Toward the Design of Molecular Chameleons: Flexible Shielding of an

Letter Cite This: Org. Lett. 2018, 20, 5737−5742

pubs.acs.org/OrgLett

Toward the Design of Molecular Chameleons: Flexible Shielding of an Amide Bond Enhances Macrocycle Cell Permeability Mohit Tyagi,† Vasanthanathan Poongavanam,† Marika Lindhagen,‡ Anna Pettersen,‡ Peter Sjö,§ Stefan Schiesser,∥ and Jan Kihlberg*,† †

Department of Chemistry−BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden Early Product Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden § Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis Dunant, 1202 Geneva, Switzerland ∥ Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden Org. Lett. 2018.20:5737-5742. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 09/21/18. For personal use only.

‡

S Supporting Information *

ABSTRACT: A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH−π interaction. This resulted in increased cell permeability, suggesting that NH−π interactions may be used in the design of molecular chameleons.

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recognition16 and were found to stabilize complexes by energies comparable to half a hydrogen bond. However, to the best of our knowledge, the effect of intramolecular NH−π interactions on cell permeability of macrocycles and other molecular chameleons has not been investigated. We therefore designed a set of rigid macrocycles, each of which contained three amide bonds (1a−f, Figure 1A): a recurring motif in drugs and drug candidates.17 Compounds 1a−f were inspired by the natural product hymenocardine18,19 and the related compounds K-1320 and OF4949-III21 (Figure 1B). They were used to investigate if replacement of the aliphatic side chain of homoleucine (1a) by phenyl groups attached to the macrocycle core via linkers of decreasing length and flexibility (1b−f) allows for the formation of intramolecular NH−π interactions with either of the adjacent amide bonds. The macrocycles also allowed assessment of how dynamic shielding of amide bonds by a phenyl group affects their diffusion across Caco-2 cell monolayers. As the lipophilicity of a compound is a major determinant of its cell permeability, the six macrocycles were designed to have drug-like calculated lipophilicities (cLogD7.4 1.7−2.9). Compounds 1a, 1c, and 1d have almost identical lipophilicities to facilitate analysis of to what extent their side chains shield the adjacent polar amide bonds and how this affects cell permeability. Macrocycles 1b and 1e, having their phenyl

acrocycles, as compared to nonmacrocyclic compounds, may offer enhanced opportunities for binding to difficult drug targets having flat or groove-shaped binding sites.1,2 In contrast to biologics, macrocycles may also be cell permeable, which allows modulation of intracellular difficultto-drug targets and potentially also for oral administration. Recent studies on drugs and clinical candidates in the chemical space beyond Lipinski’s rule of 5 (bRo5)3−5 suggest that they behave as molecular chameleons when molecular weight increases above 600−700 Da.6−10 Because of the appropriate conformational flexibility, such compounds adjust their conformations and polar surface areas to match the properties of the surrounding environment, i.e., they adopt a more lipophilic conformation when crossing a cell membrane and a more hydrophilic conformation in the polar, aqueous medium outside and inside the cell. Despite recent insight into the extent of bRo5 space in which orally absorbed drugs may be discovered,11 we are still far from understanding how to design molecular chameleons. Further advances will benefit from understanding how weak intramolecular interactions contribute to provide dynamic, environment-dependent shielding of the polar groups. To increase the understanding of how to design molecular chameleons, we investigated how shielding of an amide bond by formation of an NH−π interaction with an aromatic group may affect cell permeability. NH−π interactions of amide bonds have previously been described from studies of ligand− protein complexes,12,13 folding of peptides,14,15 and host−guest © 2018 American Chemical Society

Received: August 1, 2018 Published: September 12, 2018 5737

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Figure 2. Conformations of macrocycles 1a−e obtained by conformational sampling in OMEGA and energy minimization using MMFF94 in implicit solvation (ε = 4.8). (A) Overlays of two selected low energy conformations (in yellow and cyan) of 1a in which the orientation of each amide bond within the macrocycle core has been inverted as compared to the minimum energy conformer (in green). The two conformations are within 10 kcal/mol of the minimum energy conformer. (B−F) Overlays of all low energy conformations within 2 kcal/mol of the minimum energy conformers of 1a−e. The minimum energy conformer is marked in green for each macrocycle.

Figure 1. (A) Macrocycles designed to investigate how shielding of amide bonds by adjacent side chains affects their conformations and cell permeability. (B) Structures of hymenocardine, K-13, and OF4949-III.

groups attached to the macrocycle core with linkers of different length as compared to 1c, have higher and lower lipophilicities, respectively. Finally, 1f was included as a close analogue of 1c that has a higher lipophilicity. Conformational sampling of 1a−e, but not 1f, which differs from 1c only by having a propionyl group instead of an acetyl group, was performed using a distance-geometry-based algorithm in OMEGA22−24 that provides diverse sampling of conformational space. The resulting conformers were then energy minimized with MMFF94 (Figure 2). Sampling indicated that the macrocycle core of 1a−f was rigid but populated conformations in which the two amide bonds within the macrocycle were inverted (illustrated for 1a, Figure 2A). As expected, the side chains attached to the core displayed greater flexibility even between the low energy conformers of 1a−c, whereas the phenyl groups in 1d and 1e were rigid (Figures 2B−F). Low energy conformers were found for 1b and 1c in which their phenyl groups shielded one of the adjacent amide bonds (Figure 2C and D), suggesting the formation of weak attractive NH−π interactions for these compounds. Macrocycles 1d and 1e were not able to adopt such conformations.

The syntheses of macrocycles 1a−f were initiated by coupling of amino acids 2a−e to racemic aminoalcohol 325 using HATU/DIPEA in dichloromethane to give 4a−e in 63−76% yields (Scheme 1). After deprotection of the tbutyloxycarbonyl group of 4a−e using hydrochloric acid in acetonitrile, the resulting amines were coupled with TBDMSprotected tyrosine 526,27 using HATU/DIPEA to provide dipeptides 6a−e in 62−69% yields. Deprotection of the TBDMS group of 6a−e, and simultaneous macrocyclization by an intramolecular SNAr reaction,28,29 was performed as described for vancomycin.30,31 Thus, treatment of dilute (0.01 M) solutions of 6a−e in DMF with CsF at 50 °C provided 7a−e in 66−78% yields. The nitro group of 7a−e was removed in a three-step sequence. First, the nitro group was reduced to an amine using hydrogenation; then, the amine was transformed into a diazonium moiety using catalytic amounts of copper(I) oxide and sodium nitrite followed by reduction using hypophosphorus acid.32,33 During these steps, a side product having a molecular weight 2 Da lower than the desired product was observed for each of the five macrocycles. As the 5738

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side chains, an interaction that cannot be formed in 8a having an aliphatic side chain. In addition, the coupling constants between Hα and the two Hβ protons of the phenylalanine moiety in 8c are compatible with a dihedral angle where the phenyl group is in proximity to the NH I moiety, which further supports a conformation stabilized by an NH−π interaction (J = 4.2/5.3 and 11.5/12.6 Hz in CDCl3/DMSO-d6, respectively, cf. Figure 4a for conformation). No, or only minor, shifts were observed in both solvents for NH II and NH III in 8b and 8c, as compared to 8a, suggesting that 8b and 8c do not populate conformations in which their phenyl groups interact with NH II and NH III to any significant extent. NH II in the phenylglycine-derived macrocycles 8d and 8e is deshielded in CDCl3 and DMSO-d6 as compared to 8a (0.58 and 0.80 ppm for 8d, 0.61 and 0.89 ppm for 8e) most likely due to the fact that this proton is positioned in the plane of the phenyl ring. Macrocycle 1c was crystallized via vapor diffusion from chloroform using cyclohexane as antisolvent, and the structure was determined by single-crystal X-ray diffraction (Figure 4A). In the crystal structure, the bis-aryl ether positions the amide backbone of 1c in an extended, β-strand-like conformation. It is almost identical to the backbone conformation in one of the four families of low energy conformations predicted by OMEGA (Figure 4B). The phenyl side chain is oriented so that an NH−π interactions may be formed with NH I in

mixtures were difficult to purify, they were oxidized by IBX34−37 at 85 °C, which provided 8a−e in 12−25% yields. At this stage, the byproduct of the deamination-diazotization reaction sequence of 7c was identified as resulting from an oxidative coupling38−40 between the ortho positions of the ether-linked phenyl residues to give 9 (14%). Similar side products were obtained from 7a, 7b, 7d, and 7e, but they were not isolated and characterized. Finally, the t-butyloxycarbonyl group of macrocycles 8a−e was cleaved using HCl in acetonitrile, and the resulting amines were acylated using Ac2O/TEA or propionyl chloride/TEA to give the target compounds 1a−f in 65−82% yields. NMR spectroscopy studies in CDCl3 and DMSO-d6 were used to investigate how conformational preferences varied between nonpolar and polar environments for the tbutyloxycarbonyl-protected macrocycles 8a−e as the acetamides 1a and 1b were insoluble in CDCl3. Interestingly, macrocycles 8b and, in particular, 8c showed a large shielding of one of the amide protons (cf. NH I, shaded in green, Figure 3) as compared to 8a. This shielding was larger in CDCl3 than in DMSO-d6, e.g., 1.43 versus 0.19 ppm for 8c, revealing a significant influence of the polarity of the solvent. These observations suggest that the conformations of 8b, and to an even greater extent 8c, are stabilized by an intramolecular NH−π interaction between the amide bond and their phenyl 5739

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Figure 3. 1H NMR spectra of macrocycles 8a−e in (A) CDCl3 and (B) DMSO-d6. Spectra were recorded on an Agilent Technologies 400 NMR spectrometer at 298 K.

the polar surface area.10,44,45 For delineating how the lipophilicity and conformational preferences influence the permeabilities of 1a−f, their lipophilicities (logD7.4) and effluxinhibited (passive) permeabilities across Caco-2 cell monolayers were determined (Figure 5). Interestingly, macrocycles 1a, 1b, 1d, and 1e displayed an excellent correlation between cell permeability and lipophilicity, whereas the permeabilities of the phenylalanine derivatives 1c and 1f were significantly higher (∼3-fold) than predicted by this correlation. The higher permeability of 1c than expected from its lipophilicity is also revealed by comparison to 1a and 1d, both of which have higher lipophilicity yet lower cell permeability. We conclude that the high permeability of 1c, and analogue 1f, which has a higher lipophilicity, most likely results from formation of an NH−π interaction during the passive diffusion across the membrane of the Caco-2 cells, as supported by NMR spectroscopy in CDCl3 and X-ray crystallography for 1c. In depth studies of cyclosporin A,46 a cyclic peptide model system,47 and a set of stereoisomeric de novo-designed

agreement with the conclusions from conformational sampling and NMR spectroscopy. The distance from the nitrogen atom of NH I to the center of the phenyl ring is close to the optimum range reported for NH−π interactions (4.3 vs 2.9− 3.6 Å).41 As crystal structures may be influenced by crystal packing,42,43 the structure was energy minimized with three different force fields (Figure 4C). This resulted in minor adjustments of the position of one of the O-phenyl groups. In addition, minor adjustments in the peptide backbone and the phenyl side chain led to reduced NH−phenyl distances with the one determined by OPLS3 being within the optimum range for an NH−π interaction. Thus, the crystal structure of 1c supports that an intramolecular NH−π interaction stabilizes the conformation of 1c in a nonpolar environment. It is well-established that cell permeability depends on lipophilicity within a series of structurally related compounds. In addition, recent studies of macrocycles have highlighted that their conformational preferences also have a significant influence by providing dynamic shielding and exposure of 5740

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and aqueous solubility in contrast to rigid analogues.7,44 Moreover, a recent study suggested that an appropriate degree of conformational flexibility is a general feature of drugs and clinical candidates in the bRo5 space required for them to behave as molecular chameleons that adapt their properties to the polarity of the environment.10 Flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds were proposed to be particularly effective features of molecular chameleons. Introduction of hydrogen bond acceptor−donor pairs in peptidic and nonpeptidic model compounds has revealed that intramolecular hydrogen bonding can be used in the design to improve membrane permeability while retaining or improving other drug properties.48,49 Herein, we have demonstrated that an appropriately positioned aryl group that forms intramolecular interactions with polar groups, i.e., NH−π interactions that shield amide bonds, can be used in the design of molecular chameleons. We propose that this will expand the tool box used by medicinal chemists for the design of cell-permeable macrocycles. Future studies of how intramolecular NH−π interactions are affected by factors such as the rigidity of the macrocycle and the nature of the aryl group are required to understand its scope and limitations.

Figure 4. (A) Structure of macrocycle 1c determined by X-ray crystallography. The coordinates have been deposited in the Cambridge Structural Database (CSD), reference: 1853494. (B) Crystal structure of 1c (green) superimposed with the minimum energy conformation obtained by sampling in OMEGA (violet). (C) Crystal structure of 1c superimposed with structures obtained after energy minimization with OPLS3, MMFF94s, and B3LYP. Energy minimizations were done in implicit chloroform (ε = 4.8). The distance between NH I and the center of the phenyl ring is tabulated for each of the structures.

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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.orglett.8b02447. Experimental procedures, spectra for characterization of compounds synthesized, single-crystal X-ray structure, and computational details (PDF) Accession Codes

CCDC 1853494−1853495 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], Tel: +46 (0)18 4713801. ORCID

Vasanthanathan Poongavanam: 0000-0002-8880-9247 Jan Kihlberg: 0000-0002-4205-6040

Figure 5. Cell permeability [log(Papp AB + Inh)] as a function of lipophilicity (logD7.4) for macrocycles 1a−f. Cell permeability was determined in the apical-to-basolateral (AB) direction across Caco-2 cell monolayers in the presence of a cocktail of inhibitors of efflux transporters (quinidine, sulfasalazine, and benzobromarone, noted by “+ Inh”). Standard errors (SEM) are shown as bars and are based on 3−5 repeats. Octanol-buffer partition coefficients (logD7.4) between 1-octanol and sodium phosphate buffer (pH 7.4) were determined using a miniaturized shake-flask procedure. Standard errors (SEM) for logD were ±0.03 for 1a−d and 1f, and ±0.06 for 1e. They are based on three repeats. The correlation between log(Papp AB + Inh) and logD7.4 has been derived for macrocycles 1a, 1b, 1d, and 1e, i.e., for those that display no or minor shielding of NH I according to NMR spectroscopy. Macrocycles 1a−e have an acetyl and 1f a propionyl group at their primary amino group.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by grants of the Swedish Research Council (grant 2016-05160) and AstraZeneca Gothenburg. We thank OpenEye scientific software and ChemAxon for providing free academic licenses. The authors are also grateful to the DMPK department of Pharmaron for determination of cell permeability, Linda Fredlund, Johan Wernevik, and Johan Hulthe (Discovery Sciences, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden) for determination of logD, and to James B. Orton at the UK National Crystallography Service for determining the crystal structure of macrocycle 1c. This study made use of the NMR Uppsala infrastructure, which is funded

macrocycles44 have revealed that compounds that dynamically expose or shield polarity can combine high cell permeability 5741

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by the Department of Chemistry−BMC and the Disciplinary Domain of Medicine and Pharmacy.

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