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Communication

An Exceptionally Active and Highly Selective Perchlorate Transporter Containing a Trimesic Amide Scaffold

by
Shaowen Deng
1,
Zhongyan Li
2,
Lin Yuan
1,* and
Huaqiang Zeng
2,*
1
College of Chemistry and Bioengineering, Hunan University of Science and Engineering, Yongzhou 425100, China
2
College of Chemistry, Fuzhou University, Fuzhou 350116, China
*
Authors to whom correspondence should be addressed.
Molecules 2024, 29(5), 1118; https://doi.org/10.3390/molecules29051118
Submission received: 3 February 2024 / Revised: 27 February 2024 / Accepted: 29 February 2024 / Published: 1 March 2024
(This article belongs to the Section Macromolecular Chemistry)
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Abstract

:
We report here a series of alkyl group-modified trimesic amide molecules (TAs) with excellent anion transport activities. Among them, TA6, with the highest ion transport activity and excellent selectivity, efficiently transports anions across the membrane in the order of ClO4− > I− > NO3− > Br− > Cl−, with an EC50 value as low as 17.6 nM (0.022 mol% relative to lipid molecules) for ClO4−, which outperforms other anions by 5- to 22-folds and manifests as the best perchlorate transporter ever reported.

Graphical Abstract

1. Introduction

Intracellular life activities are closely related to specific ion concentrations, which are regulated by channel proteins on the cell membrane. The imbalance of specific ions can lead to a series of channel diseases, such as cystic fibrosis (Cl−) [1,2], iodine deficiency, paralysis (Na+) [3,4], epilepsy (K+) [5,6] and malignant hyperthermia (Ca2+) [7,8,9,10]. Therefore, the study of ion transport by membrane channel proteins and their synthetic analogs is of great significance to human health. Given the complex structure of natural membrane proteins, it is still very challenging to design and synthesize artificial ion channels [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25], which can achieve excellent transport functions seen in the protein channels.
At present, most of the artificially designed and synthesized ion channel molecules carry central macrocyclic units, tubular cavities or one-dimensionally aligned ion-binding/transporting units [26,27,28,29,30]. Inspired by the naturally occurring pore-forming peptides [31,32,33,34] and toxins [35], α-helix bundles [35,36,37,38,39] and protein channels [40,41], which relay on side chain–side chain interactions to assemble into transmembrane pores for cell killing or controlling substance exchanges across the membrane, one recently emerging strategy also made similar uses of such noncovalent interactions to drive the channel formation for inducing transmembrane anion transport [42,43,44,45,46].
Trimesic amides (TAs) found many applications in such as small-molecule gelators [47], low-molecular-weight organogelators [48], polyvalent inhibitors [49], artificial receptors [50], dendrimers [51], porous coordination polymers [52], supramolecular polymers [53], organic diodes [54], chiral amplification [55] and thermoplastic elastomer [56]. The three amide groups in TA are aligned in such a way that there is a tilting angle relative to the central benzene ring. While this angle is highly dependent on the peripheral substituents, it is responsible for generating intermolecular stacking among TAs via intermolecular H-bonds and the π-π stacking forces. In a particular case such as TA3 (Figure 1a,b), a triple helical network of intermolecular H-bonds cross-links six adjacent TA3 molecules, and the concurrent side chain–side chain associations produce sizeable channels measuring 2 Å across (Figure 1c) [57].
We speculated that such a small hydrophobic pore may become sufficiently or transiently larger to achieve specific and efficient anion transport by fine-tuning the length of the appended alkyl chains or when the molecules are embedded within the lipid bilayer membrane. To confirm this hypothesis, we designed and synthesized five TA molecules (TAn, n = 4–12, Figure 1a).

2. Results and Discussion

To evaluate the ion transport activities of these five TA transporters, we performed the HPTS-based LUV assay, with both intra- and extravesicular regions filled with 100 mM NaCl and the same type of HEPES buffer (Figure 2a), with a pH gradient of 7 to 8 across the membrane. In this method, one of the four ion exchange modes (Na+/H+ antiport, Na+/OH− symport, Cl−/OH− antiport or Cl−/H+ symport) may occur during the ion transport process, inevitably resulting in an increase in the pH inside the LUV and consequently increasing the fluorescence intensity of the pH-sensitive HPTS dye. At the same transporter concentration, the changes in fluorescence intensity over time can be used to compare the relative ion transport capacity of transporters. Using this assay, at 2.5 μM, hexyl group-containing TA6 showed the highest ion transport activity of 97%, followed by TA4 > TA8 > TA12 > TA10 (Figure 2a).
Although we are not exactly sure why TA6 is the best transporter, given that the pores formed by TA molecules are generated via side chain–side chain interactions, these alkyl side chains should play two important roles. That is, certain parts of the chain are engaged in the pore formation, with certain parts of the chain responsible for generating sufficiently large side chain–side chain interaction forces to maintain the pore. Therefore, we believe an intermediate chain length, as in TA6, enables both roles to be fulfilled well. While the shorter chain length, as in TA4, cannot produce sufficiently large side chain–side chain interaction forces to maintain the pore, the longer chains in TA8–TA12 might favor side chain–side chain interactions over the pore formation.
As hypothesized, TA molecules may associate with each other via side chain–side chain interactions to generate the pores for ion transport. In this pore-forming pathway, the interior of the pore is going to be very hydrophobic, most likely favoring the transport of anions rather than cations. To elucidate which types of ions are transported by TA molecules, the chloride-sensitive SPQ assay was conducted first to assess the chloride transport capacity of TA transporters (Figure 2b). The principle behind this assay is that the fluorescence intensity of SPQ dye is quenched with an increasing concentration of chloride anions. If TA molecules transport anions, an exchange of NO3− and Cl− will take place, leading to decreased intensities of SPQ dyes. Based on the extent of the fluorescence intensities of SPQ, we observed the chloride transport activities of the five transporters in the order of TA6 > TA4 > TA8 > TA12 > TA10 (Figure 2b), a trend that is in excellent consistency with the above activity order obtained using the HPTS assay (Figure 2b).
To rule out the possibility of cation transport, the ion transport activities were also measured by varying the extravesicular MCl salts (M = Li, Na, K, Rb and Cs, Figure 2c). If TA molecules transport cations by varying the M+ ions in the extravesicular region, one expects to see significant differences in ion transport activity. Our results, however, reveal insignificant differences in transport activity, indicating that the metal ions were not transported by TA6 or the corresponding transport activities were almost the same.
Further, using the LUV assay containing 200 mM Na2SO4 (Figure 3a), the change in fluorescence intensity of TA6 at 2.5 μM was nearly identical to that of the background signal, demonstrating that TA6 does not mediate transports of Na+ ions, protons, OH− and SO42− anions. In contrast, the fluorescence intensity increased by almost 100% when Na+/proton-transporting gramicidin A (gA) was present at 2 μM (Figure 3b). Similar results were obtained when the extravesicular Na2SO4 was changed to K2SO4 (Figure 3c). Taken together with the data from Figure 2c, these data clearly show that transporters TAn transport anions rather than cations or protons.
These above comparative results collectively establish chloride ions as the transportable ions by TA transporters, thereby suggesting the ion exchange mode during the TA-mediated ion transport process to be either Cl−/OH− antiport or Cl−/H+ symport. Considering the central highly hydrophobic region of the membrane favors OH− over H+, the hydrated OH− anions should be more capable of passing the membrane than hydrated H+ ions. In other words, Cl−/OH− antiport exchange is more likely, with TA-mediated influx of the chloride ions compensated by the passive efflux of OH− to reach a charge neutrality condition of the system.
To differentiate the transport rate between Cl− and OH− anions, a potent H+ carrier, FCCP (carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone), was employed (Figure 4a). For this assay, if the transport rate of Cl− is faster than that of OH−, the build-up of OH− over time will be quickly dissipated by the FCCP-mediated efflux of protons, resulting in considerably larger changes in fluorescence intensity. What was seen in Figure 4b is in great accord with such expectation, implying that the transport rate of Cl− is faster than OH− anions.
Applying 5(6)-carboxyfluorescein (CF) molecules that have a dimension of <1.0 nm in size and that self-quench at high concentration, the CF assay, having intravesicular region filled with CF at 50 mM, was carried out (Figure 4b). We found that the lysosomal melittin, which forms transmembrane pores of >1 nm, led to 25.5% and 100% outflow of CF molecules at 0.03 and 0.15 μM, respectively (Figure 4b). Even at a concentration of 1 μM, TA6, however, only produced a negligible CF efflux of 2.9%. These findings clearly support that (1) the integrity of the membrane is well maintained in the presence of a high concentration of TA6, and (2) TA6 does not generate pores larger than 1 nm.
To determine the anion selectivity of the best transporter TA6, both the intravesicular and extravesicular NaX salts were systematically varied to include five types of anions (Figure 5a). It was found that TA6 exhibits a very significant anion selectivity in the order of ClO4− > I− > NO3− > Br− > Cl− at a concentration of 0.04 μM (Figure 5b). More quantitative results in anion selectivity were obtained by determining the EC50 values at which the transporters reach 50% ion transport activity. As shown in Figure 5c,d and Supplementary Materials Figures S1–S5, the EC50 values of different anions for TA6 were 17.6 nM (0.022 mol% relative to lipids) for ClO4−, 86.6 nM for I−, 108.6 nM for NO3−, 303.3 nM for Br− and 392.6 nM for Cl−. Based on these EC50 values, TA6 transports ClO4− 5–22 times better than the other four anions. Interestingly, the TA6-mediated anion transport activities increase with decreased hydration energy (Figure 5d).
Lastly, we have attempted but failed to record the single-channel currents. One possible reason is that pores formed via side chain–side chain interactions mediate anion transport predominantly through the hydrophobic methylene CH2 groups that decorate the pore interior. The corresponding chloride transport current likely is very low (earlier pore-forming molecules all end up with <0.1 pA current [43,44,45,46]). Recording these low current signals requires advanced set-up, which we do not have in our current lab. Since TA molecules lack suitable functional groups to serve as the carrier for anion transport, we believe they should function as channels, particularly in view of recently reported pore-forming systems that generate pores through side chain–side chain interactions [43,44,45,46].

3. Materials and Methods

3.1. General Considerations

All the reagents were obtained from commercial suppliers and used as received unless otherwise noted. 1H and 13C NMR spectra were recorded on a Bruker AVANCE III HD 400 spectrometer (Bruker, Switzerland, German). Mass spectra were acquired with a Shimadzu LCMS-8030 (Shimadzu, Tokyo, Japan). The model number of the fluorescence spectrophotometer is RF-6000 (Shimadzu, Tokyo, Japan).

3.2. General Procedure for the Synthesis of TAn Molecules as Typified Using TA6

Trimesoyl chloride (265 mg, 1.00 mmol) and triethylamine (2.40 mL, 3.30 mmol) were dissolved in CH2Cl2 (20 mL), and then hexylamine (2.53 mL, 3.30 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 48 h. The solvent was then removed in vacuo, and the crude product was purified by flash column chromatography (ethyl acetate/petroleum ether = 1:2, v:v) to afford the target compound TA6 as a yellow solid. Yield: 360 mg, 80%. 1H NMR (400 MHz, chloroform-d) δ 8.28 (s, 3H), 6.74 (t, J = 5.7 Hz, 3H), 3.43 (q, J = 6.7 Hz, 7H), 1.61 (q, J = 7.2 Hz, 7H), 1.30 (qd, J = 10.4, 5.9 Hz, 18H), 0.89 (d, J = 6.5 Hz, 10H). 13C NMR (101 MHz, chloroform-d) δ 166.88, 135.41, 127.46, 40.29, 31.53, 29.38, 26.73, 22.62, 14.08. MS-ESI: calculated for [M + Na]+ (C27H45N3O3Na): m/z 482.35, found: m/z 482.41.

4. Conclusions

In summary, we have successfully established a class of structurally simple anion-transporting transporter system, which are easy to synthesize and displays excellent anion transport activities. As the best among the five transporter molecules studied, TA6 demonstrates an extremely low EC50 value of 17.6 nM (0.022 mol% relative to lipids) for ClO4−, with selectivity factors 5–22-folds greater than four other types of anions (I−, NO3−, Br− and Cl−). To our best knowledge, an EC50 value of 0.022 mol% is the lowest for ClO4−, with the second lowest being 0.052 mol%, as recently reported [43].

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules29051118/s1, indicating the 1H and 13C spectra of the new compounds, as well as the determination of EC50 value for TA6-mediated transport of anions. Figure S1: Determination of EC50 values for Cl− anions using the ratiometric values of I460/I403 at different concentrations as a function of time. Figure S2: Determination of EC50 values for Br− anions using the ratiometric values of I460/I403 at different concentrations as a function of time. Figure S3: Determination of EC50 values for NO3− anions using the ratiometric values of I460/I403 at different concentrations as a function of time. Figure S4: Determination of EC50 values for I− anions using the ratiometric values of I460/I403 at different concentrations as a function of time. Figure S5: Determination of EC50 values for ClO4− anions using the ratiometric values of I460/I403 at different concentrations as a function of time. Table S1: TA-mediated anion transport activities obtained using the HPTS assay. Scheme S1: Synthetic route that affords Trimesic amide-based pores.

Author Contributions

S.D. conducted the synthesis and data curation, Z.L. conducted some formal analysis, L.Y. conceptualized/supervised the project and H.Z. conceptualized/supervised the project and wrote the paper. All authors have read and agreed to the published version of the manuscript.

Funding

This work is funded by the Natural Science Foundation of Hunan Province of China (2021JJ30291), the National Natural Science Foundation of China (22271049), and the Scientific Research Fund of Hunan Provincial Education Department (21A0518 and 21C0691).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

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Molecules 29 01118 g001
Figure 1. (a) Molecular design and chemical structures of TAn (n = 4, 6, 8, 10 and 12) studied in this work. (b) Crystal structure of TA3, showing that every TA molecule is linked to six adjacent molecules through intermolecular H-bonds with three molecules above and the other three below it; (c) TA3′s molecular packing in solid state to generate noticeable pores measuring 2 Å across [56].
Figure 1. (a) Molecular design and chemical structures of TAn (n = 4, 6, 8, 10 and 12) studied in this work. (b) Crystal structure of TA3, showing that every TA molecule is linked to six adjacent molecules through intermolecular H-bonds with three molecules above and the other three below it; (c) TA3′s molecular packing in solid state to generate noticeable pores measuring 2 Å across [56].
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Figure 2. (a) Schematic diagram of the HPTS assay for evaluating ion transport activities of TAn at 2.5 μM; here, RCl− = (ICl− − I0)/(ITriton − I0), whereas ICl− and I0 are the ratiometric values of I460/I403 at t = 300 s before addition of triton, and ITriton is the ratiometric value of I460/I403 at t = 300 s right after addition of triton. (b) Chloride-sensitive SPQ assay confirming that TAs can transport chloride anions. (c) Ion transport activities by varying the extravesicular MCl salts, confirming that TAs lack the ability to transport cations.
Figure 2. (a) Schematic diagram of the HPTS assay for evaluating ion transport activities of TAn at 2.5 μM; here, RCl− = (ICl− − I0)/(ITriton − I0), whereas ICl− and I0 are the ratiometric values of I460/I403 at t = 300 s before addition of triton, and ITriton is the ratiometric value of I460/I403 at t = 300 s right after addition of triton. (b) Chloride-sensitive SPQ assay confirming that TAs can transport chloride anions. (c) Ion transport activities by varying the extravesicular MCl salts, confirming that TAs lack the ability to transport cations.
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Figure 3. (a) The sulfate-containing HPTS assay, which confirms TA molecules do not transport (b) either Na+ or (c) K+ ions.
Figure 3. (a) The sulfate-containing HPTS assay, which confirms TA molecules do not transport (b) either Na+ or (c) K+ ions.
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Figure 4. (a) FCCP-based LUV assay for assessing the relative transport rates between OH− and Cl−. (b) CF dye assay to reveal membrane integrity in the presence of TA molecules or TA molecules does not generate pores larger than 1 nm.
Figure 4. (a) FCCP-based LUV assay for assessing the relative transport rates between OH− and Cl−. (b) CF dye assay to reveal membrane integrity in the presence of TA molecules or TA molecules does not generate pores larger than 1 nm.
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Figure 5. (a) and (b) illustrate TA6-mediated anion selectivity obtained by varying extravesicular NaX salts. (c) EC50 value determined for TA6-mediated perchlorate transport and (d) correlation between EC50 values and the hydration energies of anions.
Figure 5. (a) and (b) illustrate TA6-mediated anion selectivity obtained by varying extravesicular NaX salts. (c) EC50 value determined for TA6-mediated perchlorate transport and (d) correlation between EC50 values and the hydration energies of anions.
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Deng, S.; Li, Z.; Yuan, L.; Zeng, H. An Exceptionally Active and Highly Selective Perchlorate Transporter Containing a Trimesic Amide Scaffold. Molecules 2024, 29, 1118. https://doi.org/10.3390/molecules29051118

AMA Style

Deng S, Li Z, Yuan L, Zeng H. An Exceptionally Active and Highly Selective Perchlorate Transporter Containing a Trimesic Amide Scaffold. Molecules. 2024; 29(5):1118. https://doi.org/10.3390/molecules29051118

Chicago/Turabian Style

Deng, Shaowen, Zhongyan Li, Lin Yuan, and Huaqiang Zeng. 2024. "An Exceptionally Active and Highly Selective Perchlorate Transporter Containing a Trimesic Amide Scaffold" Molecules 29, no. 5: 1118. https://doi.org/10.3390/molecules29051118

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