Biotin[6]uril Esters: Chloride-Selective Transmembrane Anion Carriers Employing C—H···Anion Interactionsby Micke Lisbjerg, Hennie Valkenier, Bo M. Jessen, Hana Al-Kerdi, Anthony P. Davis, Michael Pittelkow

J. Am. Chem. Soc.


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Biotin[6]uril Esters: Chloride-Selective Transmembrane Anion

Carriers Employing CH···Anion Interactions

Micke Lisbjerg,†,‡ Hennie Valkenier,‡ Bo M. Jessen,† Hana Al-Kerdi,† Anthony P. Davis,*,‡ and Michael Pittelkow*,† †Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark ‡School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom *S Supporting Information

ABSTRACT: Biotin[6]uril hexaesters represent a new class of anionophores which operate solely through C

H···anion interactions. The use of soft H-bond donors favors the transport of less hydrophilic anions (e.g., Cl−,

NO3 −) over hard, stongly hydrated anions (e.g., HCO3 − and SO4 2−). Especially relevant is the selectivity between chloride and bicarbonate, the major inorganic anions in biological systems.

Transmembrane anion transport by synthetic agentspresents new opportunities for biology and medicine.1

By analogy with cation transporters (cationophores),2 anionophores could be valuable as research tools and might find therapeutic applications. For example, there is evidence that some anionophores possess anti-cancer activity.1d,3 In addition there is hope that synthetic transporters might be used to replace the activity of endogenous anion channels which are missing or defective.4,1b Such deficiencies underlie a number of conditions including the widespread genetic disease cystic fibrosis.

Recent research has yielded various structures which can transport anions through channel,5 relay,6 or mobile carrier mechanisms.3,7 High activities have been achieved in some cases,7e,f but the control of anion selectivity is still underexplored.8 From a biological perspective the most relevant issue is the distinction between chloride and bicarbonate, the dominant inorganic anions in living systems.9 Chloride/ bicarbonate selectivity may not be required for all applications,10 but for others it may be critical. Selective anionophores would be valuable as research tools, with potential to elicit new and specific biological effects.

Whatever their mechanism of action, anionophores must recognize their substrates through non-covalent interactions.

The interaction most commonly applied is hydrogen bonding between anions and conventional donors (OH, NH). However, this may not be ideal for achieving Cl−/HCO3 − selectivity.

Although bicarbonate is more strongly hydrated, it also binds well to O/NH in receptors. Thus, in studies of anion carriers employing NH···anion H-bonding, we and others have commonly observed transport of both substrates.7b,c,f,11 A promising alternative is the CH···anion hydrogen bond.12 In contrast to OH and NH, CH is recognized as a soft H-bond donor.13 It might therefore favor binding to softer, more polarizable anions (e.g., Cl−) over hard anions such as HCO3 −.

We now report the first anionophores which rely exclusively on

CH···X− interactions, without any contribution from conventional H-bonds or electrostatic interactions.14 As predicted, we find that this system is effective for chloride transport but shows minimal activity for bicarbonate, demonstrating the potential of

CH···anion interactions for moderating anionophore selectivity.

The design of the new anionophores is based on biotin[6]uril 1 (Scheme 1), a receptor for halide anions in water recently described by the Copenhagen group.15 Macrocycle 1 is prepared in a single step from biotin and formaldehyde in aqueous hydrochloric acid. The hexameric product consists of six biotin monomers in alternating orientation, connected through methylene bridges. Each biotin unit has two hydrogens on the convex face, pointing toward the center of the macrocycle. This creates a cavity bounded by 12 CH groups, positioned to bind spherical anions by CH···X− interactions (Figure 1). In aqueous solution 1 binds halides with affinities (Ka) ranging from ∼2000 M−1 for I− to ∼60 M−1 for Cl−. The mode of binding has been confirmed by an X-ray crystal structure of the 1·iodide complex.15a

Received: March 4, 2015

Scheme 1. Synthetic Pathway to Biotin[6]Uril Hexaesters 2− 4a aEsterification of biotin[6]uril 1 to biotin[6]uril hexamethyl ester 2, hexaethyl ester 3, and hexabutyl ester 4 is catalyzed by HCl.

Communication © XXXX American Chemical Society A DOI: 10.1021/jacs.5b02306

J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

To create hydrophobic analogues for transport studies, receptor 1 was treated with methanol, ethanol or butanol, with catalytic HCl, to yield hexaesters 2−4. The binding of the hexaesters to Cl−, NO3 −, HCO3 −, and SO4 2− in an organic medium (CD3CN) was first studied using 1H NMR spectroscopy. As shown in Table 1, the affinities for chloride were higher than those for nitrate and bicarbonate by roughly 2 orders of magnitude. No interaction with SO4 2− could be detected. The selectivity for chloride vs nitrate contrasts with the results for 1 in water, where the two anions were bound with similar Ka. 15 This solvent effect is not too surprising, as chloride is more hydrophilic than nitrate.16 More notable, however, are the almost identical Ka values for NO3 − and

HCO3 −. The latter is by far the more basic, and therefore the better acceptor for conventional H-bonds. The similar affinities observed here, for similarly shaped anions, confirms the difference between conventional H-bonds and CH···anion binding.13 The result supported our expectation that 2−4 would not transport bicarbonate. If affinities were low in a noncompetitive medium, the prospects for extracting hydrophilic

HCO3 − from water seemed very poor indeed.

Affinities for chloride were also measured by isothermal titration calorimetry (ITC) (Table 1). The binding interactions were all shown to be enthalpically and entropically favorable.

This is different from the trend observed for the biotin[6]uril hexaacid (1) in water where the entropy change is unfavorable.15