Publications by authors named "George W Gokel"

78 Publications

Antibiotic Potency against E. coli Is Enhanced by Channel-Forming Alkyl Lariat Ethers.

Chembiochem 2016 Nov 20;17(22):2153-2161. Epub 2016 Oct 20.

Center for Nanoscience, University of Missouri, 1 University Blvd., St. Louis, MO, 63121, USA.

Several N,N'-bis(n-alkyl-4,13-diaza[18]crown-6) lariat ethers were found to significantly enhance the potency of rifampicin and tetracycline, but not erythromycin and kanamycin, against the non-pathogenic DH5α and K-12 strains of Escherichia coli when administered at levels below their minimum inhibitory concentrations (MICs). The enhancements in antibiotic potency observed for the lariat ethers ranged from three- to 20-fold, depending on the strain of E. coli, the antibiotic, and the lengths of the alkyl chains attached at the macroring nitrogen atoms. The dialkyl lariat ethers, previously thought to only be cation carriers, formed well-behaved, ion-conducting pores in soybean asolectin membranes, as judged by planar bilayer conductance measurements. The ability of lariat ethers to form stable pores, which appeared to be aggregated, depended in part on alkyl chain length and in part on the composition of the bilayer membrane in which they were studied.
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http://dx.doi.org/10.1002/cbic.201600428DOI Listing
November 2016

Reversal of Tetracycline Resistance in Escherichia coli by Noncytotoxic bis(Tryptophan)s.

J Am Chem Soc 2016 08 16;138(33):10571-7. Epub 2016 Aug 16.

Center for Nanoscience, Departments of ‡Chemistry & Biochemistry and §Biology, University of Missouri - St. Louis , 1 University Blvd., St. Louis, Missouri 63121, United States.

Nine bis(tryptophan) derivatives (BTs) and two control compounds were synthesized and tested for antimicrobial activity against two Escherichia coli strains and a Staphylococcus aureus strain. The effects of linker type, shape, and conformational rigidity were manifested in dramatic differences in altering tetracycline potency when coadministered with that antibiotic. A reversal of resistance was observed for an E. coli strain having a TetA efflux pump. Survival of mammalian cells was assayed with good result.
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http://dx.doi.org/10.1021/jacs.6b05578DOI Listing
August 2016

A Simplified Direct Lipid Mixing Lipoplex Preparation: Comparison of Liposomal-, Dimethylsulfoxide-, and Ethanol-Based Methods.

Sci Rep 2016 Jun 21;6:27662. Epub 2016 Jun 21.

Center for Nanoscience, University of Missouri - St. Louis, 1 University Blvd., St. Louis, MO 63121, USA.

Established transfection methodology often uses commercial reagents, which must be formed into liposomes in a sequence of about half a dozen steps. The simplified method reported here is a direct lipid mixing approach that requires fewer steps, less manipulation, and is less time-consuming. Results are comparable to those obtained with more commonly used methods, as judged by a variety of analytical techniques and by comparisons of transfection results. The method reported here may be applied to non-liposome-forming compounds, thereby greatly expanding the range of structures that can be tested for transfection ability.
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http://dx.doi.org/10.1038/srep27662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914933PMC
June 2016

Hydraphiles enhance antimicrobial potency against Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis.

Bioorg Med Chem 2016 06 27;24(12):2864-70. Epub 2016 Apr 27.

Center for Nanoscience, University of Missouri-St. Louis, 1 University Blvd., St. Louis, MO 63121, USA; Department of Chemistry & Biochemistry, University of Missouri-St. Louis, 1 University Blvd., St. Louis, MO 63121, USA; Department of Biology, University of Missouri-St. Louis, 1 University Blvd., St. Louis, MO 63121, USA; Upaya Pharmaceuticals, LLC, 4633 World Pkwy. Cir., Berkeley, MO 63134, USA. Electronic address:

Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of Escherichia coli, they enhanced the drug's potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function of hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors.
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http://dx.doi.org/10.1016/j.bmc.2016.04.058DOI Listing
June 2016

Hydraphile synthetic ion channels alter root architecture in Arabidopsis thaliana.

Chem Commun (Camb) 2014 Oct;50(78):11562-4

Center for Nanoscience, University of Missouri-St. Louis, 1 University Blvd., St. Louis, MO 63121, USA.

The presence of low concentrations of hydraphile synthetic amphiphiles have been found to dramatically alter the primary/lateral root architectural balance in the A. thaliana plant model system and a correlation to ion transport by the hydraphiles is consistent with the effects.
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http://dx.doi.org/10.1039/c4cc04769aDOI Listing
October 2014

Synthetic ion channels: from pores to biological applications.

Acc Chem Res 2013 Dec 5;46(12):2824-33. Epub 2013 Jun 5.

Departments of †Chemistry & Biochemistry and ‡Biology, §Center for Nanoscience, University of Missouri-St. Louis , St. Louis, Missouri 63121, United States.

In this Account, we describe the development of several diverse families of synthetic, membrane-active amphiphiles that form pores and facilitate transport within membrane bilayers. For the most part, the compounds are amphiphiles that insert into the bilayer and form pores either on their own or by self-assembly. The first family of synthetic ion channels prepared in our lab, the hydraphiles, used crown ethers as head groups and as a polar central element. In a range of biophysical studies, we showed that the hydraphiles formed unimolecular pores that spanned the bilayer. They mediated the transport of Na(+) and K(+) but were blocked by Ag(+). The hydraphiles are nonrectifying and disrupt ion homeostasis. As a result, these synthetic ion channels are toxic to various bacteria and yeast, a feature that has been used therapeutically in direct injection chemotherapy. We also developed a family of amphiphilic heptapeptide ion transporters that selected Cl(-) >10-fold over K(+) and showed voltage dependent gating. The formed pores were approximately dimeric, and variations in the N- and C-terminal anchor chains and the acids affected transport rates. Surprisingly, the longer N-terminal anchor chains led to less transport but greater Cl(-) selectivity. A proline residue, which is present in the ClC protein channel's conductance pore, proved to be critical for Cl(-) transport selectivity. Pyrogallol[4]arenes are macrocycles formed by acid-catalyzed condensation of four 1,2,3- trihydroxybenzenes with four aldehydes. The combination of 12 hydroxyl groups on one face of the macrocycle and four pendant alkyl chains conferred considerable amphiphilicity to these compounds. The pyrogallol[4]arenes inserted into bilayer membranes and conducted ions. Based on our experimental evidence, the ions passed through a self-assembled pore comprising four or five amphiphiles rather than passing through the central opening of a single macrocycle. Pyrogallol[4]arenes constructed with branched chains are also amphiphilic and active in membranes. The pyrogallol[4]arene with 3-pentyl sidechains formed a unique nanotube assembly and functioned as an ion channel in bilayer membranes. Finally, we showed that dianilides of either isophthalic or dipicolinic acids, compounds which have been extensively studied as anion binders, can self-assemble to form pores within bilayers. We called these dianilides tris-arenes and have shown that they readily bind to phosphate anions. These structures also mediated the transport of DNA plasmids through vital bilayer membranes in the bacterium Escherichia coli and in the yeast Saccharomyces cerevisiae . This transformation or transfection process occurred readily and without any apparent toxicity or mutagenicity.
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http://dx.doi.org/10.1021/ar400026xDOI Listing
December 2013

Hydraphiles: a rigorously studied class of synthetic channel compounds with in vivo activity.

Int J Biomed Imaging 2013 15;2013:803579. Epub 2013 Jan 15.

Departments of Chemistry and Biochemistry and Biology, Center for Nanoscience, University of Missouri-St. Louis, St. Louis, MO 63121, USA.

Hydraphiles are a class of synthetic ion channels that now have a twenty-year history of analysis and success. In early studies, these compounds were rigorously validated in a wide range of in vitro assays including liposomal ion flow detected by NMR or ion-selective electrodes, as well as biophysical experiments in planar bilayers. During the past decade, biological activity was observed for these compounds including toxicity to bacteria, yeast, and mammalian cells due to stress caused by the disruption of ion homeostasis. The channel mechanism was verified in cells using membrane polarity sensitive dyes, as well as patch clamping studies. This body of work has provided a solid foundation with which hydraphiles have recently demonstrated acute biological toxicity in the muscle tissue of living mice, as measured by whole animal fluorescence imaging and histological studies. Here we review the critical structure-activity relationships in the hydraphile family of compounds and the in vitro and in cellulo experiments that have validated their channel behavior. This report culminates with a description of recently reported efforts in which these molecules have demonstrated activity in living mice.
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http://dx.doi.org/10.1155/2013/803579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3562588PMC
February 2013

Anion complexation and transport by isophthalamide and dipicolinamide derivatives: DNA plasmid transformation in E. coli.

J Am Chem Soc 2012 Aug 10;134(33):13546-9. Epub 2012 Aug 10.

Department of Chemistry & Biochemistry, and Center for Nanoscience, University of Missouri-St. Louis, St. Louis, Missouri 63121, USA.

Tris-arenes based on either isophthalic acid or 2,6-dipicolinic acid have been known for more than a decade to bind anions. Recent studies have also demonstrated their ability to transport various ions through membranes. In this report, we demonstrate two important properties of these simple diamides. First, they transport plasmid DNA into Escherichia coli about 2-fold over controls, where the ampicillin resistance gene is expressed in the bacteria. These studies were done with plasmid DNA (~2.6 kilobase (kb)) in JM109 E. coli cells. Second, known methods do not typically transport large plasmids (>15 kb). We demonstrate here that transformation of large pVIB plasmids (i.e., >20 kb) were enhanced over water controls by ~10-fold. These results are in striking contrast to the normal decrease in transformation with increasing plasmid size.
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http://dx.doi.org/10.1021/ja304816eDOI Listing
August 2012

Rapid acyl migration between pyrogallyl 1,2- and 1,3-dipivaloates.

Nat Prod Commun 2012 Mar;7(3):333-6

Center for Nanoscience, University of Missouri, Saint Louis, MO 63121, USA.

Pyrogallol and its derivatives are biologically active compounds, and pyrogallol also forms the basis of an increasingly important tetrameric supramolecular scaffold. Pyrogallol[4]arenes are tetrameric macrocycles that form from 1,2,3-trihydroxybenzene and aldehydes under acidic conditions. Pyrogallol was treated with two equivalents of pivaloyl chloride to form pyrogallyl dipivaloate. A mixture of regioisomers was invariably obtained and a rapid equilibrium was observed between the 1,2- and 1,3-diesters in polar solvents. A pure sample of solid pyrogallyl 1,2-dipivaloate was isolated and its crystal structure was obtained. The pure compound was shown to rearrange to mixtures similar to those isolated initially.
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March 2012

Aggregation and supramolecular membrane interactions that influence anion transport in tryptophan-containing synthetic peptides.

Chemistry 2012 Jun 26;18(24):7608-23. Epub 2012 Apr 26.

Center for Nanoscience, and Department of Chemistry & Biochemistry, University of Missouri-St. Louis, St. Louis, MO 6312, USA.

Self-assembly is a desired property in supramolecular chemistry, but extensive aggregation may be counterproductive. Rigid systems typically have better organization, but are inherently less dynamic. This work shows that ion transport by amphiphilic heptapeptides (synthetic anion transporters or SATs) is affected by aggregation of the monomers in the bulk aqueous phase to which they are added and within the bilayer. Ion transport was assessed for all compounds by assay of Cl(-) release from liposomes. The mechanism of ion transport was confirmed by planar bilayer conductance studies for two compounds at opposite ends of the efficacy scale. Dynamic light scattering, the Langmuir trough, transmission electron microscopy, ion release from liposomes, and planar bilayer conductance studies were used to assess the importance of self-assembly versus aggregation in ion transport. Generally, greater aggregation was has an adverse effect on the transport, although at least dimerization is required for amphiphilic heptapeptides to readily transport Cl(-). Anion transport in these systems was found to be sensitive to changes in the C-terminal portion of the (Gly)(3)Pro(Gly)(3) sequence. Moreover, a significant difference in transport efficacy was apparent when L-Trp was replaced by D-Trp in the same position.
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http://dx.doi.org/10.1002/chem.201103203DOI Listing
June 2012

Synthetic membrane active amphiphiles.

Adv Drug Deliv Rev 2012 Jun 27;64(9):784-96. Epub 2012 Jan 27.

Center for Nanoscience, Department of Chemistry & Biochemistry, University of Missouri - Saint Louis, Saint Louis, MO 63121, USA.

During the past several decades, various synthetic organic compounds that form pores in bilayer membranes have been prepared and studied. These membrane active amphiphiles have also proved to be useful in affecting the transport of molecules into or through the bilayer. This article discusses the evolution of these compounds and exemplifies recent applications such as enhancement of antimicrobial activity.
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http://dx.doi.org/10.1016/j.addr.2012.01.011DOI Listing
June 2012

Pyrogallol[4]arenes show highly variable amphiphilic behavior at the air-water interface dependent upon side chain length and branching.

Chemistry 2011 Aug 17;17(32):8913-21. Epub 2011 Jun 17.

Department of Chemistry & Biochemistry, Center for Nanoscience, University of Missouri-St. Louis, St. Louis, MO 63121, USA.

The behavior of pyrogallol[4]arenes (Pgs) substituted with normal and branched alkyl side chains at the air-water interface was examined on a Langmuir trough. The amphiphilic systems studied form stable monolayers when the straight chains are as short as n-propyl. Remarkably, n-propylpyrogallol[4]arene shows a behavior at the air-water interface that is indistinguishable from that of pyrogallolarenes bearing n-hexyl, n-nonyl, and n-dodecyl side chains. There is no report of amphiphilic side-chain-length dependence or Langmuir trough behavior for families of branched alkyl chain calixarenes or resorcinarenes. In the Pg family reported here, Pgs with straight chains (except for methyl and ethyl) behave very similarly to each other and very differently from symmetrical branched chain analogues having the same total number of carbon atoms. For example, the shortest possible branched side chain of a Pg, isopropyl-Pg, forms stable monolayers by a unique molecular subduction mechanism. Isopropyl-Pg (dimethylmethyl side chain, iPrPg) and 3-pentyl-Pg (diethylmethyl side chain, 3-pentylPg) both show high levels of organization, albeit by quite different mechanisms, at the air-water interface. Both iPrPg and 3-pentylPg differ in behavior from 4-heptylPg. Brewster angle microscopy revealed differences in organization of the Pgs that supports the mechanistic suggestions offered herein.
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http://dx.doi.org/10.1002/chem.201100221DOI Listing
August 2011

In vivo cell death mediated by synthetic ion channels.

Chem Commun (Camb) 2011 Jul 17;47(28):7977-9. Epub 2011 Jun 17.

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.

Synthetic ion channel hydraphiles, which are known to infiltrate membranes and disrupt ion homeostasis, were tested as direct injection toxins in live mice as potential schlerotic agents. The study uses a near-IR dye to image and evaluate the success of the approach.
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http://dx.doi.org/10.1039/c1cc12933cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608405PMC
July 2011

Pore formation in phospholipid bilayers by amphiphilic cavitands.

Org Biomol Chem 2011 Jun 20;9(12):4498-506. Epub 2011 Apr 20.

School of Chemistry, University of KwaZulu-Natal, Westville Campus, Private Bag X54001, Durban, 4000, South Africa.

Five new cavitands were prepared that have four pendant n-undecyl chains and "headgroups" connected by 2-carbon spacers. The headgroups were ~OCH(2)CONH-Ala-OCH(3), 1; ~OCH(2)CONH-Phe-OCH(3), 2; ~OCH(2)CONH-Ala-OH, 3; ~OCH(2)CONH-Phe-OH, 4; and ~OCH(2)CONHCH(2)CH(2)-thyminyl, 5. Pore formation by each cavitand was studied by use of the planar bilayer conductance experiment. All five compounds were found to form pores in asolectin bialyer membranes. Compounds 1-3 behaved in a generally similar fashion and exhibited open-close dynamics. Compounds 4 and 5 formed pores more rapidly, were more dynamic, and led more quickly to membrane rupture. Differences in the ion transport activity are rationalized in terms of structure and aggregate cavitand assemblies.
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http://dx.doi.org/10.1039/c0ob01236jDOI Listing
June 2011

UV resonance Raman study of cation-π interactions in an indole crown ether.

J Raman Spectrosc 2011 Apr;42(4):633-638

Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA 92093 USA.

UV resonance Raman (UVRR) spectroscopy is used to probe changes in vibrational structure associated with cation-π interactions for the most prevalent amino acid π -donor, tryptophan. The model compound studied here is a diaza crown ether with two indole substituents. In the presence of sodium or potassium sequestered in the crown ether, or a protonated diaza group on the compound, the indole moieties participate in a cation-π interaction in which the pyrrolo group acts as the primary π-donor. Systematic shifts in relative intensity in the 760-780 cm region are observed upon formation of this cation-π interaction; we propose that these modifications reflect shifts of the delocalized, ring-breathing W18 and hydrogen-out-of-plane (HOOP) vibrational modes in this spectral region. The observed changes are attributed to perturbations of the π-electron density as well as of normal modes that involve large displacement of the hydrogen atom on the C2 position of the pyrrole ring. Modest variations in the UVRR spectra for the three complexes studied here are correlated to differences in cation-π strength. Specifically, the UVRR spectrum of the sodium-bound complex differs from those of the potassium-bound or protonated-diaza complexes, and may reflect the observation that the C2 hydrogen atom in the sodium-bound complex exhibits the greatest perturbation relative to the other species. Normal modes sensitive to hydrogen-bonding, such as the tryptophan W10, W9, and W8 modes, also undergo shifts in the presence of the salts. These shifts reflect the strength of interaction of the indole N-H group with the iodide or hexafluorophosphate counteranion. The current observation that the W18 and HOOP normal mode regions of the indole crown ether compound are sensitive to cation-pyrrolo π interactions suggests that this region may provide reliable spectroscopic evidence of these important interactions in proteins.
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http://dx.doi.org/10.1002/jrs.2781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4307609PMC
April 2011

Pore formation in phospholipid bilayers by branched-chain pyrogallol[4]arenes.

J Am Chem Soc 2011 Mar 22;133(10):3234-7. Epub 2011 Feb 22.

Center for Nanoscience, Department of Chemistry & Biochemistry, University of Missouri-Saint Louis, Saint Louis, Missouri 63121, United States.

Pyrogallolarenes are tetrameric macrocycles that form from 1,2,3-trihydroxybenzene and aldehydes under acidic conditions. When 2-ethylbutanal or 2-propylpentanal was so treated, the branched-chain pyrogallolarenes crystallized as nanotubes or bilayers, respectively. When the behavior of each compound was assessed by using the planar bilayer conductance method, pore formation was observed. The properties of the pores were significantly different from each other, probably reflecting different types of pore organization within the membrane.
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http://dx.doi.org/10.1021/ja1085645DOI Listing
March 2011

In vivo optical imaging of acute cell death using a near-infrared fluorescent zinc-dipicolylamine probe.

Mol Pharm 2011 Apr 1;8(2):583-90. Epub 2011 Mar 1.

Department of Chemistry and Biochemistry, 236 Nieuwland Science Hall, University of Notre Dame, Notre Dame, Indiana 46556, USA.

Cell death is a fundamental biological process that is present in numerous disease pathologies. Fluorescent probes that detect cell death have been developed for a myriad of research applications ranging from microscopy to in vivo imaging. Here we describe a synthetic near-infrared (NIR) conjugate of zinc(II)-dipicolylamine (Zn²+-DPA) for in vivo imaging of cell death. Chemically induced in vivo models of myopathy were established using an ionphore, ethanol, or ketamine as cytotoxins. The Zn²+-DPA fluorescent probe or corresponding control was subsequently injected, and whole animal fluorescence imaging demonstrated probe uptake at the site of muscle damage, which was confirmed by ex vivo and histological analyses. Further, a comparative study with a NIR fluorescent conjugate Annexin V showed less intense uptake at the site of muscle damage and high accumulation in the bladder. The results indicate that the fluorescent Zn²+-DPA conjugate is an effective probe for in vivo cell death detection and in some cases may be an appropriate alternative to fluorescent Annexin V conjugates.
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http://dx.doi.org/10.1021/mp100395uDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3608398PMC
April 2011

Halide ions complex and deprotonate dipicolinamides and isophthalamides: assessment by mass spectrometry and UV-visible spectroscopy.

J Org Chem 2010 Dec 11;75(23):8112-6. Epub 2010 Nov 11.

Department of Chemistry, Washington University, St. Louis, Missouri 63130, USA.

The F(-), Cl(-), and Br(-) binding selectivity of bis(p-nitroanilide)s of dipicolinic and isophthalic acids was studied by using competitive electrospray mass spectrometry and UV-Visible spectroscopy. Both hosts prefer binding Cl(-) over either F(-) or Br(-). Host deprotonation was observed to some extent in all experiments in which the host was exposed to halide ions. When F(-) was present, host deprotonation was often the major process, whereas little deprotonation was observed by Cl(-) or Br(-), which preferred complexation. A solution of either host changed color when mixed with a F(-), H(2)PO(4)(-), di- or triphenylacetate solution.
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http://dx.doi.org/10.1021/jo101749aDOI Listing
December 2010

Enhancement of antimicrobial activity by synthetic ion channel synergy.

Chem Commun (Camb) 2010 Nov 8;46(43):8166-7. Epub 2010 Oct 8.

Department of Chemistry & Biochemistry, Center for Nanoscience, University of Missouri-Saint Louis, Saint Louis, MO 63121, USA.

Hydraphile synthetic ion channels were found to enhance the cytotoxicity to E. coli and B. subtilis of erythromycin, kanamycin, rifampicin, and tetracycline when co-administered with the antibiotic at sublethal concentrations of channel.
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http://dx.doi.org/10.1039/c0cc03138kDOI Listing
November 2010

Dianilides of dipicolinic acid function as synthetic chloride channels.

Chem Commun (Camb) 2010 Apr 4;46(16):2838-40. Epub 2010 Mar 4.

Department of Chemistry, Washington University, Saint Louis, MO, USA.

We report that N(2),N(6)-bis(4-nitrophenyl)pyridine-2,6-dicarboxamide, which is related to known isophthalic acid dianilides, transports Cl(-) ions through phospholipid bilayer membranes and shows clear evidence of channel activity.
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http://dx.doi.org/10.1039/b924812aDOI Listing
April 2010

Self-assembled, cogged hexameric nanotubes formed from pyrogallol[4]arenes with a unique branched side chain.

Chem Commun (Camb) 2009 Dec 12(48):7497-9. Epub 2009 Nov 12.

Department of Chemistry & Biochemistry, Center for Nanoscience, University of Missouri-Saint Louis, One University Boulevard, Saint Louis, MO 63121, USA.

A branched side chain pyrogallol[4]arene self-assembles into a previously-unreported cogged hydrogen-bonded nanotube structure in the solid state and self-assembles at the air-water interface on the Langmuir trough.
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http://dx.doi.org/10.1039/b917431aDOI Listing
December 2009

Pyrogallarene-based ion-conducting pores that show reversible conductance properties.

Chem Commun (Camb) 2009 Oct 26(40):6092-4. Epub 2009 Aug 26.

Department of Chemistry, Washington University, St. Louis, MO 63130, USA.

Pyrogallol[4]arene macrocycles prepared from pyrogallol and n-dodecanal insert in phospholipid bilayers and form conducting pores that undergo reversible switching over a wide range of potentials.
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http://dx.doi.org/10.1039/b907750bDOI Listing
October 2009

Membrane-length amphiphiles exhibiting structural simplicity and ion channel activity.

Chemistry 2009 Oct;15(40):10543-53

Department of Chemistry, Washington University, St. Louis, MO 63130, USA.

A number of synthetic ion channels have been reported in recent years that incorporate unusual or sophisticated design elements. The present work demonstrates that extremely simple compounds can function as ion channels (insert in bilayers, exhibit open-close behavior) if they meet minimum criteria. A simple membrane spanning structure may function as a channel if 1) it possesses polar headgroups (is bolaamphiphilic), 2) possesses a "central relay," and 3) channel function (open-close behavior) must be detected after insertion of the amphiphile directly into the aqueous liposomal or cellular suspension. We show here compounds that are simple spans to which we have given the name "aplosspan" (from the Greek alpha pi lambda omicron sigma + span) that meet these criteria. They are similar to, but simpler than, structures reported in the literatures that incorporate more complex design features.
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http://dx.doi.org/10.1002/chem.200900898DOI Listing
October 2009

"Aplosspan:" a bilayer-length, ion-selective ionophore that functions in phospholipid bilayers.

Chem Commun (Camb) 2009 Feb 26(8):911-3. Epub 2009 Jan 26.

Department of Chemistry, Washington University, St. Louis, MO 63130, USA.

A structurally simple, novel, membrane-active ionophore has been designed, prepared, characterized, and shown to conduct Na(+), Cl(-), and carboxyfluorescein anions, probably as a dimer, across liposomal bilayers.
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http://dx.doi.org/10.1039/b816819aDOI Listing
February 2009

Air-water interfacial behavior of amphiphilic peptide analogs of synthetic chloride ion transporters.

J Memb Sci 2008 Aug;321(1):43-50

Department of Chemistry, Washington University, St. Louis, MO 63130, United States.

A family of heptapeptide-based chloride transporters (called synthetic anion transporters, SATs) were designed to insert into phospholipid membrane bilayers and form pores. Many of these compounds have proved to be chloride selective transporters. The transporters were designed to incorporate hydrophilic heptapeptides that could serves as headgroups and hydrocarbon tails that could serve as hydrophobic membrane anchors. Insertion of the SAT molecules into a bilayer requires approach to and insertion at the aqueous-membrane surface. The studies reported here were conducted to model and understand this process by studying SAT behavior at the air-water interface. A Langmuir trough was used to obtain surface pressure-area isotherm data. These data for amphiphilic SATs were augmented by Brewster angle microscopy (BAM), molecular modeling, and calculations of the hydrophobicity parameter log P. The analyses showed that the heptapeptide (hydrophilic) module of the SAT molecule rested on the water surface while the dialkyl (hydrophobic) tails oriented themselves in the air, perpendicular to the water surface. Brewster angle microscopy visually confirmed a high order of molecular organization. Results from these studies are consistent with the previously proposed mechanism of SAT membrane insertion and pore formation.
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http://dx.doi.org/10.1016/j.memsci.2008.01.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629644PMC
August 2008

Coordination and transport of alkali metal cations through phospholipid bilayer membranes by hydraphile channels.

Coord Chem Rev 2008 Apr;252(8-9):886-902

Department of Chemistry & Biochemistry and Center for Nanoscience, University of Missouri-St. Louis, One University Blvd., St. Louis, MO 63121, USA.

Hydraphiles are synthetic ionophores that were designed to mimic some properties of protein channels that conduct such cations as sodium. They use macrocyclic (crown) polyethers as amphiphilic headgroups and as entry and exit portals. Their overall length is controlled by covalent links between the two headgroups (distal macrocycles) and the "central relay" unit, typically also an azacrown. The hydraphiles insert in the bilayer membranes of synthetic phospholipid vesicles or vital cells and mediate the transport of cations. The hydraphiles were intended to be models but they are functional channels. Because they are symmetric, they are non-rectifying but they show open-close behavior characteristic of natural channels. Because they are non-rectifying, when they insert into a microbial membrane, they lead to a rapid change in osmotic balance that proves fatal to bacteria.
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http://dx.doi.org/10.1016/j.ccr.2007.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629643PMC
April 2008

A synthetic ion channel derived from a metallogallarene capsule that functions in phospholipid bilayers.

Angew Chem Int Ed Engl 2009 ;48(2):375-7

Department of Chemistry, Center for Nanoscience, University of Missouri-Saint Louis, One University Boulevard, Saint Louis, MO 63121, USA.

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http://dx.doi.org/10.1002/anie.200804099DOI Listing
February 2009

Anion transport properties of amine and amide-sidechained peptides are affected by charge and phospholipid composition.

Org Biomol Chem 2008 Aug 16;6(16):2914-23. Epub 2008 Jun 16.

Department of Chemistry, Washington University, St. Louis, MO 63130, USA.

Four synthetic anion transporters (SATs) having the general formula (n-C(18)H(37))(2)N-COCH(2)OCH(2)CO-(Gly)(3)Pro-Lys(epsilon-N-R)-(Gly)(2)-O-n-C(7)H(15) were prepared and studied. The group R was Cbz, H (TFA salt), t-Boc, and dansyl in peptides 1, 2, 3, and 4 respectively. The glutamine analog (GGGPQAG sequence) was also included. A dansyl-substituted fluorescent SAT was used to probe peptide insertion; the dansyl sidechain resides in an environment near the bilayer's midpolar regime. When the lysine sidechain was free or protected amine, little effect was noted on final Cl(-) transport rate in DOPC : DOPA (7 : 3) liposomes. This stands in contrast to the significant retardation of transport previously observed when a negative glutamate residue was present in the peptide sequence. It was also found that Cl(-) release from liposomes depended on the phospholipid composition of the vesicles. Chloride transport diminished significantly for the free lysine containing SAT, 2, when the lipid was altered from DOPC : DOPA to pure DOPC. Amide-sidechained SATs 1 and 5 showed a relatively small decrease in Cl(-) transport. The effect of lipid composition on Cl(-) transport was explained by differences in electrostatic interaction between amino acid sidechain and lipid headgroup, which was modeled by computation.
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http://dx.doi.org/10.1039/b800530cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3124115PMC
August 2008

Aggregation behavior and dynamics of synthetic amphiphiles that self-assemble to anion transporters.

Chemistry 2008 ;14(19):5871-9

Department of Chemistry, Washington University, St. Louis, MO 63130, USA.

The amphiphilic heptapeptides-referred to as synthetic anion transporters (SATs)-mediate chloride transport in planar lipid bilayer membranes, synthetic liposomes, and mammalian cells. The SATs described have the general formula R1(2)NCOCH2OCH2CO-(Gly)3-Pro-(Gly)3-OR2. Substitution at R1 and R2 with various aliphatic or aromatic groups alters the ability of SATs to transport chloride through a phospholipid bilayer membrane. Despite extensive structure-activity relationship studies concerning Cl(-)-mediated transport by SATs, relatively little was known about the mechanism of insertion and pore-formation in the membrane. In the current study, the mechanistic behavior of SATs was investigated in aqueous solution and at the air-water interface. In the latter case, Langmuir trough studies and Brewster angle microscopy (BAM) revealed the extent of monolayer stability and organization for SATs. Dynamic light scattering and transmission electron microscopy (TEM) confirmed these results and defined the aggregation behavior of SATs in solution. SAT derivatives that showed low chloride transport activity organized into stable monolayers at the air-water interface, while more active SATs formed less stable monolayers. The relationship between intermolecular organization of SATs and pore-formation in the membrane is discussed along with its implications for chloride transport.
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http://dx.doi.org/10.1002/chem.200800148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2617732PMC
September 2008

Fluorescent, synthetic amphiphilic heptapeptide anion transporters: evidence for self-assembly and membrane localization in liposomes.

Chemistry 2008 ;14(19):5861-70

Department of Chemistry, Washington University, One Brookings Drive, Saint Louis, MO 63130, USA.

Synthetic anion transporters (SATs) of the general type (n-C18H37)2N-COCH2OCH2CO-(Gly)3-Pro-(Gly)3-O-n-C7H15, 1, are amphiphilic peptides that form anion-conducting pores in bilayer membranes. To better understand membrane insertion, assembly and aggregation dynamics, and membrane penetration, four novel fluorescent structures were prepared for use in both aqueous buffer and phospholipid bilayers. The fluorescent residues pyrene, indole, dansyl, and NBD were incorporated into 1 to give 2, 3, 4, and 5, respectively. Assembly of peptide amphiphiles in buffer was confirmed by monitoring changes in the pyrene monomer/excimer peaks observed for 2. Solvent-dependent fluorescence changes that were observed for indole (3) and dansyl (4) side-chained SATs in bilayers showed that these residues experienced an environment between epsilon=9 (CH2Cl2) and epsilon=24 (EtOH) in polarity. Fluorescence resonance energy transfer (FRET) between 2 and 3 demonstrated aggregation of SAT monomers within the bilayer. This self-assembly led to pore formation, which was detected as Cl(-) release from the liposomes. The results of acrylamide quenching of fluorescent SATs supported membrane insertion. Studies with NBD-labeled SAT 5 showed that peptide partition into the bilayer is relatively slow. Dithionite quenching of NBD-SATs suggests that the amphiphilic peptides are primarily in the bilayer's outer leaflet. Images obtained by using a fluorescence microscope revealed membrane localization of a fluorescent SAT. Taken together, this study helps define the insertion, membrane localization, and aggregation behavior of this family of synthetic anion transporters in liposomal bilayers.
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http://dx.doi.org/10.1002/chem.200800147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2617740PMC
September 2008
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