High-Affinity Binding of Metallacarborane Cobalt ... - ACS Publications

Article Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX

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High-Affinity Binding of Metallacarborane Cobalt Bis(dicarbollide) Anions to Cyclodextrins and Application to Membrane Translocation Khaleel I. Assaf,*,†,‡ Barbara Begaj,† Angelina Frank,† Mohamed Nilam,† Ali S. Mougharbel,† Ulrich Kortz,† Jan Nekvinda,§ Bohumír Grüner,§ Detlef Gabel,† and Werner M. Nau*,† †

Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, D-28759 Bremen, Germany Department of Chemistry, Faculty of Science, Al-Balqa Applied University, Al-Salt 19117, Jordan § Institute of Inorganic Chemistry, Czech Academy of Sciences, v.v.i., Hlavní 1001, CZ-250 68 Ř ež, Czech Republic

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‡

S Supporting Information *

ABSTRACT: Metallacarboranes are a class of inorganic boron clusters that have recently been recognized as biologically active compounds. Herein, we report on the host−guest complexation of several cobalt bis(1,2-dicarbollide) anions (COSANs) with cyclodextrins (CDs) in aqueous solution. The binding affinities reach micromolar values, which are among the highest known values for native CDs, and exceed those for neutral hydrophobic organic guest molecules. The entrapment of the COSANs inside the cavity of CDs was confirmed using NMR and UV−visible spectroscopy, mass spectrometry, cyclic voltammetry, and isothermal titration calorimetry. Complexation by CDs greatly influences the photophysical and electrochemical properties of COSANs. In combination with indicator displacement assays, a label-free fluorescence-based method was developed to allow real-time monitoring of the translocation of COSANs through lipid bilayer membranes.

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INTRODUCTION Host−guest pairs that exhibit high binding affinity are prime targets in supramolecular chemistry.1−3 They allow for a deeper understanding of biological receptor−ligand interactions and enable applications in several directions, including enzyme-linked immunosorbent assays, protein and nucleic acid detection as well as purification, immobilization of biomolecules on surfaces, and material-science-related applications such as self-healing polymers or supramolecular velcro.4−9 Cyclodextrins (CDs; Figure 1) are a class of naturally occurring macrocyclic molecules, first discovered in 1891, composed of α-(1,4) linked glucopyranose subunits.10 α-CD, β-CD, and γ-CD, which are comprised of six, seven, and eight glucose units, respectively, are the most common homologous hosts in supramolecular chemistry.11−13 They take the shape of a truncated cone with the wider rim formed by secondary hydroxyl groups and the narrower one by primary hydroxyl groups. Their cavity is lined with skeletal carbons and ethereal oxygens of the glucose residue, which imposes a hydrophobic character. CDs are well-known for their ability to complex a wide range of guests, including drug molecules, amino acids, peptides, saccharides, steroids, and dyes in aqueous solution.12,14−16 Accordingly, CDs have found many applications, such as in pharmaceutical formulations, as food additives, in catalysis, and for drug delivery.17−23 Despite the large number © XXXX American Chemical Society

of reported host−guest complexes with CDs, most guest molecules are weakly bound. Globular hydrophobic residues, such as adamantyl or ferrocenyl, present well-known affinity standards in the CD field. For example, the reported binding affinity for adamantane, diamantane, and triamantane derivatives with CDs falls in the range of 103−105 M−1, with the highest affinity for the triamantane carboxylic acid with γ-CD (Ka = 3 × 105 M−1).24,25 With these and other neutral organic residues, the binding is thought to be driven by the hydrophobic effect. Recently, superchaotropic anions,26−32 such as dodecaborate clusters (B12X122−, X = H, Cl, Br, and I; shown in Figure 1) and Keggin and Dawson-type polyoxometalates were found to form very stable complexes with γ-CD (Ka up to 106 M−1) in aqueous solution.26,33−39 The high affinity was traced back to the chaotropic effect, which has been recognized as a generic driving force for the association of large anions to macrocycles26,27,40,41 and to biomolecules in aqueous solution.42,43 The chaotropic effect has been established as an orthogonal assembly motif to the hydrophobic effect, which has recently spiked interest in the search for new tight binders that exploit the chaotropic rather than hydrophobic properties of guest Received: June 24, 2019 Published: July 5, 2019 A

DOI: 10.1021/acs.joc.9b01688 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

Figure 1. Three-dimensional structures of (a) o-carborane, (b) dodecaborate anion, (c) B21H182− cluster, and (d) the parent COSAN. Chemical structures of (e) native CDs and (f) COSAN derivatives investigated in this work.

molecules.27,40,41 Cobalt bis(dicarbollide) derivatives, for which the acronym COSANs has been created (CObalt SANdwich),44 are candidates for boron-based anions with superchaotropic character, which we have tested herein. Polyhedral clusters containing boron, in combination with other elements (Figure 1), have become an interesting class of inorganic compounds due to their unique structure, bonding, and reactivity.45,46 They have found interest and practical applications, among others in biology and medicine,47−49 in particular, for boron neutron capture therapy of cancer and in the design of novel bioactive molecules and potential drugs.50−54 The structures of carboranes,55 boranes,56 and metallacarboranes 57 (Figure 1a−d) have led to their implementation as unique pharmacophores in biologically active compounds.58−62 Metallacarbaranes are a sandwich of two [C2B9H11]2− (dicarbollide) clusters with a metal ion in the center (Figure 1f).63 COSANs,63,64 which are among the first synthesized metallacarborane anions,57 show high thermal, radiation, redox, and chemical stability, as well as relatively high water solubility. COSANs have been associated with several potential applications, such as the synthesis of human immunodeficiency virus inhibitors Protease (HIV-PR) and boron delivery platforms, the removal of radionuclides from

waste solution, the design of thermally stable conducting polymers, metal−organic frameworks, and ion-selective electrodes and sensors.63 Recently, the tendency of COSANs to self-assemble to aggregates and colloids in water has been reported by Matějič́ ek and co-workers.44 This accounts also for their high propensity to accumulate at the water−air surface, which leads to surfactant-like behavior, such as a reduction of surface tension. Because they lack the polar head group/ hydrophobic tail design of classical amphiphiles, they have also been classified as nonclassical surfactants or “intrinsic amphiphiles”.65 On a continuous scale for ion solvation in water, they can be assigned superchaotropic character, with emerging hydrophobic ionic properties.27 In line with this finding, COSANs have also been reported to pass through synthetic lipid membranes and living cells without affecting the morphology of the membrane.66−69 This presents an interesting bioactivity, which we were also able to investigate in further detail in this study, taking advantage of their affinity to CDs, in the development of a new type of membrane translocation assay. The complexation of a ReC2B9H11 cluster with CDs has been reported.70 Chetcuti et al. studied its solid-state structure complexed with α- and β-CD and found that their affinity B


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Figure 2. 1H NMR spectra of 1 in the presence of (a) α-CD, (b) β-CD, and (c) γ-CD; all measured in unbuffered D2O at 25 °C.

Figure 3. UV−visible titration of 3 (10 μM) with β-CD (left) and γ-CD (right) in water. Inset: fitting plots obtained by assuming a 1:1 binding model. Note that the binding constant of 3 with γ-CD (right) was independently determined by ITC (Table 1) because the high affinity prevents an accurate determination by UV titration.

reached millimolar values.70 The supramolecular host−guest complexation of metallacarboranes has not been yet systematically studied. We are aware of only one example in which Rak et al. reported the complexation of COSAN 1 (see Figure 1f) with CDs.71 In this work, we investigate the complexation of several COSAN derivatives with CDs (Figure 1e,f). Different spectroscopic techniques are applied to fully characterize the resulting host−guest complexes, including NMR, UV−visible, and fluorescence spectroscopy. The binding affinity and the associated thermodynamic data are obtained by isothermal titration calorimetry (ITC). Furthermore, we develop a sensitive fluorescence-based assay to assess and monitor their membrane translocation behavior.

example, the complexation of 1 with the smallest CD homologue, α-CD, caused a large downfield shift of H3, while the other protons remained less affected. This indicated that the COSANs can only partially protrude into the α-CD cavity (see Figure 1 for dimensional comparison). Large downfield shifts of protons H2−H6 were obtained with β-CD as a host, which can be explained by a deeper immersion of the COSAN core into the larger cavity of β-CD. γ-CD allowed also for a deep inclusion of the COSANs as indicated by large complexation-induced chemical shifts (Δδ up to 0.3 ppm); comparable shifts had previously been observed with perhalogenated dodecaborate anions and large-ring cyclodextrin (γ- to ζ-CD) for which a similar deep binding applies.26,36 Additional structural information could be deduced from induced circular dichroism measurements, which confirmed the formation of inclusion complexes and suggested an axial alignment of 3 in the smaller β-CD and a more tilted co-conformation in the larger γ-CD (see the Supporting Information). Interestingly, COSANs are intrinsically chromophoric and their complexation with CDs affects their photophysical (as well as electrochemical, see the Supporting Information) properties, which allowed for direct binding constant determinations using optical spectroscopy. Furthermore, in contrast to aromatic planar molecules, chromophoric globular or egg-shaped guests are finding interesting applications.72 In general, COSANs show three absorption bands at around 313, 400 (shoulder), and 500 nm (Figure 3), in agreement with the computed UV−visible spectrum using time-dependent density functional theory calculations (see the Supporting Information, Table S1). The titration of 3 with α-CD did not show significant changes in the absorption spectra, which agrees with the shallower binding of COSANs with α-CD. Upon complexation with β- and γ-CD, COSANs showed noticeable

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RESULTS AND DISCUSSION The investigated COSANs, as caesium salts, include unsubstituted and substituted ones (Figure 1f). COSAN 1 (ortho-COSAN) and 2 (meta-COSAN) are isomeric structures and differ only in the position of the carbon atoms. The other COSAN derivatives contain substituents at the carbon atoms (3 and 9) as well as at the boron atoms (4−8). The complexation of these COSANs with different CD homologues was investigated in solution by means of 1H NMR spectroscopy, which was possible due to their sufficient (mM) solubility in water. 1H NMR spectroscopy experiments were conducted for all COSANs with α-, β-, and γ-CD in D2O (Figures 2 and S1−S4 in the Supporting Information). Spectral changes (complexation-induced chemical shifts, Δδ) upon addition of COSAN derivatives were observed with all CDs. In particular, we followed the pronounced complexation-induced shift of the H3 and H5 protons (Figure 2), which are located inside the cavity near the secondary (wider) and primary hydroxyl (narrower) rim, respectively; their selective shifts signal the formation of inclusion complexes.26,35,36 For C


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CD and 104−106 M−1 with γ-CD. Interestingly, 1 and 2 showed largely different binding affinities with both β- and γCD. Maximum affinities of 7.1 × 105 and 3.0 × 106 M−1 for 2 were achieved with β-CD and γ-CD, respectively. Interestingly, these values are larger than those observed for dodecaborate cluster dianions, which indicates that the larger size of COSANs, in combination with their lower charge, presumably increases their chaotropicity and affinities to CDs. For the previously investigated dodecaborate cluster series, perhalogenation (Cl, Br, I) was required to increase their affinities,26 while several COSANs reach the same affinities even without halogenation. In fact, the attachment of single or double halogen atoms (COSANs 4−6) had even a detrimental effect on their affinities, presumably because the equatorial attachment of the substituents introduced steric hindrance toward binding of these ellipsoidal guests. As an additional difference, the ITC experiments suggested a higher-order complexation between γ-CD and COSANs 4 and 6. Invariably, the binding is an enthalpically driven process. The relatively high enthalpic contribution is counterbalanced by an entropic penalty, that is, enthalpy−entropy compensation applies, as is common for CDs.73 This thermodynamic fingerprint contrasts what is known for the complexation of hydrophobic guest with CDs (hydrophobic effect)74 and matches that for the binding of large anions (chaotropic effect).26,27 The chaotropic effect is a composite effect, which results from both desolvation and dispersion effects.27 Since the net charges of the isomeric 1 and 2 are the same, and their polarizabilities (39.7 and 39.3 Å3, respectively) and molecular volumes (both ca. 281 Å3) are also virtually identical, the observed large difference in affinities is derived presumably from their largely different dipole moments (6.1 and 2.4 D, respectively). In other words, the less dipolar 2 displays a stronger binding, as would be observed with conventional (nonchaotropic) guests. On the continuous scale of solvation in water, the higher dipole moment of 1 is likely to infer some kosmotropic (coordinative bonding-type) behavior with water, which reduces the affinity to nonpolar phases and concavities.27 Guest molecules that bind to macrocyclic host molecules can be utilized, in combination with suitable indicator dyes, in functional assays, known as supramolecular tandem enzyme or membrane assays.75−79 Supramolecular tandem assays present time-resolved version of indicator displacement assays,80 in

changes in the course of the UV−visible titrations. The encapsulation of 3 (see Figure 3) afforded a bathochromic shift of about 13 nm with β- and γ-CD (Figure 3), with three isosbestic points at 319, 324, and 393 nm. The optical titration data could be fitted according to a 1:1 complexation stoichiometry, which afforded high binding affinities (Ka > 104 M−1) that qualify COSANs as high-affinity binders. The stability of the resulting ionic host−guest complexes was tested in the presence of different salts. The resulting complexes were found to retain their stability even at high salt concentration (up to 1 M). Electrospray ionization mass spectrometry (MS) experiments showed that the stable complexes can even be transferred into the gas phase, where they were observed as (sodiated) 1:1 host−guest inclusion complexes (see the Supporting Information, Figure S5). Isothermal titration calorimetry (ITC) measurements were performed to accurately determine the binding affinity of COSANs to CDs and to analyze their complexation thermodynamics (Figure 4 and Table 1). The results

Figure 4. Microcalorimetric titration results in neat water: Raw ITC data (top) for sequential injections of a 1 mM CD solution into a solution of 2 (0.1 mM) and apparent reaction heats (bottom) obtained from the integration of the calorimetric traces. (a) β-CD with 2 and (b) γ-CD with 2.

corroborated stoichiometric (1:1) binding for COSANs 1−3, 5, 7, and 8. The binding affinities were 104−105 M−1 with β-

Table 1. Binding Constants (Ka in M−1) and Complexation Thermodynamic Data (in kcal mol−1) Measured for the Host− Guest Complexes of COSANs 1−9a with β-CD and γ-CD in Aqueous Solution β-CD 1 2 3 4 5 6 7 8 9

γ-CD

Ka/103

ΔH

TΔS

Ka/103

ΔH

TΔS

26 710 21 19b 24 38b 180 55 59b

−13.1 −12.3 −17.6 −22.9 −15.7 −22.7 −10.7 −9.0 −10.2

−7.1 −4.3 −11.7 −17.0 −9.7 −14.4 −3.5 −2.6 −3.7

191 3000 ± 480 300 3600 ± 770, 90 ± 10c 1300 ± 182 60 ± 12, 8000 ± 5000c 72 12 ± 5 720b

−7.7 −7.6 −11.8 −10.0, −53.9±14.7 −7.4 −28.5, −12.2 −5.0 −4.5 ± 1.3 −9.1

−0.4 1.3 −4.3 −1.0, −47.1 0.9 −22.0, −2.8 1.6 1.1 −1.1

Measured by ITC in neat water at 25 °C, as caesium salts; error in data is 20% for the Ka values and ±0.4 kcal mol−1 for ΔH and TΔS. bA 1:2 binding stoichiometry with n ∼ 0.5 was found. cA 2:1 binding stoichiometry was found, which resulted in two binding constants. Errors in ΔH and Ka are less than 5 and 10%, respectively, unless explicitly stated. a

D


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Figure 5. Schematic representation of COSAN translocation through a vesicular lipid bilayer as monitored by the supramolecular tandem membrane assay principle, using γ-CD/DSS as encapsulated reporter pair and exploiting the affinity of COSANs to γ-CD as a signaling principle.

followed by 2 and 5. COSANs 4−6 bear halogen substituents (Cl or I) on the boron atoms, which increase their chaotropic character, in analogy to the previously described behavior of substituted dodecaborate dianions26 and a different series of halogenated COSANs.67,85 The higher propensity of the halogenated COSANs to translocate through the membrane is in agreement with literature.85 On the other hand, COSANs 8 and 9 displayed slow kinetics, as expected from the ether and hydroxyl moieties present in these guests, which are expected to increase their hydrophilicity. Interestingly, 1 showed a lower translocation propensity than 2, a trend that is in line with the measured affinities to CDs and can be reconciled in terms of the higher dipolarity of 1 (see above). The relative translocation rates of the investigated clusters followed the order of 6, 4 > 2, 5 > 3 > 1, 7 > 8, 9 ≫> B12H122−. It should be noted that liposomes retain their integrity at the given COSAN concentrations, as confirmed through the carboxyfluorescein leakage assay, where no leakage was observed upon addition of COSAN. Expectedly, increasing the COSAN concentrations resulted in faster kinetics and a larger fluorescence decrease (Figure 7). The associated Hill analysis of the fractional activity at different COSAN concentration yielded apparent halfsaturation concentrations (EC50 values) of 1.0 and 0.6 μM for 1 and 2, respectively, which confirmed the differences in translocation propensity. The translocation of COSANs through the bilayer can be described as a simple passive diffusion. As can be seen, the affinity of COSANs to CDs can be practically exploited to assess their bioactivity with membranes, and our fluorescence-based technique complements previous methods such as the use of inductively coupled plasma mass spectrometry to detect membrane translocation.67,85

which changes in analyte concentration are continuously monitored.81−84 Although COSANs do not serve as enzymatic substrates or products, they could be found incorporated into active sites of some enzymes50,96 and have recently been reported to interact with and even translocate through membranes,66,67,85 which allows their study by supramolecular tandem membrane assays. Accordingly, by exploiting the high affinity between COSANs and CDs, we developed a fluorescence-based method to allow real-time monitoring of their translocation through lipid bilayer membranes (Figure 5). In the actual assay, a solution of liposomes loaded with host/ dye reporter pair was first prepared and purified by sizeexclusion chromatography. The addition of analyte to the solution affects the dye fluorescence only if it is able to enter the endo-liposomal space and displace the dye from the host cavity.77 As a fluorescent indicator dye, we selected dapoxyl sodium sulfonate (DSS), which experiences an increase in fluorescence upon the complexation with γ-CD due to the formation of a 1:2 complex (Figure S9).86 The addition of any competitor, in this case COSANs, should result in the displacement of the dye from the host cavity. This allows their sensing at low micromolar concentration (Figure S9) and a convenient bioassay to be set up. The passage of different COSANs was accordingly monitored through the time-resolved changes in fluorescence intensity (Figure 6). All COSAN derivatives were found to cross the membrane bilayer, as indicated by a decrease of the fluorescence intensity due to the displacement of DSS from γCD, but with different translocation kinetics. COSANs 4 and 6 showed the fastest kinetics compared to the other derivatives,

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CONCLUSIONS COSAN derivatives bind strongly to CDs, particularly to β-CD and γ-CD. The binding affinities of the inclusion complexes exceed those of highly hydrophobic nanodiamonds of the triamantane type24,25 and reach those of perhalogenated dodecaborate clusters.26,36 The enthalpically driven complexation (with a large entropic penalty) with CDs is in line with the thermodynamic fingerprint of the recently introduced chaotropic effect.26,27 The encapsulation of COSAN by CDs showed significant alterations of their photophysical and electrochemical properties. The strong and selective binding of COSAN to CDs, in combination with a suitable indicator

Figure 6. Time-dependent fluorescence changes of POPC/POPS⊃γ− CD/DSS liposomes upon addition of 5 μM COSANs in 10 mM sodium phosphate buffer, pH 7.0. Fluorescence of the DSS dye was monitored at 500 nm, with excitation at 337 nm. E


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Figure 7. Left: time-dependent fluorescence changes of POPC/POPS⊃γ-CD/DSS liposomes upon addition of different concentrations of 2 in 10 mM sodium phosphate, pH 7.0. Fluorescence of DSS was monitored at 500 nm, with excitation at 337 nm. Right: dependence of fractional activity Ymax on the concentration of COSANs (and B12H122−, as a negative control) 1 and 2 and the corresponding Hill analysis. addition, the atmosphere in the cell was continuously purged with argon throughout the measurement. The cyclic voltammograms of the COSAN solutions were recorded before and after addition of 1−10 equiv of CDs. Preparation of Liposome-Loaded γ-CD/Dapoxyl Sodium Sulfonate (DSS). A solution of 25 mg mL−1 of 1-palmitoyl-2-oleoylsn-glycero-3-phosphocholine (POPC) (100 μL) and 10 mg mL−1 of persistent organic pollutants (POPS) (33 μL) in chloroform was purged with nitrogen and dried overnight under high vacuum. The resulting lipid film was hydrated with 1 mL of 10 mM sodium phosphate buffer, pH 7.0, containing 0.8 mM DSS and 20 mM γ-CD, and stirred at room temperature for 30 min. The liposome suspension was subjected to 20 freeze−thaw cycles. The resulting γ-CD/DSSloaded liposomes were separated from unencapsulated γ-CD and DSS by size-exclusion chromatography with 10 mM sodium phosphate buffer. The size distribution of the liposomes (ca. 150 nm diameter; Figure S7 in the Supporting Information) was obtained using a Zetasizer Nano from Malvern Instruments. Fluorescence Kinetic Measurements. In all experiments the POPC/POPS⊃γ-CD/DSS liposome solutions prepared above (20 μL) were diluted with 10 mM sodium phosphate buffer (pH 7.0) to a total volume of 2.0 mL and stirred. Fluorescence was monitored at λem = 500 nm (λexc = 337 nm) as a function of time after addition of analyte.

dye, was successfully applied to assess the translocation of several COSAN derivatives through lipid bilayer membranes using supramolecular tandem membrane assays, which allow real-time monitoring of their translocation by fluorescence.

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EXPERIMENTAL SECTION

Synthesis of COSANs. The cesium salt of parent COSAN [(1,2C2B9H11)2-3,3′-Co]Cs (1) was purchased from Katchem, Ltd., Prague. The other compounds in the series (2−9) were selected to cover several structural features such as isomeric nature (1,2), cage boron, and carbon substitutions by polar and nonpolar groups (3 to 6 versus 9) or by a diatomic and monoatomic bridge that partly and completely hinders movement of the ligand planes around the metal atom. The compounds were synthesized by procedures known for [(1,7-C2B9H11)2-2,2′-Co]Cs (2),87 [(1,2-Me2-1,2-C2B9H9)2-3,3′Co]Cs (3),87 [(8,8′-Cl2-(1,2-C2B9H10)2-3,3′-Co]Cs (4),88 [(8-l-1,2C2B9H10)(1′,2′-C2B9H11)-3,3′-Co]Cs (5),89 [(8,8′-l2-(1,2-C2B9H10)23,3′-Co]Cs (6),89,90 [(8,8′-μ-O-(1,2-C2B9H10)2-3,3′-Co]Cs (7),91,92 [(8,8′-μ-(O-CH 2)-(1,2-C 2 B 9 H 10) 2 -3,3′-Co]Cs (8), 93 and [(1HOC2H4-1,2-C2B9H10)(1′,2′-C2B9H11)-3,3′-Co]Cs (9)94 Their identity was examined by 11B and 1H NMR spectroscopies and mass spectrometry (MS); the values of the NMR shifts and MS base mass peaks were found to correspond to the reported data. The purity assay of all compounds was performed by high-performance liquid chromatography with a diode-array detector, according to the previously published IP-RP method.95,96 Instrumentation. UV−visible measurements were performed on a Varian Cary 4000 spectrophotometer, and fluorescence measurements were done on a Varian Cary Eclipse fluorimeter. Optical titrations were done in a quartz cuvette with 1 cm optical path length, and measurements were taken directly, without incubation time. 1H NMR spectra were recorded on a JEOL ECX 400 MHz NMR spectrometer. MS experiments were performed on a Bruker ion trap mass spectrometer. Isothermal titration calorimetry (ITC) experiments were carried out on VP-ITC from Microcal, Inc., at 25 °C. The binding equilibria were studied using a COSAN solution of 100 μM in the inner compartment, to which 10−30 times more concentrated CD solution was titrated. Typically, 27 consecutive injections of 10 μL were used. All solutions were degassed prior to titration. Heats of dilution were determined by titration of the COSAN solution into water. The first data point was removed from the data set prior to curve fitting with Origin 7.0 software. The knowledge of the complex stability constant (Ka) and molar reaction enthalpy (ΔH°) enabled the calculation of the standard free energy (ΔG°) and entropy changes (ΔS°) according to ΔG° = −RT ln Ka = ΔH° − TΔS°. Cyclic voltammograms were collected on a potentiostat from CH instruments connected to a three-electrode cell in which the working electrode is a glassy carbon electrode, the reference electrode is a saturated calomel electrode, and the counter electrode is a platinum wire. The solutions were prepared by dissolving 0.1 mM COSANs in a 0.1 M sodium acetate solution buffer, pH 5. All solutions were bubbled with argon for at least five minutes before measurement. In

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b01688. 1 H NMR data; mass spectrometry results; circular dichroism experiments; calculated and experimental absorption maxima of 3; transition dipoles of the corresponding electric transition; electrochemical measurements; complementary experiments for the membrane translocation assays; and DLS results (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected], [email protected]. jo (K.I.A.). *E-mail: [email protected] (W.M.N.). ORCID

Khaleel I. Assaf: 0000-0003-4331-8492 Ali S. Mougharbel: 0000-0003-0108-3920 Ulrich Kortz: 0000-0002-5472-3058 Bohumír Grüner: 0000-0002-2595-9125 Werner M. Nau: 0000-0002-7654-6232 Notes

The authors declare no competing financial interest. F


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ACKNOWLEDGMENTS W.M.N. and K.I.A. are grateful to the DFG for grant NA-686/8 within the priority program SPP 1807 “Control of London Dispersion Interactions in Molecular Chemistry”. B.G., J.N., and D.G. appreciate partial support from DAAD-CAS project no. DAAD 17-22.

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