Anion recognition plays a critical role in a range of biological processes, and a variety of rece... more Anion recognition plays a critical role in a range of biological processes, and a variety of receptors and carriers can be found throughout the natural world. Chemists working in the area of supramolecular chemistry have created a range of anion receptors, drawing inspiration from nature as well as their own inventive processes. This book traces the origins of anion recognition chemistry as a unique sub-field in supramolecular chemistry while illustrating the basic approaches currently being used to effect receptor design. The combination of biological overview and summary of current synthetic approaches provides a coverage that is both comprehensive and comprehensible. First, the authors detail the key design motifs that have been used to generate synthetic receptors and which are likely to provide the basis for further developments. They also highlight briefly some of the features that are present in naturally occurring anion recognition and transport systems and summarise the applications of anion recognition chemistry. Providing as it does a detailed review for practitioners in the field and a concise introduction to the topic for newcomers, Anion Receptor Chemistry reflects the current state of the art. Fully referenced and illustrated in colour, it is a welcome addition to the literature.
This new text forms part of the on-going 'Primer Series' and as such provides a concise and fully... more This new text forms part of the on-going 'Primer Series' and as such provides a concise and fully illustrated introduction to the exciting field of Supramolecular Chemistry, which deals with interactions between molecules, and has become one of the fundamental areas of chemical research. This inderdisciplinary research area plays an increasingly important role for a number of reasons, ranging from the design of extraction agents for environmentally toxic species to the development of new pharmaceuticals. The book is structured in a logical manner which forms an ideal basis for a short lecture course suitable for advanced undergraduate or graduate students. Firstly, the general approach to supramolecular chemistry is discussed followed by the specific methods used to bind cationic, anionic and neutral guests. The discussion is then broadened to encompass the use of these methods to assemble remarkable, eye-catching architectures, and finally, the current and future applications of supramolecular chemistry are outlined. At the end of each chapter is a carefully selected list of leading references, and thus the book provides an ideal start for the initiate student.
Exceptionally powerfula nion receptors have been constructed by placing squaramide groups in axia... more Exceptionally powerfula nion receptors have been constructed by placing squaramide groups in axial positions on as teroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on ab ound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously-used ureas or thioureas.B inding constants exceeding 10 14 m À1 have been measured for tetraethylammonium salts in chloroform by employingav ariation of Crams extraction procedure.T he receptors have also been studied as transmembrane anion carriers in unilamellar vesicles.U nusually their activities do not correlate with anion affinities,t hus suggesting an upper limit for binding strength in the design of anion carriers.
A series of fluorescent anion transporters consisting of a urea or thiourea group linked to a nap... more 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 all anionophores cross the plasma membrane and localise within the interior of cells. The most lipophilic, aromatic substituted transporters localise homogeneously throughout the cell and are toxic towards cancer cells with the highly fluorinated compound 6 being the most effective. The least lipophilic, alkyl substituted transporters localise in specific vesicles and are non-toxic to cells. This work provides new insight to the actions of anionophores in cells and may be useful in the design of novel antineoplastic agents.
The transmembrane anion transport activity of 43 synthetic molecules based on the structure of ma... more The transmembrane anion transport activity of 43 synthetic molecules based on the structure of marine alkaloid tambjamine were assessed in model phospholipid (POPC) liposomes. The anionophoric activity of these molecules showed a parabolic dependence with lipophilicity, with an optimum range for transport efficiency. Using a quantitative structure–transport activity (QSAR) approach it was possible to rationalize these results and to quantify the contribution of lipophilicity to the transport activity of these derivatives. While the optimal value of log P and the curvature of the parabolic dependence is a property of the membrane (and so similar for the different series of substituents) we found that for relatively simple substituents in certain locations on the tambjamine core, hydrophobic interactions clearly dominate, but for others, more specific interactions are present that change the position of the membrane hydrophobicity parabolic envelope.
Gated ion transport across biological membranes is an intrinsic process regulated by protein chan... more Gated ion transport across biological membranes is an intrinsic process regulated by protein channels. Synthetic anion carriers (anionophores) have potential applications in biological research; however, previously reported examples are mostly nonspecific, capable of mediating both electrogenic and electroneutral (nonelectro-genic) transport processes. Here we show the transmembrane Cl − transport studies of synthetic phenylthiosemicarbazones mimicking the function of acid-sensing (proton-gated) ion channels. These anionophores have remarkable pH-switchable transport properties with up to 640-fold increase in transport efficacy on going from pH 7.2 to 4.0. This " gated " process is triggered by protonation of the imino nitrogen and concomitant conformational change of the anion-binding thiourea moiety from anti to syn. By using a combination of two cationophore-coupled transport assays, with either monensin or valinomycin, we have elucidated the fundamental transport mechanism of phenylthiosemicarbazones which is shown to be nonelectrogenic, inseparable H + /Cl − cotransport. This study demonstrates the first examples of pH-switchable nonelectrogenic anion transporters.
Synthetic anion transporters can facilitate H + transport via deprotonation, or OH- transport via... more Synthetic anion transporters can facilitate H + transport via deprotonation, or OH- transport via hydrogen bonding to OH- , thus allowing dissipation of transmembrane pH gradients, an undesired side-effect for biomedical applications as Cl- ionophores. To address this limitation, Gale and colleagues have developed two anionophores that show high Cl- > H + /OH - selectivity. Preliminary cellular studies support the biological relevance of the selectivity.
The synthesis and anion transport properties of a series of transmembrane anion transporters base... more The synthesis and anion transport properties of a series of transmembrane anion transporters based on an isophthalamide scaffold with phenyl, naphthyl or anthracenyl central rings are reported. Anion transport studies using POPC vesicles, showed that the compounds have Hill coefficients >1. This is indicative of higher order complex formation, evidence that leads us to suggest that the compounds are not functioning solely as mobile carriers but rather that a cooperative transport mechanism is being observed. Fluorescence spectroscopy was used to show that the compounds aggregate in the phospholipid bilayer, which provides evidence that these compounds function as a self-assembled anion-conducting aggregate.
The anion transport properties of a range of alkyl-substituted phenylthioureas were tested in ves... more The anion transport properties of a range of alkyl-substituted phenylthioureas were tested in vesicles of different lipid composition. Although changes in the bilayer affected the rate of transport for all compounds in the series, the ‘ideal’ log P for peak activity did not change depending on the composition of the bilayers tested.
Exceptionally powerful anion receptors have been
constructed by placing squaramide groups in axi... more Exceptionally powerful anion receptors have been
constructed by placing squaramide groups in axial positions on
a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on
a bound anion, while maintaining solubility in nonpolar
media. The acidic NH groups confer higher affinities than
previously-used ureas or thioureas. Binding constants exceeding
10e14M-1 have been measured for tetraethylammonium salts
in chloroform by employing a variation of Crams extraction
procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually
their activities do not correlate with anion affinities, thus
suggesting an upper limit for binding strength in the design of
anion carriers.
ABSTRACT: We report a dynamic covalent approach to
transmembrane transport of amino acids by the ... more ABSTRACT: We report a dynamic covalent approach to transmembrane transport of amino acids by the formation of a three-component assembly. A mixture of a squaramide and a lipophilic and electrophilic aldehyde is shown to synergistically transport highly polar glycine (Gly) across vesicle membranes. The transport was investigated by a 13C NMR assay, an osmotic response assay, a newly developed fluorescence assay suitable for measuring Gly influx, and other fluorescence assays for leakage and pH change. The transport is proposed to occur via a hydrogen-bonded anionic glycine hemiaminal/imine, accompanied by transport of OH− in the opposite direction. Several control experiments support the role of hemiaminal/imine in the observed facilitated Gly transport. Proton NMR studies of a biphasic system show the presence of both the hemiaminal and imine formed between Gly and an aldehyde. Interestingly, the synergistic effect has also been observed for sarcosine, which can form hemiaminals but not imines. The results demonstrate the potential of hemiaminal formation for the facilitated transport of substrates containing primary and secondary amino groups.
Anion recognition plays a critical role in a range of biological processes, and a variety of rece... more Anion recognition plays a critical role in a range of biological processes, and a variety of receptors and carriers can be found throughout the natural world. Chemists working in the area of supramolecular chemistry have created a range of anion receptors, drawing inspiration from nature as well as their own inventive processes. This book traces the origins of anion recognition chemistry as a unique sub-field in supramolecular chemistry while illustrating the basic approaches currently being used to effect receptor design. The combination of biological overview and summary of current synthetic approaches provides a coverage that is both comprehensive and comprehensible. First, the authors detail the key design motifs that have been used to generate synthetic receptors and which are likely to provide the basis for further developments. They also highlight briefly some of the features that are present in naturally occurring anion recognition and transport systems and summarise the applications of anion recognition chemistry. Providing as it does a detailed review for practitioners in the field and a concise introduction to the topic for newcomers, Anion Receptor Chemistry reflects the current state of the art. Fully referenced and illustrated in colour, it is a welcome addition to the literature.
This new text forms part of the on-going 'Primer Series' and as such provides a concise and fully... more This new text forms part of the on-going 'Primer Series' and as such provides a concise and fully illustrated introduction to the exciting field of Supramolecular Chemistry, which deals with interactions between molecules, and has become one of the fundamental areas of chemical research. This inderdisciplinary research area plays an increasingly important role for a number of reasons, ranging from the design of extraction agents for environmentally toxic species to the development of new pharmaceuticals. The book is structured in a logical manner which forms an ideal basis for a short lecture course suitable for advanced undergraduate or graduate students. Firstly, the general approach to supramolecular chemistry is discussed followed by the specific methods used to bind cationic, anionic and neutral guests. The discussion is then broadened to encompass the use of these methods to assemble remarkable, eye-catching architectures, and finally, the current and future applications of supramolecular chemistry are outlined. At the end of each chapter is a carefully selected list of leading references, and thus the book provides an ideal start for the initiate student.
Exceptionally powerfula nion receptors have been constructed by placing squaramide groups in axia... more Exceptionally powerfula nion receptors have been constructed by placing squaramide groups in axial positions on as teroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on ab ound anion, while maintaining solubility in nonpolar media. The acidic NH groups confer higher affinities than previously-used ureas or thioureas.B inding constants exceeding 10 14 m À1 have been measured for tetraethylammonium salts in chloroform by employingav ariation of Crams extraction procedure.T he receptors have also been studied as transmembrane anion carriers in unilamellar vesicles.U nusually their activities do not correlate with anion affinities,t hus suggesting an upper limit for binding strength in the design of anion carriers.
A series of fluorescent anion transporters consisting of a urea or thiourea group linked to a nap... more 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 all anionophores cross the plasma membrane and localise within the interior of cells. The most lipophilic, aromatic substituted transporters localise homogeneously throughout the cell and are toxic towards cancer cells with the highly fluorinated compound 6 being the most effective. The least lipophilic, alkyl substituted transporters localise in specific vesicles and are non-toxic to cells. This work provides new insight to the actions of anionophores in cells and may be useful in the design of novel antineoplastic agents.
The transmembrane anion transport activity of 43 synthetic molecules based on the structure of ma... more The transmembrane anion transport activity of 43 synthetic molecules based on the structure of marine alkaloid tambjamine were assessed in model phospholipid (POPC) liposomes. The anionophoric activity of these molecules showed a parabolic dependence with lipophilicity, with an optimum range for transport efficiency. Using a quantitative structure–transport activity (QSAR) approach it was possible to rationalize these results and to quantify the contribution of lipophilicity to the transport activity of these derivatives. While the optimal value of log P and the curvature of the parabolic dependence is a property of the membrane (and so similar for the different series of substituents) we found that for relatively simple substituents in certain locations on the tambjamine core, hydrophobic interactions clearly dominate, but for others, more specific interactions are present that change the position of the membrane hydrophobicity parabolic envelope.
Gated ion transport across biological membranes is an intrinsic process regulated by protein chan... more Gated ion transport across biological membranes is an intrinsic process regulated by protein channels. Synthetic anion carriers (anionophores) have potential applications in biological research; however, previously reported examples are mostly nonspecific, capable of mediating both electrogenic and electroneutral (nonelectro-genic) transport processes. Here we show the transmembrane Cl − transport studies of synthetic phenylthiosemicarbazones mimicking the function of acid-sensing (proton-gated) ion channels. These anionophores have remarkable pH-switchable transport properties with up to 640-fold increase in transport efficacy on going from pH 7.2 to 4.0. This " gated " process is triggered by protonation of the imino nitrogen and concomitant conformational change of the anion-binding thiourea moiety from anti to syn. By using a combination of two cationophore-coupled transport assays, with either monensin or valinomycin, we have elucidated the fundamental transport mechanism of phenylthiosemicarbazones which is shown to be nonelectrogenic, inseparable H + /Cl − cotransport. This study demonstrates the first examples of pH-switchable nonelectrogenic anion transporters.
Synthetic anion transporters can facilitate H + transport via deprotonation, or OH- transport via... more Synthetic anion transporters can facilitate H + transport via deprotonation, or OH- transport via hydrogen bonding to OH- , thus allowing dissipation of transmembrane pH gradients, an undesired side-effect for biomedical applications as Cl- ionophores. To address this limitation, Gale and colleagues have developed two anionophores that show high Cl- > H + /OH - selectivity. Preliminary cellular studies support the biological relevance of the selectivity.
The synthesis and anion transport properties of a series of transmembrane anion transporters base... more The synthesis and anion transport properties of a series of transmembrane anion transporters based on an isophthalamide scaffold with phenyl, naphthyl or anthracenyl central rings are reported. Anion transport studies using POPC vesicles, showed that the compounds have Hill coefficients >1. This is indicative of higher order complex formation, evidence that leads us to suggest that the compounds are not functioning solely as mobile carriers but rather that a cooperative transport mechanism is being observed. Fluorescence spectroscopy was used to show that the compounds aggregate in the phospholipid bilayer, which provides evidence that these compounds function as a self-assembled anion-conducting aggregate.
The anion transport properties of a range of alkyl-substituted phenylthioureas were tested in ves... more The anion transport properties of a range of alkyl-substituted phenylthioureas were tested in vesicles of different lipid composition. Although changes in the bilayer affected the rate of transport for all compounds in the series, the ‘ideal’ log P for peak activity did not change depending on the composition of the bilayers tested.
Exceptionally powerful anion receptors have been
constructed by placing squaramide groups in axi... more Exceptionally powerful anion receptors have been
constructed by placing squaramide groups in axial positions on
a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on
a bound anion, while maintaining solubility in nonpolar
media. The acidic NH groups confer higher affinities than
previously-used ureas or thioureas. Binding constants exceeding
10e14M-1 have been measured for tetraethylammonium salts
in chloroform by employing a variation of Crams extraction
procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually
their activities do not correlate with anion affinities, thus
suggesting an upper limit for binding strength in the design of
anion carriers.
ABSTRACT: We report a dynamic covalent approach to
transmembrane transport of amino acids by the ... more ABSTRACT: We report a dynamic covalent approach to transmembrane transport of amino acids by the formation of a three-component assembly. A mixture of a squaramide and a lipophilic and electrophilic aldehyde is shown to synergistically transport highly polar glycine (Gly) across vesicle membranes. The transport was investigated by a 13C NMR assay, an osmotic response assay, a newly developed fluorescence assay suitable for measuring Gly influx, and other fluorescence assays for leakage and pH change. The transport is proposed to occur via a hydrogen-bonded anionic glycine hemiaminal/imine, accompanied by transport of OH− in the opposite direction. Several control experiments support the role of hemiaminal/imine in the observed facilitated Gly transport. Proton NMR studies of a biphasic system show the presence of both the hemiaminal and imine formed between Gly and an aldehyde. Interestingly, the synergistic effect has also been observed for sarcosine, which can form hemiaminals but not imines. The results demonstrate the potential of hemiaminal formation for the facilitated transport of substrates containing primary and secondary amino groups.
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Books by Philip A Gale
Papers by Philip A Gale
isophthalamide scaffold with phenyl, naphthyl or anthracenyl central rings are reported. Anion transport
studies using POPC vesicles, showed that the compounds have Hill coefficients >1. This is indicative of
higher order complex formation, evidence that leads us to suggest that the compounds are not functioning
solely as mobile carriers but rather that a cooperative transport mechanism is being observed. Fluorescence
spectroscopy was used to show that the compounds aggregate in the phospholipid bilayer, which provides
evidence that these compounds function as a self-assembled anion-conducting aggregate.
constructed by placing squaramide groups in axial positions on
a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on
a bound anion, while maintaining solubility in nonpolar
media. The acidic NH groups confer higher affinities than
previously-used ureas or thioureas. Binding constants exceeding
10e14M-1 have been measured for tetraethylammonium salts
in chloroform by employing a variation of Crams extraction
procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually
their activities do not correlate with anion affinities, thus
suggesting an upper limit for binding strength in the design of
anion carriers.
transmembrane transport of amino acids by the formation of a
three-component assembly. A mixture of a squaramide and a
lipophilic and electrophilic aldehyde is shown to synergistically
transport highly polar glycine (Gly) across vesicle membranes.
The transport was investigated by a 13C NMR assay, an osmotic
response assay, a newly developed fluorescence assay suitable
for measuring Gly influx, and other fluorescence assays for
leakage and pH change. The transport is proposed to occur via
a hydrogen-bonded anionic glycine hemiaminal/imine, accompanied
by transport of OH− in the opposite direction. Several
control experiments support the role of hemiaminal/imine in
the observed facilitated Gly transport. Proton NMR studies of a
biphasic system show the presence of both the hemiaminal and
imine formed between Gly and an aldehyde. Interestingly, the synergistic effect has also been observed for sarcosine, which can
form hemiaminals but not imines. The results demonstrate the potential of hemiaminal formation for the facilitated transport of
substrates containing primary and secondary amino groups.
isophthalamide scaffold with phenyl, naphthyl or anthracenyl central rings are reported. Anion transport
studies using POPC vesicles, showed that the compounds have Hill coefficients >1. This is indicative of
higher order complex formation, evidence that leads us to suggest that the compounds are not functioning
solely as mobile carriers but rather that a cooperative transport mechanism is being observed. Fluorescence
spectroscopy was used to show that the compounds aggregate in the phospholipid bilayer, which provides
evidence that these compounds function as a self-assembled anion-conducting aggregate.
constructed by placing squaramide groups in axial positions on
a steroidal framework. The steroid preorganizes the squaramide NH groups such that they can act cooperatively on
a bound anion, while maintaining solubility in nonpolar
media. The acidic NH groups confer higher affinities than
previously-used ureas or thioureas. Binding constants exceeding
10e14M-1 have been measured for tetraethylammonium salts
in chloroform by employing a variation of Crams extraction
procedure. The receptors have also been studied as transmembrane anion carriers in unilamellar vesicles. Unusually
their activities do not correlate with anion affinities, thus
suggesting an upper limit for binding strength in the design of
anion carriers.
transmembrane transport of amino acids by the formation of a
three-component assembly. A mixture of a squaramide and a
lipophilic and electrophilic aldehyde is shown to synergistically
transport highly polar glycine (Gly) across vesicle membranes.
The transport was investigated by a 13C NMR assay, an osmotic
response assay, a newly developed fluorescence assay suitable
for measuring Gly influx, and other fluorescence assays for
leakage and pH change. The transport is proposed to occur via
a hydrogen-bonded anionic glycine hemiaminal/imine, accompanied
by transport of OH− in the opposite direction. Several
control experiments support the role of hemiaminal/imine in
the observed facilitated Gly transport. Proton NMR studies of a
biphasic system show the presence of both the hemiaminal and
imine formed between Gly and an aldehyde. Interestingly, the synergistic effect has also been observed for sarcosine, which can
form hemiaminals but not imines. The results demonstrate the potential of hemiaminal formation for the facilitated transport of
substrates containing primary and secondary amino groups.