensing, transmembrane anion transport, extraction, crystal engineering, self-assembly, and catalysis—began to blossom. This Perspective highlights the recent developments in this area and examines future challenges.
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- 2020
19. Advances in anion transport and supramolecular medicinal chemistry
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Roberto Quesada, Philip A. Gale, and Jeffery T. Davis
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010405 organic chemistry ,Chemistry ,technology, industry, and agriculture ,Supramolecular chemistry ,macromolecular substances ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences - Abstract
Advances in anion transport by synthetic supramolecular systems are discussed in this article. Developments in the design 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.
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- 2020
20. Advances in Anion Receptor Chemistry
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Philip A. Gale, Li-Jun Chen, Xin Wu, Stuart N. Berry, and Ethan N. W. Howe
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Molecular switch ,Halogen bond ,Chemistry ,Hydrogen bond ,General Chemical Engineering ,Biochemistry (medical) ,Extraction (chemistry) ,Supramolecular chemistry ,0303 Macromolecular and Materials Chemistry ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,0104 chemical sciences ,Catalysis ,Molecular recognition ,anion receptor chemistry ,Materials Chemistry ,Environmental Chemistry ,0210 nano-technology ,Anion receptor - Abstract
Summary 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.
- Published
- 2020
21. Development of a Library of Thiophene‐Based Drug‐Like Lego Molecules: Evaluation of Their Anion Binding, Transport Properties, and Cytotoxicity
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Michael J. Spooner, Ethan N. W. Howe, Odete A. B. da Cruz e Silva, Vítor Félix, Cristina Moiteiro, Claudia Y. Leung, Margarida Q. Miranda, Paulo Jorge Vieira, Li-Jun Chen, Philip A. Gale, Sílvia Carvalho, Carl Zhen, Bárbara Morgado, and Igor Marques
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Anions ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Thiophenes ,Crystallography, X-Ray ,Anion transport • thiophene-based molecules • efflux studies • molecular modelling • cytotoxicity ,010402 general chemistry ,01 natural sciences ,Catalysis ,chemistry.chemical_compound ,Chlorides ,Cell Line, Tumor ,Thiophene ,Structural isomer ,Humans ,Urea ,Molecule ,Anion binding ,Ion Transport ,010405 organic chemistry ,Vesicle ,Organic Chemistry ,Biological Transport ,0303 Macromolecular and Materials Chemistry ,General Chemistry ,0104 chemical sciences ,3. Good health ,chemistry ,Symporter ,Proton NMR ,Efflux - Abstract
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, yielding six subsets of positional isomers. Through H NMR, X-ray crystallography, molecular modelling, and anion efflux studies, it is demonstrated that the most active transporters adopt a pre-organized binding conformation capable of promoting the recognition of chloride, using urea and C−H binding groups in a cooperative fashion. Additional large unilamellar vesicle-based assays, carried out under electroneutral and electrogenic conditions, together with N-methyl-d-glucamine chloride assays, have indicated that anion efflux occurs mainly through an H/Cl symport mechanism. On the other hand, the most efficient anion transporter displays cytotoxicity against tumor cell lines, while having no effects on a cystic fibrosis cell line.
- Published
- 2019
22. Design of Chiral Supramolecular Polymers Exhibiting a Negative Nonlinear Response
- Author
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Yun-Bao Jiang, Xiao-Yan Lin, Eric V. Anslyn, Philip A. Gale, Xuan-Xuan Chen, and Xin Wu
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chemistry.chemical_classification ,010405 organic chemistry ,Chemistry ,polymer ,Organic Chemistry ,Supramolecular chemistry ,0303 Macromolecular and Materials Chemistry ,Polymer ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Article ,0104 chemical sciences ,Supramolecular polymers ,Nonlinear system ,Enantiomeric excess - Abstract
Many synthetic and supramolecular chiral polymeric systems are known to exhibit the “majority rules effect” (MRE), a positive nonlinear response in which a small enantiomeric excess (ee) of the chiral building blocks leads to unproportionally large chiroptical signals near zero ee. In contrast, the opposite “racemate rules effect” (RRE), a negative nonlinear response in which the chiroptical signals are “at near zero ee, while giving large nonlinear chiroptical responses to ee at high values, has only been occasionally observed. The origin of this unusual ee dependence remains elusive largely because few systems have been established that exhibit this effect. Herein, we present a design approach that enables the development of chiral supramolecular polymers with a pronounced negative nonlinear response akin to RRE. This is achieved by in situ generating a bidentate inducer for supramolecular polymerization that exists in both meso- and homochiral forms upon reacting with chiral guests. The presence of the meso-inducer creates an aggregate structure that has a little response in the circular dichroism (CD) spectra as a function of ee at a particular wavelength, but a homochiral inducer gives large changes in response to ee at this wavelength. This allowed for an RRE-like response to be observed when the CD intensity of the supramolecular polymers was plotted against the ee of the chiral guests that generate the meso- and homochiral inducers without the necessity of the racemic guest preferentially being incorporated into the polymer.
- Published
- 2019
23. Organoplatinum Compounds as Anion-Tuneable Uphill Hydroxide Transporters
- Author
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Li‐Jun Chen, Xin Wu, Alexander M. Gilchrist, and Philip A. Gale
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Anions ,Kinetics ,Organoplatinum Compounds ,Hydroxides ,Membrane Transport Proteins ,Biological Transport ,General Medicine ,General Chemistry ,Hydrogen-Ion Concentration ,Catalysis ,Membrane Potentials - Abstract
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 Pt
- Published
- 2021
24. Halide-selective, proton-coupled anion transport by phenylthiosemicarbazones
- Author
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William Lewis, Ethan N. W. Howe, Philip A. Gale, Xin Wu, Lauren K. Macreadie, Vai-Vai Tiffany Chang, and Mohamed Fares
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Hydrogen bonding ,Anions ,Thiosemicarbazones ,Biochemistry & Molecular Biology ,Imine ,Biophysics ,Halide ,Protonation ,010402 general chemistry ,Crystallography, X-Ray ,Photochemistry ,01 natural sciences ,Biochemistry ,Chloride ,Switchable receptors ,chemistry.chemical_compound ,Chlorides ,Anion transport ,0399 Other Chemical Sciences ,medicine ,Anion binding ,Ion Transport ,Nitrates ,010405 organic chemistry ,Hydrogen bond ,Cell Biology ,Hydrogen-Ion Concentration ,0104 chemical sciences ,0601 Biochemistry and Cell Biology, 0699 Other Biological Sciences, 0904 Chemical Engineering ,Kinetics ,Thiourea ,chemistry ,Nitrate transport ,Protons ,medicine.drug - Abstract
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 imine protonation at pH 4.5. The rate-determining process of the pH switch, however, was not examined. We here develop a new series of PTSCs and demonstrate their conformational behaviour by X-ray crystallographic analysis and pH-switchable anion transport properties by liposomal assays. We report the surprising finding that the protonated PTSCs are extremely selective for halides over oxyanions in membrane transport. Owing to the high chloride over nitrate selectivity, the pH-dependent chloride/nitrate exchange of PTSCs originates from the rate-limiting nitrate transport process being inhibited at neutral pH.
- Published
- 2021
25. Coumarin-bisureas as potent fluorescent transmembrane anion transporters
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Alexander M. Gilchrist, Mohamed Fares, Alain Arias-Betancur, Philip A. Gale, Xin Wu, Daniel A. McNaughton, William Lewis, Ricardo Pérez-Tomás, and Paul A. Keller
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chemistry.chemical_compound ,Membrane ,chemistry ,Hydrogen bond ,Urea ,Transporter ,Coumarin ,Lipid bilayer ,Combinatorial chemistry ,Fluorescence ,Transmembrane protein - Abstract
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.
- Published
- 2021
26. Coumarin-bisureas as potent fluorescent transmembrane anion transporters
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Mohamed Fares, Xin Wu, Daniel A. McNaughton, Alexander M. Gilchrist, William Lewis, Paul A. Keller, Alain Arias-Betancur, Ricardo Pérez-Tomás, and Philip Alan Gale
- Abstract
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.
- Published
- 2021
27. NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas
- Author
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Damjan Makuc, Jennifer R. Hiscock, Mark E. Light, Philip A. Gale, and Janez Plavec
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anion recognition ,conformation analysis ,host–guest systems ,NMR spectroscopy ,Science ,Organic chemistry ,QD241-441 - Abstract
The conformational properties of 1,3-diindolylureas and thioureas were studied by a combination of heteronuclear NMR spectroscopy and quantum mechanics calculations. NOE experiments showed that the anti–anti conformer along the C7–N7α bonds was predominant in DMSO-d6 solution in the absence of anions. Anion-induced changes in the 1H and 15N chemical shifts confirm the weak binding of chloride anions with negligible conformational changes. Strong deshielding of ureido protons and moderate deshielding of indole NH was observed upon the addition of acetate, benzoate, bicarbonate and dihydrogen phosphate, which indicated that the predominant hydrogen bond interactions occurred at the urea donor groups. Binding of oxo-anions caused conformational changes along the C7–N7α bonds and the syn–syn conformer was preferred for anion–receptor complexes. The conformational changes upon anion binding are in good agreement with energetic preferences established by ab initio calculations.
- Published
- 2011
- Full Text
- View/download PDF
28. Delivering anion transporters to lipid bilayers in water
- Author
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Tsz Ying Teresa To, Philip A. Gale, David E. Hibbs, Bryson A. Hawkins, and Daniel A. McNaughton
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chemistry.chemical_classification ,anion transport ,Cyclodextrin ,010405 organic chemistry ,Chemistry ,Organic solvent ,Organic Chemistry ,Squaramide ,Transporter ,010402 general chemistry ,hydrogen bonding ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,supramolecular chemistry ,0104 chemical sciences ,Ion ,chemistry.chemical_compound ,cyclodextrin ,0399 Other Chemical Sciences ,Urea ,lipids (amino acids, peptides, and proteins) ,Physical and Theoretical Chemistry ,Lipid bilayer - Abstract
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.
- Published
- 2021
29. Halide-selective, proton-coupled anion transport by phenylthiosemicarbazones
- Author
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Ethan N.W. Howe, Vai-Vai Tiffany Chang, Xin Wu, William Lewis, Lauren K. Macreadie, and Philip Alan Gale
- Abstract
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 imine protonation at pH 4.5. The rate-determining process of the pH switch, however, was not examined. We here develop a new series of PTSCs and demonstrate their conformational behaviour by X-ray crystallographic analysis and pH-switchable anion transport properties by liposomal assays. We report the surprising finding that these compounds are extremely selective for halides over oxyanions in membrane transport. Owing to the high chloride over nitrate selectivity, the pH-dependent chloride/nitrate exchange of PTSCs originates from the rate-limiting nitrate transport process being inhibited at neutral pH, whereas chloride transport remains efficient under both neutral and acidic conditions.
- Published
- 2021
30. Supramolecular methods: the 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) transport assay
- Author
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Alexander M. Gilchrist, Israel Carreira-Barral, Philip A. Gale, Xin Wu, Daniel Alonso-Carrillo, Roberto Quesada, and Patrick Wang
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Facilitated diffusion ,010405 organic chemistry ,Transport activity ,Vesicle ,Phospholipid ,Supramolecular chemistry ,General Chemistry ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,chemistry.chemical_compound ,Membrane ,chemistry ,Biophysics - Abstract
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 transport assay, detailing both the perks and pitfalls of using this method to determine the activity of an anionophore and the transport mechanism.
- Published
- 2021
31. Acridinone-based anion transporters
- Author
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Daniel McNaughton, Lauren Macreadie, and Philip Alan Gale
- Subjects
3. Good health - Abstract
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-withdrawing groups to the peripheral phenyl moieties. HIgh levels of activity were achieved by the most effective compounds in the series, which facilitated strictly electroneutral transport.
- Published
- 2021
32. A Calix[4]pyrrole-Based Selective Amino Acid Transporter
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Philip A. Gale
- Subjects
chemistry.chemical_classification ,Liposome ,Stereochemistry ,General Chemical Engineering ,Biochemistry (medical) ,Cavitand ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Amino acid ,chemistry.chemical_compound ,Membrane ,chemistry ,Materials Chemistry ,Environmental Chemistry ,Amino acid transporter ,0210 nano-technology ,Pyrrole - Abstract
In this issue of Chem, Palacin, 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.
- Published
- 2020
33. Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter
- Author
-
Charles G. Cranfield, Xin Wu, Philip A. Gale, Benjamin B. Noble, Callum Clarke, Megan L. O'Mara, Michael Murray, William Lewis, Hugo MacDermott-Opeskin, Tristan Rawling, Ariane Roseblade, Kirsi Bourget, and Curtis Pazderka
- Subjects
chemistry.chemical_classification ,0304 Medicinal and Biomolecular Chemistry ,010405 organic chemistry ,Stereochemistry ,Fatty acid ,General Chemistry ,Mitochondrion ,010402 general chemistry ,01 natural sciences ,0104 chemical sciences ,3. Good health ,Chemistry ,Deprotonation ,chemistry ,Mitochondrial matrix ,Moiety ,Intermembrane space ,Electrochemical gradient ,Inner mitochondrial membrane ,03 Chemical Sciences - Abstract
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-permeable anionic species that can return to the intermembrane space after deprotonation in the mitochondrial matrix. Previously described protonophores contain acidic groups that are part of delocalised π-systems that provide large surfaces for charge delocalisation and facilitate anion permeation across the MIM. Here we present a new class of protonophoric uncoupler based on aryl-urea substituted fatty acids in which an acidic group and a π-system are separated by a long alkyl chain. The aryl-urea group in these molecules acts as a synthetic anion receptor that forms intermolecular hydrogen bonds with the fatty acid carboxylate after deprotonation. Dispersal of the negative charge across the aryl-urea system produces lipophilic dimeric complexes that can permeate the MIM and facilitate repeated cycling. Substitution of the aryl-urea group with lipophilic electron withdrawing groups is critical to complex lipophilicity and uncoupling activity. The aryl-urea substituted fatty acids represent the first biological example of mitochondrial uncoupling mediated by the interaction of a fatty acid and an anion receptor moiety, via self-assembly., A new mitochondrial uncoupler that forms membrane permeable dimers through interactions of remote acidic and anion receptor groups.
- Published
- 2021
34. A Two-Dimensional Metallacycle Cross-Linked Switchable Polymer for Fast and Highly Efficient Phosphorylated Peptide Enrichment
- Author
-
Hai-Bo Yang, Jin Wen, Xu-Qing Wang, Philip A. Gale, Jun-Long Zhu, Xiang Wang, Sean J. Humphrey, Li-Jun Chen, and Fan-Fan Zhu
- Subjects
Phosphopeptides ,Organoplatinum Compounds ,Polymers ,010402 general chemistry ,01 natural sciences ,Biochemistry ,supramolecular chemistry ,Catalysis ,Article ,Colloid and Surface Chemistry ,Microscopy, Electron, Transmission ,analytical chemistry ,0399 Other Chemical Sciences ,Phosphorylation ,chemistry.chemical_classification ,Molecular Structure ,Chemistry ,Phosphopeptide ,General Chemistry ,Polymer ,Metallacycle ,Combinatorial chemistry ,Phosphorylated Peptide ,0104 chemical sciences ,Supramolecular polymers ,Cross-Linking Reagents - Abstract
The selective and efficient capture of phosphopeptides is critical for comprehensive and in-depth phosphoproteome analysis. Reported here is a new switchable two-dimensional (2D) supramolecular polymer that can serve as an ideal platform for the enrichment of phos-phopeptides. A well-defined, positively charged metallacycle incorporated into the polymer endows the resultant polymer with a high affinity for phosphopeptides. Importantly, the stimuli-responsive nature of the polymer facilitates switchable binding affinity of phos-phopeptides, thus resulting in excellent performance in phosphopeptide enrichment and separation from model proteins. The polymer has a high enrichment capacity (165 mg/g) and detection sensitivity (2 fmol), high enrichment recovery (88%), excellent specificity, and rapid enrichment and separation properties. Additionally, we have demonstrated the capture of phosphopeptides from the tryptic digest of real bio-samples, thus illustrating the potential of this polymeric material in phosphoproteomic studies.
- Published
- 2021
35. Measuring anion transport selectivity: a cautionary tale
- Author
-
Philip A. Gale and Xin Wu
- Subjects
anion transport ,Chemistry ,Metals and Alloys ,selectivity ,General Chemistry ,Combinatorial chemistry ,Catalysis ,Transmembrane protein ,supramolecular chemistry ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,0399 Other Chemical Sciences ,Materials Chemistry ,Ceramics and Composites ,Selectivity ,transport assays - Abstract
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.
- Published
- 2021
36. Determinants of Ion-Transporter Cancer Cell Death
- Author
-
In Hong Hwang, Sanghyun Park, Philip A. Gale, Nathalie Busschaert, Gabriela I. Vargas-Zúñiga, Seong-Hyun Park, Ethan N. W. Howe, Ji Young Hyun, Injae Shin, Li-Jun Chen, and Jonathan L. Sessler
- Subjects
Osmotic shock ,General Chemical Engineering ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Lysosome ,Materials Chemistry ,medicine ,Environmental Chemistry ,Ion transporter ,chemistry.chemical_classification ,Reactive oxygen species ,Biochemistry (medical) ,Autophagy ,General Chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Cell biology ,medicine.anatomical_structure ,chemistry ,Apoptosis ,Cancer cell ,0210 nano-technology ,Intracellular - Abstract
Recently, we showed that synthetic anion transporters DSC4P-1 and SA-3 had activity related to cancer cell death. They were found to increase intracellular chloride and sodium ion concentrations. They were also found to induce apoptosis (DSC4P-1) and both induce apoptosis and inhibit autophagy (SA-3). However, determinants underlying these phenomenological findings were not elucidated. The absence of mechanistic understanding has limited the development of yet-improved systems. Here, we show that three synthetic anion transporters, DSC4P-1, SA-3, and 8FC4P, induce osmotic stress in cells by increasing intracellular ion concentrations. This triggers the generation of reactive oxygen species via a sequential process and promotes caspase-dependent apoptosis. In addition, two of the transporters, SA-3 and 8FC4P, induce autophagy by increasing the cytosolic calcium ion concentration promoted by osmotic stress. However, they eventually inhibit the autophagy process as a result of their ability to disrupt lysosome function through a transporter-mediated decrease in a lysosomal chloride ion concentration and an increase in the lysosomal pH.
- Published
- 2021
37. Tetraurea Macrocycles: Aggregation-Driven Binding of Chloride in Aqueous Solutions
- Author
-
Xin Wu, Osman Catal, Philip A. Gale, Patrick Wang, Donald S. Thomas, Peter Turner, and William Lewis
- Subjects
General Chemical Engineering ,Supramolecular chemistry ,Stacking ,anion recognition ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Chloride ,supramolecular chemistry ,chemistry.chemical_compound ,Materials Chemistry ,medicine ,Environmental Chemistry ,Acetonitrile ,Anion binding ,Aqueous solution ,Hydrogen bond ,Chemistry ,Biochemistry (medical) ,aggregation ,General Chemistry ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,Small molecule ,0104 chemical sciences ,0210 nano-technology ,Selectivity ,medicine.drug - Abstract
Artificial receptors that recognise anionic species vianoncovalent interactions have a wide range of biomedical, industrial and environmental applications. A major challenge in this area of research is to achieve high affinity and selective anion binding in aqueous media. So far, only a few examples of receptors capable of strong (> 105M-1) anion binding in solutions containing > 50% water are available and none show selectivity for chloride. We report here the discovery of a D4h-symmetric fluorinated tetraurea macrocycle that fulfils this function owing to its unique self-assembly properties. The macrocycle has a strong tendency to self-associate into columnar aggregates viaintermolecular hydrogen bonds and aromatic stacking. In aqueous solutions, macrocycle aggregation generates hydrophobic and size-selective binding pockets favourable for hydrogen bonding with chloride. As a result, micromolar affinity and highly selective chloride binding has been achieved with this simple small molecule (MW < 700) in 60 vol% water/acetonitrile.
- Published
- 2019
38. A highly selective superphane for ReO4− recognition and extraction
- Author
-
Wei Zhou, Aimin Li, Philip A. Gale, and Qing He
- Subjects
General Energy ,General Engineering ,General Physics and Astronomy ,General Materials Science ,General Chemistry - Published
- 2022
39. Anion receptor chemistry: Highlights from 2016
- Author
-
Philip A. Gale, Ethan N. W. Howe, Michael J. Spooner, and Xin Wu
- Subjects
010405 organic chemistry ,Chemistry ,Supramolecular chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,supramolecular chemistry ,0104 chemical sciences ,Catalysis ,Inorganic Chemistry ,Materials Chemistry ,Physical and Theoretical Chemistry ,Anion receptor - Abstract
This review covers recent advances in anion receptor chemistry from 2016, including developments in self-assembly, sensing, anion separation, transport, catalysis and fundamental advances in anion recognition systems. ARC, EPSRC
- Published
- 2018
40. Acridinone-based anion transporters
- Author
-
Philip A. Gale, Lauren K. Macreadie, and Daniel A. McNaughton
- Subjects
anion transport ,010405 organic chemistry ,Hydrogen bond ,acridinone ,Organic Chemistry ,Thio ,Transporter ,010402 general chemistry ,hydrogen bonding ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Chloride ,0104 chemical sciences ,3. Good health ,Ion ,chemistry.chemical_compound ,chemistry ,supramolecular chemistryolecular chemistry ,0399 Other Chemical Sciences ,medicine ,Urea ,Physical and Theoretical Chemistry ,medicine.drug - Abstract
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-withdrawing groups to the peripheral phenyl moieties. High levels of activity were achieved by the most effective compounds in the series, which facilitated strictly electroneutral transport.
- Published
- 2021
41. Anion binding in metal-organic frameworks
- Author
-
Philip A. Gale, Xin Wu, and Lauren K. Macreadie
- Subjects
010405 organic chemistry ,Chemistry ,fungi ,Supramolecular chemistry ,Cationic polymerization ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Inorganic Chemistry ,Covalent bond ,Materials Chemistry ,Molecule ,Metal-organic framework ,Physical and Theoretical Chemistry ,Anion binding - Abstract
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 based on different design strategies including cationic MOFs with anion-exchange capabilities, neutral MOFs that feature anion coordination to metal nodes, as well as MOFs functionalized with non-covalent or covalent anion-recognition motifs. We also discuss the advantages of using the MOF scaffold for anion binding compared with small-molecules anion receptors.
- Published
- 2021
42. Synthesis, X-ray crystallographic analysis, DFT studies and biological evaluation of triazolopyrimidines and 2-anilinopyrimidines
- Author
-
Mohamed Fares, Peter Canfield, Muhammad A. Alsherbiny, William Lewis, Anthony C. Willis, Chun Guang Li, Johan Neyts, Dirk Jochmans, Philip A. Gale, and Paul A. Keller
- Subjects
Science & Technology ,IDENTIFICATION ,Chemistry, Physical ,CHIKUNGUNYA VIRUS ,Cytotoxicity ,Organic Chemistry ,ANTIVIRAL ACTIVITY ,IN-VITRO ,0305 Organic Chemistry ,DFT ,SCXRD ,Analytical Chemistry ,Inorganic Chemistry ,Chemistry ,0306 Physical Chemistry (incl. Structural), 0307 Theoretical and Computational Chemistry ,Physical Sciences ,REPLICATION ,ACID ,Triazolopyrimidine ,ARBIDOL ,FUNCTIONALIZED PYRIMIDINONES ,Inorganic & Nuclear Chemistry ,Antiviral ,INHIBITORS ,Spectroscopy - Abstract
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 revealed the coplanarity of the fused [1,2,4]triazolo[4,3-a]pyrimidine rings with the aryl side group. DFT studies revealed insights into the mechanism of the micro-reversible cyclisation step using DFT [B3LYP-D3(BJ)/6-31++G(d,p)]. The pharmacokinetic properties and calculation of drug likeness scores (DLS) of (5a-e) and (14a-k) suggested good traditional drug-like properties and led to the synthesis of derivatives (14a-k) which were evaluated for their anti-viral activity with the most potent derivatives subjected to cytotoxicity screening. Compounds (14a), (14c), (14e), (14f) and (14k) showed moderate to strong antiviral activity with EC50 values 38 - 186 μM. Compound (14e) (DLS = 0.29) showed the best anti-CHIKV activity (EC50 = 38 μM) and lowest cytotoxicity (CC50 > 300 μg/ml) against against breast cancer cell lines, MCF-7 and MD-AMB-231 and normal cell line EA.hy926. Simplification of [1,2,4]triazolo[4,3-a]pyrimidine ring, led to series (5a-e) (DLS = 0.03 - 0.77). Derivatives (5a-d) showed fair anti-CHIKV activity (EC50 > 200 μM), while (5e) emerged as the most active antiviral agent, however the most cytotoxic.
- Published
- 2022
43. Stimuli-Responsive Cycloaurated ‘OFF-ON’ Switchable Anion Transporters
- Author
-
Ethan N. W. Howe, Ricardo Pérez-Tomás, Philip A. Gale, Mohamed Fares, Xin Wu, Paul A. Keller, William Lewis, and Deepthi Ramesh
- Subjects
Molecular switch ,Programmed cell death ,chemistry.chemical_compound ,chemistry ,Reducing agent ,Supramolecular chemistry ,Biophysics ,Transporter ,Glutathione ,Homeostasis ,Function (biology) - Abstract
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 higher concentrations in tumours than in healthy tissue and hence offers a strategy to target these systems to tumours.
- Published
- 2020
44. Tetrapodal Anion Transporters
- Author
-
Ethan N. W. Howe, Alexander M. Gilchrist, Philip A. Gale, William Lewis, Xin Wu, Lauren K. Macreadie, and Li-Jun Chen
- Subjects
Anions ,anion transport ,Magnetic Resonance Spectroscopy ,Anion Transport Proteins ,Lipid Bilayers ,Supramolecular chemistry ,anion-selective transport ,Pharmaceutical Science ,Crystallography, X-Ray ,Chloride ,Article ,supramolecular chemistry ,Analytical Chemistry ,lcsh:QD241-441 ,chemistry.chemical_compound ,Chlorides ,lcsh:Organic chemistry ,Proton transport ,Drug Discovery ,medicine ,Carboxylate ,Physical and Theoretical Chemistry ,Lipid bilayer ,Ion Transport ,Nitrates ,Pyrenes ,Fatty Acids ,Organic Chemistry ,Transporter ,0303 Macromolecular and Materials Chemistry ,Combinatorial chemistry ,lipid bilayer ,Membrane ,chemistry ,Chemistry (miscellaneous) ,Molecular Medicine ,Chromatography, Thin Layer ,Sulfonic Acids ,Selectivity ,medicine.drug - Abstract
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 scaffold to maximize the selective interaction with spherical chloride over binding the carboxylate headgroup of fatty acids. One of the new transporters demonstrated a high selectivity for chloride uniport over fatty acid-induced proton transport while being >, 10 times more active in chloride uniport than strapped calixpyrroles that were previously the only class of compounds known to possess similar selectivity properties.
- Published
- 2020
45. A Two-Dimensional Metallacycle Cross-Linked Switchable Polymer for Fast and Highly Efficient Phosphorylated Peptide Enrichment
- Author
-
Li-Jun Chen, Hai-Bo Yang, Philip A. Gale, Jun-Long Zhu, Fan-Fan Zhu, Jin Wen, and Xu-Qing Wang
- Subjects
chemistry.chemical_classification ,Supramolecular polymers ,chemistry ,Phosphopeptide ,Supramolecular chemistry ,Polymer ,Metallacycle ,Combinatorial chemistry ,Phosphorylated Peptide - Abstract
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 ideal platform for the enrichment of phosphopeptides. A positively charged metallacycle incorporated into the polymer endows the material with a high affinity for phosphopeptides. Importantly, the stimuli-responsive nature of the polymer facilitates switchable binding affinity of phosphopeptides, resulting in its excellent performance in phosphopeptide enrichment and separation from model proteins. The polymer has a high enrichment capacity (165 mg/g) and detection sensitivity (2 fmol), high enrichment recovery (88%), excellent specificity, and rapid enrichment and separation properties. Additionally, we have demonstrated the capture of phosphopeptides from the tryptic digest of real bio-samples illustrating the potential of this polymeric material in phosphoproteomic studies.
- Published
- 2019
46. Anion carriers as potential treatments for cystic fibrosis: transport in cystic fibrosis cells, and additivity to channel-targeting drugs
- Author
-
Christopher M. Dias, Marion Kieffer, Nathalie Busschaert, Abigail G. Thorne, Anthony P. Davis, Hongyu Li, Hennie Valkenier, James A. Cooper, David N. Sheppard, and Philip A. Gale
- Subjects
Yellow fluorescent protein ,010402 general chemistry ,01 natural sciences ,Cystic fibrosis ,supramolecular chemistry ,Ivacaftor ,BCS and TECS CDTs ,chemistry.chemical_compound ,Physico-chimie générale ,Chimie des colloïdes ,medicine ,Chimie ,Therapeutic strategy ,biology ,010405 organic chemistry ,Transport activity ,Lumacaftor ,Biological activity ,Chimie des surfaces et des interfaces ,General Chemistry ,medicine.disease ,Transmembrane protein ,3. Good health ,0104 chemical sciences ,Chimie organique ,chemistry ,Biochemistry ,biology.protein ,medicine.drug - Abstract
Synthetic anion transporters are active in cystic fibrosis cells, and are additive to clinically-approved drugs, suggesting new combination therapies for this lethal genetic condition., info:eu-repo/semantics/published
- Published
- 2019
47. Fluorescent and colorimetric sensors for anionic species
- Author
-
Philip A. Gale and Claudia Caltagirone
- Subjects
Halogen bond ,Hydrogen ,010405 organic chemistry ,Chemistry ,chemistry.chemical_element ,010402 general chemistry ,Excimer ,Photochemistry ,01 natural sciences ,Fluorescence ,0104 chemical sciences ,Inorganic Chemistry ,Materials Chemistry ,Physical and Theoretical Chemistry ,Boron - Abstract
The development of new fluorescent and colorimetric anion sensors is surveyed in this review including hydrogen and halogen bond donating chemosensors, charged systems, boron-based chemosensors, systems that employ anion-pi interactions and excimer formation, molecular logic gates and arrays of sensors.
- Published
- 2018
48. A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations
- Author
-
Igor Marques, Nathalie Busschaert, Yoon Pyo Choi, Seong Hyun Park, Ethan N. W. Howe, Vítor Félix, Injae Shin, Louise E. Karagiannidis, Philip A. Gale, Jonathan L. Sessler, Kyung Hwa Baek, Jinhong Park, Jennifer R. Hiscock, and Wan Namkung
- Subjects
Programmed cell death ,General Chemical Engineering ,Apoptosis ,010402 general chemistry ,01 natural sciences ,Article ,Structure-Activity Relationship ,Chlorides ,Cellular ion homeostasis ,Autophagy ,Humans ,QD ,Ion transporter ,Ion Transport ,Dose-Response Relationship, Drug ,Molecular Structure ,Quinine ,010405 organic chemistry ,Chemistry ,Transporter ,General Chemistry ,Hydrogen-Ion Concentration ,0104 chemical sciences ,Cell biology ,Cytosol ,Biochemistry ,Chloride channel ,HeLa Cells - Abstract
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.
- Published
- 2017
49. Small-Molecule Uncoupling Protein Mimics: Synthetic Anion Receptors as Fatty Acid-Activated Proton Transporters
- Author
-
Xin Wu and Philip A. Gale
- Subjects
Models, Molecular ,Protein Conformation ,Protonophore ,Lipid Bilayers ,Phospholipid ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Permeability ,Catalysis ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Biomimetic Materials ,Proton transport ,Uncoupling protein ,Inner mitochondrial membrane ,chemistry.chemical_classification ,Binding Sites ,Ion Transport ,010405 organic chemistry ,Chemistry ,Fatty Acids ,Fatty acid ,Hydrogen Bonding ,General Chemistry ,Small molecule ,0104 chemical sciences ,Adenosine diphosphate ,Mitochondrial Uncoupling Proteins ,Protons - Abstract
Uncoupling proteins (UCPs) regulate energy expenditure in living cells by inducing proton leakage across the mitochondrial inner membrane, thereby uncoupling ADP phosphorylation from nutrient oxidation. The proton transport activity of UCP1 and UCP2 requires activation by fatty acids. We report here the first examples of synthetic small molecules performing this biologically important fatty acid-activated function. We have shown that a tripodal thiourea possesses poor H+/OH? transport activity without fatty acids, but in the presence of long-chain fatty acids is “switched on” as a proton transporter with an activity close to a commonly used protonophore. The fatty acid-enhanced proton transport was also observed for other hydrogen and halogen bond-based synthetic anion transporters. We propose that these compounds induce proton permeability by catalyzing transbilayer movement (“flip-flop”) of anionic fatty acids, so allowing the fatty acids to complete a proton transport cycle. Several lines of evidence have been provided to support such a fatty acid cycling mechanism. Our findings open up new applications of anion receptor chemistry, and provide important clues for understanding biological activities of synthetic anion transporters and potentially the uncoupling mechanism of naturally occurring membrane proteins.
- Published
- 2016
50. Hydroquinone-Based Anion Receptors for Redox-Switchable Chloride Binding
- Author
-
Deanna M. D'Alessandro, Xiaochen Fu, Daniel A. McNaughton, William Lewis, and Philip A. Gale
- Subjects
Amide binding ,Hydroquinone ,Hydrogen bond ,switchable system ,General Medicine ,chloride receptor ,Chloride ,Combinatorial chemistry ,Quinone ,anion binding ,chemistry.chemical_compound ,hydroquinone ,chemistry ,Amide ,Intramolecular force ,redox switch ,medicine ,Anion binding ,medicine.drug - Abstract
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 intramolecular hydrogen bond between the amide and the quinone carbonyl, which blocks the amide binding site. The reversibility of this oxidation process highlighted the potential of these systems for use as redox-switchable receptors. 1H-NMR binding studies confirmed stronger binding capabilities of the hydroquinone form compared to the quinone; however, X-ray crystal structures of the free hydroquinone receptors revealed the presence of an analogous inhibiting intramolecular hydrogen bond in this state of the receptor. Binding studies also revealed interesting and contrasting trends in chloride affinity when comparing the two switch states, which is dictated by a secondary interaction in the binding mode between the amide carbonyl and the hydroquinone/quinone couple. Additionally, the electrochemical properties of the systems have been explored using cyclic voltammetry and it was observed that the reduction potential of the system was directly related to the expected strength of the internal hydrogen bond.
- Published
- 2019
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