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Communication
Peptide Metal-Organic Frameworks for
enantioselective separation of chiral drugs
Jose Navarro-Sánchez, Ana I. Argente-García, Yolanda Moliner-Martínez, Daniel Roca-Sanjuán,
Dmytro Antypov, Pilar Campíns-Falcó, Matthew J. Rosseinsky, and Carlos Marti-Gastaldo
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00280 • Publication Date (Web): 09 Mar 2017
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7 Peptide Metal-Organic Frameworks for enantioselective separation
8
9
of chiral drugs
10
José Navarro-Sáncheza‡, Ana I. Argente-Garcíab‡, Yolanda Moliner-Martínezb, Daniel Roca-Sanjuána, Dmytro Antypovc, Pilar Campíns-
11
Falcó,b Matthew J. Rosseinskyc and Carlos Martí-Gastaldo*a
12
13 a
Universidad de Valencia (ICMol), Catedrático José Beltrán-2, 46980, Paterna (Spain)
14 b
MINTOTA research group. Departament de Química Analítica, Facultat de Química, Universitat de Valencia, Doctor Moliner, 50, 46100
15 Burjassot, (Spain).
16 c
17 Department of Chemistry, University of Liverpool. Crown Street, Liverpool, L697ZD (UK)
18 E-mail: carlos.marti@uv.es
19 Metal-Organic Frameworks, enantioselective separation, chiral recognition, ephedrine, solid-phase extraction
20
21 ABSTRACT: We report the ability of a chiral Cu(II) 3D MOF based on the tripeptide Gly-L-His-Gly (GHG) for the enantioselective sep-
22 aration of metamphetamine and ephedrine. Monte Carlo simulations suggest that chiral recognition is linked to preferential binding of one of
23 the enantiomers as result of either stronger or additional H-bonds with the framework that lead to energetically more stable diastereomeric
24 adducts. Solid phase extraction (SPE) of a racemic mixture by using Cu(GHG) as extractive phase permits isolating more than 50% of the
25 (+)-ephedrine enantiomer as target compound in only four minutes. To the best of our knowledge, this represents the first example of a MOF
26 capable of separating chiral polar drugs.
27
28
29 Metal-Organic Frameworks (MOFs) are crystalline, porous ma- chiral linkers like camphoric and tartaric acid, amino acids (aa’s) or
30 terials built from the interconnection of metal ions or clusters and oligopeptides. Among these, peptides are well suited to producing
31 organic linkers to produce porous architectures. Besides other functional, chiral MOFs whose robustness, chemical stability and
32 applications like catalysis or sensing, their unlimited structur- porous response can be effectively modulated by suitable choice of
33 al/chemical flexibility enables rational tailoring of the chemical aa’s in the peptidic sequence. 7-10 The broad choice of sidechain
34 function and pore dimensions for more efficient and selective groups available from proteinogenic aa’s can be also used to engi-
35 separation of gases,1 hydrocarbons2,3 or aromatic compounds.4 In neer the chiral pockets in their structure with specific functions.
36 this context, separation of chiral molecules with biological activity Due to their crystalline nature, peptide MOFs are also well-suited
37 is also very relevant. A large number of drug compounds are often for theoretical modelling of the enantiomer interactions in a con-
38 dosed as racemic mixtures. Enantiomers generally display different fined space, that is important to accelerate screening of materials
39 pharmacological and/or toxicological properties which can lead to already available and guide the design of more efficient systems.
40 a loss in activity or even to undesired side-reactions. Discovery of Metamphetamine (MA) and ephedrine (EP) are chiral com-
41 chiral adsorbents that permit rapid separation of individual enanti- pounds of use as recreational drugs, but also as components in
42 omers is of utmost importance to the early stages of drug research pharmaceutical preparations of therapeutic use as bronchodilators
43 in the pharmaceutical industry. This type of separation relies on and respiratory stimulants.
44 chiral recognition rather than shape/size selectivity. Hence, prefer- Both compounds possess a
ential interaction of one of the enantiomers with the homochiral chiral center and exist as a
45
adsorbent must lead to the formation of a transient diastereomeric pair of enantiomers which
46
adsorbate, whose free energy shall be sufficiently different for enan- may differ in their pharma- Scheme 1. Structure of MA and EP.
47
tiomeric separation to take place. cological activity as well as in their metabolic and pharmacokinetic
48
49 Compared to classical adsorbents like zeolites or activated car- characteristics. Separation of MA or EP enantiomers is frequently
50 bons, MOFs are arguably more promising candidates for chiral required in clinical, forensic and toxicological laboratories. We
51 separation. They can be more easily engineered to deploy a period- report the ability of a chiral Cu(II) 3D MOF based on the tripep-
52 ic array of chiral channels that are accessible to guest sorption and tide Gly-L-His-Gly (GHG) for their separation and provide clear
53 can be modified in size, shape and chemical function to optimize insights on the experimental stereo selectivity by theoretical simula-
54 mass transfer rates and chiral recognition. However, the application tions, that reveal how intermolecular interactions between the
55 of MOFs in enantioselective separation remains still limited by drugs and the peptide backbone guide chiral recognition. We are
56 small number of homochiral, microporous phases available.5,6 confident our results might guide the development of efficient
These are typically prepared either by using chiral templates that porous media for enantioselective applications.
57
drive enantiomeric resolution, by post-synthetic linker exchange for Cu(GHG) was synthesized by slow diffusion of glycyl-L-
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partial grafting of chiral linkers in the metal struts at expense of histidylglycine and Cu(II) acetate to produce prismatic, micromet-
59
accessible porosity or direct synthesis from enantiopure linkers.5 ric blue crystals by following a synthetic procedure recently report-
60
This last route is compatible with the use of naturally occurring ed by some of us.11 As shown in Figures SI1-4, phase purity was
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crystallizes in the tetragonal, polar space group P41212 to produce

1 an open 3D framework, built from the interconnection of 4-fold
2 helicoidal Cu-peptide-Cu chains by µ2-carboxylate bridges in C-
3 term Gly (Figure 1a). Porosity arises from the interconnection of
4 1D empty channels that account for a solvent accessible volume
5 close to 60% of the total volume. Use of peptides as metal connect-
6 ors enables to decorate the surface of the empty space with carbox-
7 ylate, amide, amino and imidazole groups pointing inwards the
8 channels (Figure 1b). This renders chemically versatile channels
9 featuring a manifold of interaction sites for modulating frame-
10 work/guest interactions (Figure 1c). Study of the porosity metrics
11 with Zeo++ yields diameters of the largest included (Di) and free
12 spheres (Df) above 2 nm, big enough to accommodate small drugs
13 like ephedrine or methamphetamine (Figure SI6). For these guests,
14 recognition can potentially be triggered by preferential sorption in
15 the chiral pockets of the MOF rather than interactions at the sur-
16 face of the solid.
17 Monte Carlo (MC) simulations were used for a better under-
18 standing of the role played by the functional groups from the pep-
19 tide in controlling preferential adsorption for more favorable bind-
20 ing sites. We simulated the adsorption of the two enantiomers (+,-)
21 of MA and EP (Figure 2). Structure of Cu(GHG) (CCDC
22 961607) was first prepared for the theoretical study by removal of
23 solvent molecules occupying the pores. Most stable conformations
24 of MA and EP enantiomers were explored by randomly changing
25 the torsion angles. Next, MC computations were carried for each
26 enantiomer to determine their most stable locations within the
27 MOF upon sorption (See SI2 for details). Figure 2 summarizes the
28 adsorption energies and preferential binding sites for the most
29 representative host-guest adducts calculated. Adsorption of both
30 MA enantiomers is preferentially directed by the formation of
31 hydrogen bonds between the amine and the imidazole group in His
32 sidechain. We have used discrete models of the MOF and quan-
Figure 1. (a) Structure of helicoidal chains in Cu(GHG) MOF. (b) tum-chemistry calculations to confirm that this interaction is ener-
33 Functional groups in the peptidic backbone decorating the surface of
34 getically most favorable, at least 4 kcal.mol-1 stronger, than those
the pores. (c) 1D channels in Cu(GHG) are surrounded by functional
accessible by interaction with other functional groups in the pocket
35 sites prone to establish supramolecular interactions, well fitted for
involving C-term and N-term Gly (Figure SI7, Table SI1). Regard-
36 chiral recognition and discrimination.
ing enantiomeric recognition, (+)-MA is accommodated closer to
37
studied by CHN, FT-IR, Scanning Electron Microscopy (SEM), the pocket for a stronger interaction via imidazole H-bond. This
38
thermogravimetric analysis and powder X-ray diffraction (PXRD). elongates from 1.87 Å for (+)-MA to 2.03 Å when interacting with
39
Analysis of the PXRD collected at room temperature is consistent (-)-MA, due to small changes in the adsorption configurations of
40
with the single-crystal data available, thus confirming the isolated the enantiomers (Figure 2). The higher binding energy observed
41 solid is isostructural with the phase reported.11 Homochirality of for (+)-MA mainly arises from stronger van der Waals interactions
42 the solid was
43 also confirmed
44 by solid-state
45 circular dichro-
46 ism (CD), that
47 displays a posi-
48 tive Cotton
49 effect in the
50 UV-Vis spec-
51 trum of the
52 MOF at 610
53 cm-1 linked to
54 Cu(II) com-
55 plexation with
56 enantiopure
57 glycil-L- Figure 2 Representative MC binding geometries of (+,-)MA and EP enantiomers within the structure of Cu(GHG) and corre-
58 histidylglicine sponding adsorption energies as absolute values calculated with respect to gas phase. Most relevant H-bonds in directing guest
59 (Figure SI5). binding are annotated in each case. See Figure SI9 for an overall view of geometries and more favorable binding sites in the
60 Cu(GHG) framework. Dotted lines represent H-bonds with N-H (blue) and O-H (red) donor groups.
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due to a better fit to the shape of the pocket. This agrees well with
1 the energy variation for increasing H-bond distances calculated by
2 quantum-chemistry methods for short range imidazole-
3 dimethylamine interactions (Figure SI8). While the accuracy of the
4 force-field model and the difficulty of replicating experimental
5 solvation effects do not allow for quantitative prediction of chiral
6 selectivities, our simulations suggest that more effective enantiose-
7 lective recognition is expected for ephedrine as result of coopera-
8 tive supramolecular interactions. As shown in Figure 2, adsorption
9 of (-)-EP is solely directed by the formation of a weak elongated H-
10 bond (2.36 Å) with the amide bond in C-term Gly. In contrast,
11 (+)-EP combines short His-EP H-bonds (1.89 Å), equivalent to
12 that with (+)-MA, with auxiliary bonds with the carboxylate and
13 amino groups (2.09 and 2.40 Å) in the C-term and N-term Gly
14 amino acids of Cu(GHG) for more favorable adsorption. It is the
15 strength and number of H-bonds, EP has two hydrogen bonding
16 groups capable of interacting synergically with the environment of
17 the peptide MOF, that translates into a bigger difference in adsorp-
18 tion energies close to 13 kcal.mol-1.
19 MC simulations suggest that Cu(GHG) might display stereo se-
20 lective, in particular for EP enantiomers, associated with the control
21 of non-covalent interactions over their binding geometries. This
22 promising result prompted us to attempt actual separation experi-
23 ments from solutions of the racemates. One of the key limitations
24 of flexible MOFs is their poor mechanical robustness that results in
25 collapse of the structure upon solvent removal. This is also the case
26 for Cu-GHG which displays sponge-like behavior with a crystalline- Figure 3. Evolution of the enantioselective recognition of Cu(GHG)
27 to-amorphous transformation after activation that can be reverted for chiral drugs in ethanol:water 75:25 solution with contact time for:
28 to the original state in presence of polar solvents.11 Though this is a (a) MA and (b) EP. Chiral adsorption was evaluated from chromato-
key limitation for gas storage, which requires the porous material to graphic analysis of the supernatant solution. See Fig.SI10 for more
29
be activated prior to gas sorption, chiral recognition is a dynamic details.
30
31 process and prior filling of the pores is not imperative since the variable time. As shown in Figure SI15, spectra remain constant
32 solvent molecules occupying the pores can be progressively ex- and there is no signature of Cu(II) leaching that might account for
33 changed with the chiral guests in solution. Hence, all separation partial dissolution. As for the MOF structure, PXRD of the solid
34 experiments were carried out by using non-evacuated, as- after the experiment confirms the structure remains intact (Figure
synthesized materials in order to preserve their structural integrity. SI16a) with only minor variations in the relative intensities of some
35
First, we studied the ability of Cu(GHG) to recognize selectively Bragg’s reflections ascribed to preferential orientation of the crys-
36
enantiomers from solution by soaking 10 mg of fresh solid in race- tals or changes in the nature of the species occupying the pores.
37
mic mixtures of MA and EP (40 µg/mL in ethanol:water 75:25).
38 Recent reports highlight the potential of chiral MOFs for the de-
Enantioselective recognition was evaluated chromatographically as
39 velopment of CSPs in the form of packed columns for high-
a function of contact time (See SI3 for experiment conditions and
40 performance liquid chromatography (HPLC) enantioselective
methodology). As shown in Figure 3, adsorption of (-)-MA and (-
41 separation.12-17 However, the limited number of tests available
)-EP can be considered negligible whereas 30±3% of (+)-MA and
42 suggest that the main limitations of MOFs as stationary phases are
37±3% (+)-EP are preferentially adsorbed after 4 and 2 hours,
43 their poor stability and particle heterogeneity. This limits the range
respectively. We attribute the long recognition times to the highly
44 of mobile phases at choice, in particular for polar analytes, and
polar mixture of solvents used. This will stabilize the chiral drugs in
45 makes it difficult to achieve efficient packing of the particles in the
solution preventing fast diffusion into the porous chiral medium for
46 column that relies on narrow distributions in size and shape for
a slow recognition process with long equilibration times. This
47 reproducible sorption/desorption kinetics. Lack of control over
experiment agrees well with the MC simulations that support pref-
48 these variables can result in high retention times, low chromato-
erential interaction of (+)-enantiomers in the chiral pocket linked
49 graphic performance and energy consuming separations. MOFs
to specific conformations that enable H-bond formation with the
50 might be instead better fitted for Solid Phase Extraction (SPE)
histidine sidechain. As described above, theoretical predictions are
51 separation technologies. In contrast to CSP, SPE enables isolation
also consistent with more favorable separation of EP enantiomers
52 of the enantiomers rather than only providing a measure of the
over MA’s based on the energy differences for enantiomer interac-
53 enantiomeric purity of a mixture. SPE can allow for more efficient
tion with Cu(GHG) that are higher for the first. We also performed
54 chromatographic analysis by removal of interferences, increase of
a control experiment by using a ground mixture of GHG and
55 trace concentration or sample simplification but use of chiral
Cu(II) acetate in the same proportion present in the MOF. Indi-
56 MOFs in this context remains still unexplored. To illustrate this
vidual components do not show measurable chiral recognition
57 concept, we packed 50 mg of Cu(GHG) in a polypropylene SPE
(Figure SI11), suggesting that the periodic distribution of chiral
58 cartridge and eluded a racemic mixture of (±)-EP in hex-
channels in the MOF scaffold is key for enantiomeric separation. In
59 ane:ethanol (75:25) at 0.25 mL min-1 followed by HPLC analysis
order to confirm the stability of the solid in the experiment condi-
60 of the resulting extract (Figure 4a). Experimental setup is shown in
tions we collected UV-Vis spectra of dispersions of Cu(GHG) at
Figure SI12. We opted for EP rather than MA based on our prelim-
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Supporting Information
1 The Supporting Information is available free of charge on the ACS
2 Publications website.
3 Synthetic and experimental details. Physical characterization and
4 supporting tables and figures (PDF)
5
6 AUTHOR INFORMATION
7
Corresponding Author
8
9 *carlos.marti@uv.es
10 Author Contributions
11 J.N and A.I.A.-G. contributed equally.
12
13 ACKNOWLEDGMENT
14 This work was supported by the EU (ERC Stg Chem-fs-MOF
15 Figure 4. (a) SPE separation of EP in hexane:EtOH 75:25 by using 714122), Spanish MINECO (Project CTQ-2014-53916-P and Unit of
16 Cu(GHG) as chiral bed. (b) HPLC chromatograms of EP racemate Excellence María de Maeztu MDM-2015-0538) and the Generalitat
17 before (dashed line) and after (solid line) passing through the MOF Valenciana (Prometeo 2016/109 and GV/2016/137). C.M.-G. and
18 bed. See SI4 for experimental details. A.I.A.-G. thank the Spanish MINECO for a Ramón y Cajal Fellowship
19 inary results that suggest faster and more efficient recognition of and FPU Scholarship, respectively.
20 the first. As shown in Figure 4b, comparison of the chromatograms
21 REFERENCES
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23 our theoretical predictions. While the peak area contribution for (- mento, O.; Forrest, K.; Pham, T.; Ma, S.; Space, B.;
24 )-EP remains constant, there is a significant decrease for the (+)- Wojtas, L.; Eddaoudi, M.; Zaworotko, M. J. Nature
25 form. Quantitatively, the chiral solid permits separating 54±2 % of 2013, 495, 80.
26 (+)-EP from equimolar mixtures of the enantiomers in 4 minutes (2) Bloch, E. D.; Queen, W. L.; Krishna, R.; Zadrozny, J.
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28 tested (Table SI3). HPLC analysis of the solution desorbed from (3) Cadiau, A.; Adil, K.; Bhatt, P. M.; Belmabkhout, Y.;
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31 lectivity (Figure SI13). Compared to SPE, direct soaking of the Chater, P. A.; Miller, G. J.; Manning, T. D.; Briggs, M.
32 crystals in a racemic mixture of (±)-EP in hexane:EtOH 75:25 also E.; Stylianou, K. C.; Claridge, J. B.; Rosseinsky, M. J.
33 leads to enantioselective separation of 44 % of (+)-EP in the same Angew. Chem. Int. Ed. 2014, 53, 4592.
34 time (Figure SI14). MOF cartridges can be used at least for two (5) Kutzscher, C.; Müller, P.; Raschke, S.; Kaskel, S. Chiral
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43 Peptide MOFs are particularly well-suited for enantioselective
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18 Scheme 1. Structure of MA and EP
19 Scheme 1
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Figure 1. (a) Structure of helicoidal chains in Cu(GHG) MOF. (b) Functional groups in the peptidic backbone
47
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48 establish supramolecular interactions, well fitted for chiral recognition and discrimination.
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20 Representative MC binding geometries of (+,-)MA and EP enantiomers within the structure of Cu(GHG) and
21 corresponding adsorption energies as absolute values calculated with respect to gas phase. Most relevant H-
22 bonds in directing guest binding are annotated in each case. See Figure SI9 for an overall view of
23 geometries and more favorable binding sites in the framework. Dotted lines represent H-bonds with N-H
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24 Figure 2
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Figure 3. Evolution of the enantioselective recognition of Cu(GHG) for chiral drugs in solution with contact
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time for: (a) MA and (b) EP. Chiral adsorption was evaluated from chromatographic analysis of the
48 enantiomers after MOF exposition. See Fig.SI10 for more details.
49 Figure 3
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Figure 4. (a) SPE separation of EP by using Cu(GHG) as chiral bed. (b) HPLC chromatograms of EP racemate
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before (dashed line) and after (solid line) passing through the MOF bed. See SI4 for experimental details.
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Table of contents artwork
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