The influence of varied amide bond positions on hydraphile ion channel activity

Weber, Michelle E.; Wang, Wei; Steinhardt, Sarah E.; Gokel, Michael R.; Leevy, W. Matthew; Gokel, George W.

doi:10.1039/b510863m

Cited by 13 publications

(11 citation statements)

References 31 publications

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“…As shown in Table 1, the EC 50 values for 3b and 3c were calculated to be 69 and 14 μ M , respectively, whereas monomer 7 and polymer 3a resulted in very large EC 50 values (>100 μ M ). It is noteworthy that the activity of 3c is comparable to those of crown ether‐based hydraphile16 and oligourea/amide macrocycles 17. Presumably, the presence of the stiff polynorbornene framework with hammock‐like crown ether pendants would enable the orientation of the crown ether moieties parallel to the membrane lipid axis, which may facilitate passage of ions across the membrane.…”

Section: Resultsmentioning

confidence: 95%

Oligonorbornenes with Hammock‐Like Crown Ether Pendants as Artificial Transmembrane Ion Channel

Lin

Xie

Huang

et al. 2013

Chemistry An Asian Journal

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Trimeric oligonorbornenes with hammock-like crown ether pendants 3b and 3c were selectively synthesized by cascade metathetical cyclopolymerization upon treatment with the first generation Grubbs catalyst. These crown-ether-containing oligonorbornenes are impregnated in egg yolk phosphatidylcholine (EYPC) liposome as an artificial ion channel. The efficiency of the sodium ion transport properties has been examined. Oligomer 3c having a polar hydroxy end group exhibits the highest transport efficiency, which is comparable with the best efficiencies reported in literature. The orientation of the crown ether moieties in these oligomers may be critical for the ion transport properties.

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Section: Resultsmentioning

confidence: 95%

Oligonorbornenes with Hammock‐Like Crown Ether Pendants as Artificial Transmembrane Ion Channel

Lin

Xie

Huang

et al. 2013

Chemistry An Asian Journal

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“…Hydraphiles facilitate the transport of Na + across lipid membranes, thereby, causing a disruption within a bacterial cell (Atkins, Patel, Cusumano, & Gokel, 2010;Gokel & Negin, 2012;Smith et al, 2011;Wang, Yamnitz, & Gokel, 2007). A multitude of different hydraphiles have been synthesized, and the facilitated transport rate of sodium ion across the lipid bilayers has been found to be highly dependent on the size and type of groups that comprise the hydraphile (Gokel, 2000;Gokel & Carasel, 2007;Shabany, Pajewski, Abel, Mukhopadhyay, & Gokel, 2001;Weber et al, 2006). Figure 1 shows the structure of a hydraphile found to be among the most effective sodium facilitators (Gokel & Daschbach, 2008), and it is the subject for the atomistic simulation reported in this study.…”

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confidence: 94%

All-atom molecular dynamics simulations of an artificial sodium channel in a lipid bilayer: the effect of water solvation/desolvation of the sodium ion

Skelton

Khedkar

Fried

2015

Journal of Biomolecular Structure and Dynamics

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All-atom molecular dynamics is used to investigate the transport of Na(+) across a 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayer facilitated by a diazacrown hydraphile. Specifically, the free energy of Na(+) passing through the bilayer is calculated using the adaptive biasing force method to study the free energy associated with the increase in Na(+) transport in the presence of the hydraphile molecule. The results show that water interaction greatly influences Na(+) transport through the lipid bilayer as water is pulled through the bilayer with Na(+) forming a water channel. The hydraphile causes a reduction in the free energy barrier for the transport of Na(+) through the head group part of the lipid bilayer since it complexes the Na(+) reducing the necessity for water to be complexed and, therefore, dragged through with Na(+), an energetically unfavorable process. The free energy associated with Na(+) being desolvated within the bilayer is significantly decreased in the presence of the hydraphile molecule; the hydraphile increases the number of solvation states of Na(+) that can be adopted, and this increase in the number of available configurations provides an entropic explanation for the success of the hydraphile.

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“…7 Recently, a number of new applications have been discovered for hydraphiles. These include antibiotic activity, 8 antibiotic synergy, 9 and direct injection chemotherapy. 10 Owing to the applications under study, we revisited our initial approach to these compounds in an attempt to develop simpler, more reliable, and versatile syntheses of hydraphiles.…”

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confidence: 99%

“…Unfortunately, this compound was found to be a relatively poor mediator of sodium cation transport from within synthetic liposomes into the bulk aqueous phase. 8 A strategy for a general tetraamide synthesis, to provide various tetraamide hydraphiles, is to mono-protect a diacid, couple it to diaza-18-crown-6 to form the two-armed diamide, and then further couple this with monobenzyl diazacrown 3. The monobenzyl ester of dodecanedioic acid is prepared by forming the potassium salt and alkylating with benzyl bromide.…”

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confidence: 99%

Improved Syntheses of Benzyl Hydraphile Synthetic Cation-Conducting Channels

et al. 2014

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The tris(macrocycle)s that function in bilayer membranes as ion channels have recently shown versatile new applications such as antibiotic synergists and as agents for direct injection chemotherapy. This report records the development of new and versatile approaches to these molecules that produce significantly better overall yields for a group of previously reported hydraphiles having spacer chains ranging from octylene to hexadecylene.The advent of synthetic ion channels can be traced to studies by Tabushi and his coworkers, who attached hydrophobic chains to β-cyclodextrin. 1 Subsequent to that, the results of three separate efforts to develop synthetic ion channels appeared almost simultaneously. In the first of these, Jullien and Lehn attached multiple, polar-groupterminated chains to an 18-crown-6 unit. 2 A similar structural element was used by Fyles and coworkers. 3 The hydraphile synthetic ion channels developed in the author's lab also incorporated a macrocycle as a central unit, but it was 4,13-diaza-18-crown-6 rather than a tetracarboxyl-18-crown-6 derivative. 4 The logic of using a diazacrown followed the experience gained from study of the lariat ethers. 5 When residues are attached to all-oxygen crowns, there is a stereochemical issue and the residues must remain on only one side of the macrocycle. When chains are linked through nitrogen atoms within the macrocycle, the system retains a high degree of flexibility and, owing to nitrogen's invertibility, does not experience stereochemical limitations. Of course, these initial examples led to a field of study: numerous synthetic ion channels are now known. 6 Synthetic ion channels have often been described as channel models. To be sure, they are channel models, but they are more than that. In many cases they selectively conduct alkali metal cations or anions such as chloride across liposomal and natural bilayer membranes. These amphiphiles insert into bilayer membranes from the bulk aqueous phase and they show the open-close behavior that is characteristic of natural protein channels. The cation channels exhibit selectivities for one alkali metal over another and larger metals block their function just as is observed in protein channels. Extensive studies defined the biophysics of the hydraphile channels and these results have been reported both in a series of papers and in summary form. 7 Recently, a number of new applications have been discovered for hydraphiles. These include antibiotic activity, 8 antibiotic synergy, 9 and direct injection chemotherapy. 10 Owing to the applications under study, we revisited our initial approach to these compounds in an attempt to develop simpler, more reliable, and versatile syntheses of hydraphiles. Our need was both for different spacer chain lengths and varied side chains. The essential hydraphile core structure is illustrated in Figure 1. In much of our previous work, we have sought to obtain compounds primarily for biological testing and the efficacy of the synthetic approach was a secondary consideration. Th...

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The influence of varied amide bond positions on hydraphile ion channel activity

Cited by 13 publications

References 31 publications

Oligonorbornenes with Hammock‐Like Crown Ether Pendants as Artificial Transmembrane Ion Channel

Oligonorbornenes with Hammock‐Like Crown Ether Pendants as Artificial Transmembrane Ion Channel

All-atom molecular dynamics simulations of an artificial sodium channel in a lipid bilayer: the effect of water solvation/desolvation of the sodium ion

Improved Syntheses of Benzyl Hydraphile Synthetic Cation-Conducting Channels

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