Structure–Activity Relationships in Cholapod Anion Carriers: Enhanced Transmembrane Chloride Transport through Substituent Tuning

McNally, Beth A.; Koulov, Atanas V.; Lambert, Timothy N.; Smith, Bradley D.; Joos, Jean‐Baptiste; Sisson, Adam L.; Clare, John P.; Sgarlata, Valentina; Judd, Luke W.; Magro, Germinal; Davis, Anthony P.

doi:10.1002/chem.200801163

Cited by 119 publications

(118 citation statements)

References 41 publications

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“…52 The steroid scaffold is known to pre-organize two or three anion-binding motifs, resulting in powerful Cl À ionophores (''cholapods''). [53][54][55] We subjected several reported and new cholapod-based urea anionophores to the selectivity test. Compound 15 53 showed modest selectivity of 3-fold, which was eliminated when a trifluoroacetamide group, 54 as an additional hydrogen-bond donor, was introduced (compound 16), likely because of its high acidity (Table 2).…”

Section: Supplemental Information For Synthesis Of New Compounds) Thmentioning

confidence: 99%

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Judd

Howe

et al. 2016

Chem

158

202

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Synthetic anion transporters can facilitate H + transport via deprotonation, or OH À transport via hydrogen bonding to OH À , thus allowing dissipation of transmembrane pH gradients, an undesired side-effect for biomedical applications as Cl À ionophores. To address this limitation, Gale and colleagues have developed two anionophores that show high Cl À > H + /OH À selectivity. Preliminary cellular studies support the biological relevance of the selectivity.

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Section: Supplemental Information For Synthesis Of New Compounds) Thmentioning

confidence: 99%

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Judd

Howe

et al. 2016

Chem

158

202

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“…We have developed a range of anionophores based on powerful anion binding sites created from hydrogen bond donor groups mounted on alicyclic scaffolds (see for example Figure 4 1) 10,27 . Scaffolds include steroids 18,28,29 , trans-decalins 30,31 and substituted cyclohexanes 32 , and the common design motif is the positioning of axially-directed H-bond donors in 1,5-relationships. Conformational factors promote the convergence of NH groups to create binding sites with high affinities for inorganic anions 10,32,29 .…”

mentioning

confidence: 99%

“…Conformational factors promote the convergence of NH groups to create binding sites with high affinities for inorganic anions 10,32,29 . Several lines of evidence suggest that the compounds act as anion carriers as opposed to self-assembled channels 10,28 . They are also electrogenic, transporting only anions and therefore mediating transmembrane flow of electrical current.…”

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confidence: 99%

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

Valkenier

Judd³

et al. 2015

Nature Chem

155

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The transport of anions across cell membranes has become an important goal for supramolecular chemistry [1][2][3][4] . It is well-known that cation carriers (cationophores) can serve as antibiotics and toxins 5,6 , and it seems likely that anion carriers might also show useful biological activity. However, suitable anionophores have only recently become available 7-10 , and the nature of their biological effects is still in question. A particular hope is that anionophores might be used to replace the activity of endogenous anion channels which are missing or defective 11,2 . Such deficiencies underlie a number of medical conditions including Best disease, Startle disease, Bartter's syndrome and, most notably, the widespread lifeshortening genetic disease cystic fibrosis (CF) 12,13 .If anionophores are to be used to treat these "channelopathies", it must be shown that they can be delivered to cells in sufficient quantities to produce substantial effects, of the same order of magnitude as endogenous anion channels, and that these quantities are not toxic to the cells. However, while a wide variety of anionophores have been studied in synthetic membranes (principally large unilamellar vesicles, or LUVs), the range of systems subjected to biological investigations is still quite limited. Moreover, from the point of view of CF treatment, the results thus far have been mixed. On the positive side, a few systems have been tested in whole cells, epithelia or (in one case) genetically modified mice 14 , using electrophysiological methods such as patch-clamp and Ussing chamber, and shown to induce anion conduction without obvious toxic effects. These anionophores include synthetic 3 peptides conceptually related to natural anion channels 11,[15][16][17] , as well as the steroid-based system 1 from the authors' laboratory 18 , and other small organic molecules 14,19,20 .Less encouragingly, a number of molecules showing anion transport in LUVs have tested positive for anti-cancer cytotoxicity (potentially valuable, but incompatible with CF treatment) 8,[21][22][23][24][25] . Many of these systems, including the well-studied prodigiosin 2 26 , transport protons as well as anions 8,[21][22][23] . Intracellular acidification can lead to apoptosis 26 , so in these cases proton transport could underlie toxicity. On the other hand, a recent study on calixpyrroles 3 suggested that anion transport as such could be cytotoxic 25 . As the transport activity of 3 was only weak, this raises the concern that powerful anionophores might be highly toxic and thus unsuitable for CF treatment. Thus far the only biological testing of these "1,5-diaxial" systems has been the early study on 1, referred to above 18 . The assay involved the application of 1 to the apical membrane of oriented Madin Darby canine kidney cell (MDCK) epithelia, mounted in an Ussing chamber, and measurement of the resulting electrical current caused by Cl − transport. The methodology is well-established, but not so convenient for screening large numbers of compounds.Mor...

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“…In some cases, the ion flux can be detected at as low as a 1:250000 receptor/lipid ratio. [16] Molecules that contain several bile acid residues exhibit self-assembly properties to form hydrophilic or hydrophobic "molecular pockets" as a function of the polarity of the media. [17] Thus, reversible cholamide-calix[4]arene-based molecular switches can respond to the changes in solvent polarity by changing between hydrophilic face-in and hydrophilic face-out conformations.…”

Section: Introductionmentioning

confidence: 99%

CuAAC Synthesis and Anion Binding Properties of Bile Acid Derived Tripodal Ligands

et al. 2015

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The copper‐catalyzed azide–alkyne cycloaddition reaction was used for the preparation of a series of bis‐ and tris‐3‐ and 24‐5β‐cholanetriazolyl derivatives of phosphorus acids, which contained anion‐binding triazolium sites and hydrophobic cholane residues. The influence of the location of the triazolium moiety (in 3α‐, 3β‐position) on fluoride‐ion complexation was investigated. The anion‐binding properties of tris(triazolium) ligands were studied for a series of inorganic and organic anions and high complexation constants were observed with fluoride, hydrosulfate, and benzoate anions.

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Structure–Activity Relationships in Cholapod Anion Carriers: Enhanced Transmembrane Chloride Transport through Substituent Tuning

Cited by 119 publications

References 41 publications

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Nonprotonophoric Electrogenic Cl− Transport Mediated by Valinomycin-like Carriers

Efficient, non-toxic anion transport by synthetic carriers in cells and epithelia

CuAAC Synthesis and Anion Binding Properties of Bile Acid Derived Tripodal Ligands

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