Molecular Recognition of Steroid Hormones in ... - ACS Publications

Subscriber access provided by KINGSTON UNIV

Article

Molecular recognition of steroid hormones in the solid state: stark differences in cocrystallization of #-estradiol and estrone Karen J Ardila-Fierro, Vânia André, Davin Tan, M. Teresa Duarte, Robert W Lancaster, Panagiotis G. Karamertzanis, and Tomislav Friscic Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg501865h • Publication Date (Web): 20 Jan 2015 Downloaded from http://pubs.acs.org on January 27, 2015

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Crystal Growth & Design is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Molecular recognition of steroid hormones in the solid state: stark differences in cocrystallization of β-estradiol and estrone Karen J. Ardila-Fierro,a Vânia André,b Davin Tan,a M. Teresa Duarte,b Robert W. Lancaster,c Panagiotis G. Karamertzanis,d Tomislav Friščić*,a a) Department of Chemistry and FRQNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke St. W., H3A 0B8 Montreal, Canada; b) Centro de Química Estrutural, Instituto Superior Técnico Universidade de Lisboa, Av Rovisco Pais, 1049-001 Lisbon, Portugal, c) Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, United Kingdom, d) Centre for Process Systems Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom. ABSTRACT: While the understanding of the supramolecular chemistry of steroidal hormones is largely based on receptor binding studies in vitro and in vivo, their solid-state molecular recognition properties remain unexplored. Here, we use mechanochemical cocrystallization and single crystal X-ray structure analysis to gain insight into the solid-state complexation of sex hormones with arenes, by systematic investigation of the ability of two important estrogens ßestradiol (bes) and estrone (est) to form cocrystals with 1,2-dimethylnaphthalene, phenanthrene, anthracene, 9,10anthraquinone, phenanthridine, benzo[h]quinoline and perfluoronaphthalene. Cocrystallization of bes reveals the formation of a novel hydrogen-bonded lattice host, exhibiting rectangular channels occupied by arene guests. In striking contrast to bes, its 17-keto-analogue est did not yield cocrystals with any of the explored arenes except perfluoronaphthalene, revealing association via arene-perfluorarene π···π stacking. The results reveal previously unknown solid-state complexation behavior of important estrogen hormones, demonstrating how minor changes in the steroid structure, in particular switching from a 17-hydroxyl to a 17-keto group, can result in extraordinary changes to their solidstate self-assembly. In that respect, solid-state chemistry of steroids appears to mirror their important signalling role in biological systems, as very small modifications to the steroid structure lead to large changes in cocrystallization propensity.

The understanding of molecular recognition and complexation of steroids, a central family of signalling molecules in living organisms, is a long standing and highly active area of research, with implications for biology, evolutionary biology, biochemistry, medicinal chemistry, as well as pharmacy and pharmacology.1-14 Current understanding of the biological recognition and activity of steroid hormones is extensive and based largely on in vitro and in vivo binding studies assisted by site-selective mutagenesis, as well as spectroscopic and X-ray diffraction studies of steroids or steroid analogues complexed with modified or non-modified biological receptors.15-26 Recently,27 we proposed mechanochemical28-31 screening for multi-component crystals (cocrystals)32-34 of steroids as a means to apply solid-state chemistry and crystal engineering in exploring their molecular recognition properties. Such a solid-state approach, although nonconventional, provides an exciting opportunity to gain information complementary to that obtained by conventional in vitro or in vivo methods. The often encountered difficulty of finding a generally applicable common solvent for the steroid and the potential cocrystal former points to mechanochemistry as the most viable means to effectively and rapidly explore steroid cocrystallization.

Our initial screen addressed cocrystallization of steroid sex hormones progesterone, pregnenolone, ß-estradiol (bes) and estrone (est) with arenes (Figure 1a), followed by X-ray structural characterization of the obtained multi-component solids.27 Whereas single crystal X-ray diffraction has been utilized extensively for studying steroids,35-44 such work has focused mostly on singlecomponent solids or fortuitously obtained solvates and hydrates. Thus, with very few exceptions,45-52 cocrystallization and solid-state complexation of steroid hormones have remained largely unexplored. The value of this mechanochemical approach for exploring steroid complexation was evidenced by discovering the outstanding propensity of progesterone for cocrystallization with arenes.27 Structural analysis explained the solid-state affinity towards arenes by a previously unknown1-26 recognition motif involving the steroid α-face and the arene π-system (Figure 1b). We now focus in more detail on the solid-state behavior of two estrogen53 sex hormones bes and est towards a small library of selected aromatic hydrocarbons and nitrogen-based heterocycles: phenanthrene (phe), anthracene (ant), 9,10-anthraquinone (anq), phenanthridine (phn), benzo(h)quinoline (bhq), 1,2-

ACS Paragon Plus Environment


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

dimethylnaphthalene (dmn) and perfluoronaphthalene (pfn) (Figure 1c). These potential cocrystal formers were selected in order to explore how modifications in guest size, shape and polarity will affect cocrystal formation with est and bes. To maximize the efficiency of cocrystal screening, we used neat grinding and liquid-assisted grinding (LAG)28-31,54,55 as methods of choice, followed by attempts of single crystal growth from solution.

Page 2 of 13

a molecule and discovery of new materials with improved physicochemical properties. The most popular applications of cocrystallization are currently in screening for new solid forms of pharmaceutical ingredients,65-73 and for the synthesis of materials with novel photo- and thermochemical, optical, electronic, or photo-mechanical properties.74-81 In a related approach, cocrystallization has been promoted as a means to facilitate single crystal growth and therefore X-ray structural characterization of complex or unstable molecular structures that are difficult to crystallize.82-84 However, cocrystallization can also provide a unique entry for crystal engineering to study molecular recognition,85-89 by systematic screening for cocrystal formation.27-31,54 In that context, mechanochemistry is especially useful as it allows rapid screening for cocrystal formation in the absence of vexatious problems of solubility and thermal sensitivity of target molecules.90-98 Although Weeks and co-workers have noted the possible use of cocrystallization to gain structural information on steroid binding in biological systems,52 this approach has remained unexplored. Instead, steroid cocrystallization has been largely used as a non-covalent means to introduce heavy atoms into crystal structures in order to facilitate X-ray structural characterization: this strategy was pioneered in the 1960s by Eger and Norton who used pbromophenol to facilitate structural characterization of steroids,50 while the Desiraju group employed a similar strategy to facilitate determination of steroid absolute configuration.51 Recently, steroid cocrystallization was brought back into the focus of solid-state chemists as a means to develop new pharmaceutical solids with improved properties (e.g. dissolution, tableting).45-49 While the herein described study is primarily of academic nature, directed towards building a fundamental understanding of steroid recognition in the solid state, it is also of potential pharmaceutical and medicinal relevance as it provides the first insights on how to design new solid forms of two steroids of medicinal and pharmaceutical use in hormonal contraception, hormone replacement therapy, as well as treatment of menopausal and postmenopausal symptoms.99

Experimental Section

Figure 1. (a) Diagrams of est and bes with the conventional atom numbering scheme; (b) the α···π “sandwich” assembly 27 of pyrene (space-filling) and progesterone (wireframe); (c) aromatic cocrystal formers used in this study: phenanthrene (phe), anthracene (ant), 9,10-anthraquinone (anq), 1,2dimethylnaphthalene (dmn), phenanthridine (phn), benzo[h]quinoline (bhq) and perfluoronaphthalene (pfn); (d) structure of the (bes)(pyrene) cocrystal, demonstrating the hydrogen-bonded framework of bes (wireframe), with 27 pyrene as guest (space-filling).

Cocrystallization32-34 is a well-established crystal engineering56-64 strategy for modifying solid-state properties of

Estrone and β-estradiol are biologically highly active substances and must be treated with precaution. All reagents were commercially available and were used without purification: β-estradiol hemihydrate (99%, Sigma-Aldrich); estrone (99%, Sigma-Aldrich); 1,2dimethylnaphthalene (95%, Sigma-Aldrich); phenanthrene (98%, Alfa Aesar); anthracene (99%, Sigma-Aldrich); 9,10-anthraquinone (97%, SigmaAldrich); phenanthridine (99%, Santa Cruz Biotechnology); benzo[h]quinoline (97%, Sigma-Aldrich); octafluoronaphthalene (96%, Alfa Aesar)

Mechanochemical screening In a typical experiment, an equimolar mixture of 200 mg of the steroid (estrone or β-estradiol hemihydrate) and the arene was milled in a Retsch MM200 mill at a


Page 3 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


frequency of 25 Hz using a 10 mL stainless steel milling jar and a single ball made of the same material (10 mm diameter) for 45 minutes. Same products were obtained by milling at 30 Hz after 20 min, using a Retsch MM400 mill. Liquid-assisted grinding was conducted in identical manner, with the addition of 50 μL nitromethane, corresponding to the liquid-to-solid ratio η=0.25 μL mg-1.93 Outcomes of mechanochemical screening are given in Table 1.

Single crystal X-ray diffraction Single crystals of (bes)(bhq) and (bes)(dmn) were obtained by slow evaporation after dissolving a sample of a mechanochemically prepared cocrystal in a mixture of methanol and chloroform (1:1). Single crystals of (bes)(phe) were grown by slow evaporation from methanol. X-ray single diffraction was conducted on Bruker D8 and X8 Apex II diffractometers equipped with MoKα X-ray sources and graphite monochromators. Multi-scan absorption correction (SADABS) was applied. Structures were solved by direct methods and refined using SHELX-97. Crystallographic and general information for all determined structures are given in Table 2. Powder X-ray diffraction (PXRD) and database searches Room temperature powder X-ray diffraction (PXRD) patterns were collected in the 2θ range from 3° to 46° on a Bruker D2 phaser X-ray diffractometer using a Cu-Kα (λ=1.54 Å) source equipped with a LinxEye detector, nickel filter and operated at 30 kV and 10 mA. Data analysis was carried out using the Panalytical X’pert Highscore Plus program. Experimental patterns were compared to simulated patterns calculated from published crystal structures using Mercury crystal structure viewing software. Structural data pertinent to published crystal structures were obtained from the Cambridge Structural Database (CSD) searches were performed using the CSD version 5.35, November 2013 update. Additional PXRD patterns are given in Supplementary Figures S1-S5. Solid-state NMR spectroscopy Cross-polarization magic angle spinning (CP-MAS) 13C solid-state nuclear magnetic resonance (13C SSNMR) spectroscopy was carried out in a 400 MHz Varian VNMR equipped with a 7.5 mm CP-MAS probe. Spectra were collected at a spin rate of 5 KHz, 2 ms contact time and 2 s recycle delay, with the application of the TOtal Suppression of Spinning sidebands (TOSS)100 sequence. Fourier-transform attenuated total reflectance (FTIRATR) spectroscopy FTIR-ATR spectra were recorded using a Bruker Vertex 70 spectrometer in the range 400 cm-1 to 4000 cm-1, and analysed using Bruker OPUS software. Additional FTIRATR spectra are given in Supplementary Figures S6-S10. Thermal analysis Simultaneous thermogravimetric (TG) and differential scanning calorimetry (DSC) analysis was conducted on a Mettler Toledo TGA/DSC 1 STARe System. All samples

were heated at a rate of 20°C/min from 30°C to 700°C in air, using a flow rate of protective N2 gas of 30 mL/min. Thermograms were analysed using Mettler Toledo TGA software. Hot-stage microscopy experiments were performed on a Leica DM2500 microscope equipped with a Mettler Toledo FP90 Central Processor with a Mettler FP 84HT hot stage TA Microscopy Cell. Example TG/DSC thermograms are given in Supplementary Figures S11-S15.

Density functional theory (DFT) calculations Density Functional Theory (DFT) calculations were performed on pyrene, phe and bhq using the Gaussian09 program package.101 Optimized gas phase structures were calculated using Becke’s three parameter functional102 and nonlocal Lee-Yang-Parr correlation functional103 (B3LYP) theory, with 6-31+G(d,p) Pople basis set104 for C, H and N atoms. 3-D visualizations of the Electrostatic Potential (ESP) map were then achieved using the Gaussview5.0.8 program105 and the dipole moments of the molecules were obtained for comparison.

Results and Discussion Mechanochemical screening Mechanochemical screening (Table 1) demonstrates a difference in their propensities of bes and est for cocrystal formation. Consistent with the previously reported screen,27 est yielded a new cocrystal phase only with the perfluorinated arene pfn. In contrast, bes was a more prolific cocrystal former, yielding four new cocrystals with phe, phn, bhq and dmn. The choice of method for mechanochemical screening did not significantly affect product formation, as the positions of X-ray reflections appearing in PXRD patterns of reaction mixtures after milling were identical for neat grinding and LAG27-31 experiments (e.g. see Figure 2). Table 1. Results of mechanochemical screening for cocrystals of bes and est, based on PXRD analysis.a cocrystal former

bes b

est -

phe

++

ant

-

-

dmn

++

-

anq

-

-

phn

+

-

bhq

++

-

pfn

-

++b

a) Appearance of new reflections in the PXRD pattern, indicative of cocrystal formation, is designated by ‘+’; absence of new reflections, indicating the failure to form a cocrystal, is given by ‘-‘. The symbol ‘++’ indicates the cocrystal was structurally characterized; b) observed in 3 previous work, structure reported herein.

Analysis of PXRD patterns of milled mixtures of steroids and cocrystal formers in respective stoichiometric ratios 2:1, 1:1 and 1:2 indicated that the cocrystals all had the 1:1 composition, with formulas (est)·(pfn),



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(bes)·(phe), (bes)·(bhq), (bes)·(phn) and (bes)·(dmn) (see Figure S1 for illustration).

Figure 2. Overlay of relevant PXRD patterns for cocrystallization of est with pfn: (a) est reactant (corresponds to the estrone polymorph 2, CCDC codes 106-108 (b) ESTRON03, ESTRON10, ESTRON13 or ESTRON14); pfn reactant; (c) 1:1 mixture of est and pfn after 45 min neat milling,; (d) 1:1 mixture of est and pfn after 45 min LAG and (e) simulated PXRD pattern for the (est)(pfn) cocrystal.

Cocrystallization of estrone with perfluoronaphthalene Consistent with our earlier study, cocrystal screening confirmed that est does not readily form cocrystals with arenes.27 A search of the Cambridge Structural Database reinforces this view: the only reported structural studies of est are those of its three known polymorphs.106-108 Single crystals of (est)(pfn) were obtained by recrystallization of the mechanochemically prepared cocrystal from a mixture of diethylether and methanol in a 1:1 volume ratio. Single crystal X-ray diffraction (Table 2) confirmed the formula (est)(pfn). Asymmetric unit of (est)(pfn) consists of four molecules: two symmetrically non-equivalent est and two symmetrically non-equivalent pfn molecules. The crystal structure strongly suggests arene···perfluoroarene interactions109-115 as the driving force for cocrystallization, as the aromatic phenol moieties of est pack closely with the rings of pfn (C···C separations: 3.2-3.4 Å) to form alternating stacks parallel to the crystallographic a-axis (Figure 3). Table 2. Crystallographic and general data for (est)(pfn), (bes)(phe), (bes)(phn) and (bes)(dmn). Cocrystal

(est)(pfn)a

(bes)(phe)

(bes)(bhq)

(bes)(dmn)

Formula

C28H22F8O2

C32H34O2

C31H33NO2

C30H36O2

Page 4 of 13

melting point / oCb

167c

172

141

165

CCDC code

1036412

1036413

1036414

1036415

Crystal system

monoclinic

orthorhombic

orthorhombic

orthorhombic

Space group

P21

P212121

P212121

P212121

a/Å

13.827(2)

7.3490(7)

7.395(8)

7.4099(4)

b/Å

7.142(4)

18.3630(18)

18.402(19)

15.8244(9)

c/Å

23.804(3)

18.6054(18)

18.563(19)

19.9836(12)

β/o

90.925(5)

90

90

90

V / Å3

2350.4(14)

2510.8(4)

2526(4)

2343.2(2)

Z

4

4

4

4

Z’

2

1

1

1

T/K

150

293

100

100

ρcalc/g cm-3

1.533

1.192

1.187

1.215

data

8435a

5981

4717

5685

data (I≥2σI)

4087a

5531

4107

5267

parameters

689

311

310

294

F(000)

1112

968

968

928

R(all data)

0.167

0.041

0.045

0.041

R(I≥2σI)

0.067

0.037

0.037

0.037

wR2 (all data)

0.120

0.100

0.091

0.093

wR2 (I≥2σI)

0.100

0. 097

0.086

0.090

S

0.91

1.05

1.06

1.02 o

a) The crystal diffracted poorly past 2θ=45 ; b) melting point measured by differential scanning calorimetry (DSC); o c) the cocrystal decomposes at 167 C, most likely forming o crystalline est which then melts at 262 C.

The PXRD pattern simulated for the (est)(pfn) single crystal structure matched very well with that measured for the mechanochemically prepared material. The est molecules in (est)(pfn) are associated by O-H···O hydrogen bonds between phenol and keto groups in neighboring molecules, forming hydrogen-bonded chains with O···O distances of 2.721(6) Å and 2.734(6) Å (Figure 4a).

Figure 3. Arene-perfluoroarene stacks in (est)(pfn), viewed parallel to the: (a) crystallographic b-axis and (b) crystallographic c-axis.


Page 5 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Resulting chains are topologically similar to those in est polymorph 3 (Figure 4b-d), with the principal difference being in the twist of molecules along the direction of chain propagation. In (est)(pfn), neighboring molecules are mutually twisted by 38o, with respect to the planar phenol groups. In est form 3 all molecules in a chain are coplanar.

Cocrystals of ß-estradiol (bes) Cocrystallization of bes was successful with four out of seven explored cocrystal formers. Similarity of PXRD patterns strongly suggests that cocrystals (bes)(phe), (bes)(phn) and (bes)(bhq) are isostructural (Figure 6). Moreover, comparison of the measured PXRD patterns to that simulated for the previously described27 cocrystal of bes with pyrene indicates that (bes)(phe), (bes)(phn) and (bes)(bhq) might all be based on a similar hydrogenbonded host framework (Figure 1d, Figure 6). This was confirmed by single crystal X-ray diffraction on (bes)(phe) and (bes)(bhq). The isostructural (bes)(phn) has not yet been obtained in the form of diffractionquality single crystals (Table 2). The asymmetric unit of (bes)(phe) contains one molecule of bes and one molecule of phe. Formation of O-H···O hydrogen bonds between alcohol and phenol moieties (Figure 7a, Table 3) of neighboring bes molecules results in a three-dimensional framework with rectangular channels running in the crystallographic a-direction (Figure 7b). The channels, with approximate inner cross-section of 6.5 × 10 Å2, are occupied by molecules of phe.

Figure 4. Hydrogen-bonded chains of est in: (a) (est)(pfn), compared to analogous architectures in different polymorphs 30 of est: (b) form 3 (CCDC ESTRON12); (c) form 2 (CCDC ESTRON14) and (d) form 1 (CCDC ESTRON11).

Cocrystallization was also detectable by 13C crosspolarization magic angle spinning solid-state nuclear magnetic resonance (CP-MAS SSNMR) spectroscopy, which confirmed the presence of two symmetrically nonequivalent est molecules in (est)(pfn). This is clearly seen from the doubling of the signal at 226 ppm, corresponding to the carbonyl group carbon atom at position 17 (Figure 5).

Figure 5. Solid-state NMR spectra of commercial est (top) and (est)(pfn) (bottom). The most readily distinguished carbon signals for positions 17 (carbonyl group) and 18 13 (methyl group) are highlighted. The C signals for the pfn cocrystal former in are very broad due to abundant fluorination.

Figure 6. Relevant PXRD patterns for cocrystallization of bes: (a) bes·½ H2O; (b) reagent phe; (c) reagent phn; (d) reagent bhq; (e) simulated for the cocrystal (bes)(pyrene); (f) cocrystal (bes)(phe) made by LAG; (g) cocrystal (bes)(phn) made by LAG; (h) cocrystal (bes)(bhq) made by LAG; (i) cocrystal (bes)(dmn) made by LAG and (i) simulated for the crystal structure of (bes)(dmn).



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 6 of 13

Whereas the hydrogen-bonded framework in (bes)(phe) is identical to that in analogous pyrene cocrystal (Table 3),27 lower symmetry of phe compared to pyrene leads to the appearance of polarity in the assembly of guest molecules within each channel. Table 3. O-H···O hydrogen bond distances in the cocrystals of bes. cocrystal

hydrogen bond distance OHphenol···Oalcohola

OHalcohol···Ophenolb

(bes)(phe)

2.673(2) Å

2.770(2) Å

(bes)(bhq)

2.684(3) Å

2.779(3) Å

(bes)(dmn)

2.654(2) Å

2.787(2) Å

a) Corresponding distance in (bes)(pyrene) cocrystal is 2.67 27 Å; b) corresponding distance in (bes)(pyrene) is 2.76 Å.

Namely, guest phe molecules in each channel are aligned in a similar fashion, with the hydrocarbon groups at 5and 6-positions always oriented in the same direction (Figure 7c). This leads to partial orientation of phe dipole moments (calculated to be 0.0142 Debye, Figure 7d) in each channel. Orientation of guest molecules is inverted in neighboring channels, resulting in no net polarity resulting from the arrangement of guests.

Figure 7. (a) Hydrogen-bonded chain of bes in the (bes)(phe) cocrystal. For clarity, hydrocarbon residues of the steroid are omitted and hydroxyl groups of phenol and alcohol moieties of bes are highlighted. (b) View of the (bes)(phe) structure parallel to the crystallographic a-axis. (c) Alignment of phe guests within a single channel of (bes)(phe) and (d) comparison of calculated electrostatic surface potentials and dipole moments, illustrating the principal differences in molecular shape and polarity between the symmetrical pyrene and less symmetrical phe and bhq guests.

Polarity of guest assembly within individual channels of bes framework is also seen in the isostructural cocrystal of benzo[h]quinoline (bhq) (Figures 7d, 8). In


Page 7 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(bes)(bhq), the bes molecules form a hydrogen-bonded framework identical to that seen in (bes)(phe) and the analogous cocrystal with pyrene. Molecules of the bhq guest in each channel adopt an arrangement that is nearly identical to that of phe molecules in (bes)(phe), resulting in a polar structure in which dipole moments of guest molecules (calculated to be 1.7567 Debye) within a channel are partially aligned by way of a two-fold screw rotation axis. However, the guest molecules in neighboring channels are oriented in opposite fashion.

shaped cross-section, with guest molecules in each channel arranged along a two-fold screw rotation axis. Such arrangement of guests again yields a polar structure in which the weak dipole moments of dmn molecules (calculated at 0.7417 Debye) are partially aligned in each channel (Figure 9b). As in (bes)(phe) and (bes)(bhq), guests in neighboring channels are aligned in opposite fashion.

Figure 9. (a) Fragment of the crystal structure of (bes)(dmn), viewed parallel to the crystallographic a-axis and (b) polar arrangement of dmn guests along a two-fold screw axis within a channel formed by bes molecules. Figure 8. Fragment of the crystal structure of (bes)(bhq), viewed parallel to the crystallographic a-axis and (b) polar arrangement of bhq guest molecules within a channel formed by bes molecules.

The structures of (bes)(phn) and (bes)(bhq) are somewhat surprising, as they demonstrate a preference of est to form cocrystals by molecular inclusion in a host framework, rather than through the often observed formation of O-H···N bonds between phenols and aromatic nitrogen atoms.116-121 Comparison of PXRD patterns indicates that (bes)(dmn) is not isostructural to (bes)(phe), (bes)(phn) and (bes)(bhq). Single crystal X-ray analysis of crystals grown by recrystallization of bes from liquid 1,2-dimethylnaphthalene confirms this conclusion (Table 2, Figure 9). The structure of (bes)(dmn) consists of a three-dimensional framework of bes with identical hydrogen-bonded connectivity to that in (bes)(phe) and (bes)(bhq) (Figure 9a). However, the guest-filled channels no longer adopt a square cross-section. Instead, the structure is skewed to form channels having a rhombus-

As it was previously established that bes does not form a cocrystal with naphthalene, the structure of (bes)(dmn) is relevant for understanding how the molecular structure of an arene impacts cocrystallization with bes. Presumably, the presence of methyl groups on the naphthalene core in dmn results in a combination of molecular size and shape that resembles phe, and is suitable for templating the bes hydrogen-bonded host. Cocrystallization with bes was also detectable by 13C CP-MAS SSNMR (Figure 10), most notably through changes in the chemical shift of the carbon atom of the methyl group in bes. In the starting material bes·½H2O the signal of the methyl group carbon atom is found at 10.5 ppm.122 In the mutually structurally similar cocrystals with phe, bhq, phn and dmn the chemical shift for this methyl group atom is 13.0 ppm. Formation of bes cocrystals, and the structural similarity of the host frameworks in (bes)(phe), (bes)(phn) and (bes)(bhq) is reflected in their FTIR-ATR spectra, especially in the region of O-H group stretching vibrations (Figure 11).



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

13

Figure 10. Selected C CP-MAS SSNMR spectra for cocrystals of bes: (a) starting material bes·½ H2O; (b) (bes)(phe) obtained by LAG; (c) (bes)(bhq) obtained by LAG. The signal of the methyl group carbon (C18) is highlighted.

While the starting material bes·½H2O exhibits two broad absorptions in this spectral region, one centered at 3409 cm-1 and the second one spanning the range between 3190 cm-1 and 3250 cm-1, the isostructural cocrystals (bes)(phe), (bes)(phn) and (bes)(bhq) exhibit only one absorption band, between 3404 cm-1 and 3406 cm-1. For the cocrystal (bes)(dmn) the corresponding absorption is significantly blue-shifted, to 3377 cm-1, tentatively reflecting the distortion of the host structure compared to that found in (bes)(phe), (bes)(phn) and (bes)(bhq).

Page 8 of 13

Conclusions The presented study reveals how minor changes in the molecular structure of a steroid can bring about pronounced changes to its solid-state complexation. Replacement of 17-hydroxyl group in β-estradiol with a keto group in estrone completely shuts off the ability to form cocrystals with herein explored arenes. Whereas the sensitivity of crystal packing to molecular structure is a wellknown property of molecular solids,123-125 such an extreme difference in cocrystallization propensity is unexpected. Crystal structure determination suggests that the difference may be traced to a reduced hydrogen-bonding ability of estrone, which prevents the formation of a threedimensional hydrogen-bonded framework. However, in the light of the earlier cocrystallization and structural investigation,27 which noted the outstanding propensity of progesterone for solid-state complexes with arenes, the present study may also indicate that fine differences in molecular structures of steroids, which are considered central to their biological roles, are reflected and perhaps even augmented in the solid state. Such a view would be in further support of using cocrystallization screening as means to detect biologically relevant differences between apparently similar steroids. Estrone shows almost no propensity to form cocrystals, except with perfluorinated naphthalene which yields arene···perfluoroarene stacks involving the phenol section of the steroid. In contrast, βestradiol readily formed cocrystals with most herein explored arenes. Unlike progesterone, where cocrystallization with arenes was traced to a discrete motif of molecular recognition,27 cocrystallization of β-estradiol is based on forming a particular extended host structure. In that respect, β-estradiol cocrystals are reminescent of the inclusion behavior of cholic acid and derivatives.126-140 However, whereas bile acids show little selectivity in inclusion behavior,141-143 cocrystallization of β-estradiol so far appears limited27 to molecules of a particular size and shape.144-146 The β-estradiol lattice host is not rigid and its shape can be distorted to fit a particular guest, as seen by comparing structures of cocrystals with phenanthrene and 1,2-dimethylnaphthalene. Outcomes of this mechanochemical and structural study may also have pharmaceutical significance, by providing the first guidelines for developing new solid forms of the explored steroids. While the structures of βestradiol cocrystals give clear geometrical guidelines for selecting suitable cocrystal formers, the cocrystal (est)(pfn) is particularly important as the first reported multi-component crystal of estrone. We are currently working on expanding our solid-state molecular recognition screening procedure to further steroid architectures.

AUTHOR INFORMATION Figure 11. Selected FTIR-ATR spectra for cocrystallization of bes: (a) starting material bes·½H2O; (b) (bes)(phe); (c) (bes)(phn); (d) (bes)(bhq) and (e) (bes)(dmn). The most significant differences in the spectra are highlighted.

Corresponding Author * Tomislav Friščić, Department of Chemistry and FRQNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke St. W., H3A 0B8 Montreal, Canada. E-mail: [email protected]


Page 9 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENT We acknowledge Prof. D. S. Bohle for aid in obtaining single crystal X-ray diffraction and Dr F. Morin for help in acquiring 13 solid-state C NMR data. D.T. acknowledges financial support of the Tak-Hing (Bill) and Christina Chan Graduate Fellowship and the NSERC CREATE program in Green Chemistry. Authors are grateful for support by the NSERC Discovery Grant program, the Canada Foundation for Innovation Leader's Opportunity Fund, and the FRQNT Nouveaux Chercheurs program. V.A. and M.T.D acknowledge the Portuguese Foundation for Science and Technology for funding (PTDC/CTM-BPC/122447/2010, RECI/QEQ-QIN/0189/2012, PEst-OE/QUI/UI0100/2013, and SFRH/BPD/78854/2011).

SUPPORTING INFORMATION AVAILABLE Crystallographic data in CIF format (CCDC deposition numbers 1036412 to 1036415), selected PXRD, FTIR-ATR and thermal analysis data. This material is available free of charge via the Internet at http://pubs.acs.org.

REFERENCES 1 Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W. Nature, 2009, 457, 219-224. 2 Goldstein, R. A.; Katzenellenbogen, J. A.; Luthey-Schulten, Z. A.; Seielstad, D. A.; Wolynes, P. G. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9949-9953. 3 Williams, S. P.; Sigler, P. B. Nature 1998, 393, 392-396. 4 Jin, L.; Li, Y. Adv. Drug Del. Rev. 2010, 62, 1218-1226. 5 Baker, M. E. Biochem. Pharmacol. 2011, 82, 1-8. 6 Nilsson, S.; Koehler, K. F.; Gustafsson, J.-Å. Nature Rev. Drug Disc. 2011, 10, 778-792. 7 Eick, G. N.; Thornton, J. W. Mol. Cell. Endocrin. 2011, 334, 3138. 8. Yang, C.; Li, Q.; Li, Y. Mar. Drugs 2014, 12, 601-635. 9 Obr, A. E.; Edwards, D. P. Mol. Cell. Endocrin. 2012, 357, 4-17. 10 Mordasini, T.; Curioni, A.; Bursi, R.; Andreoni, W. ChemBioChem 2003, 4, 155-161. 11 Burris, T. P.; Solt, L. A.; Wang, Y.; Crumbley, C.; Banerjee, S.; Griffett, K.; Lundasen, T.; Hughes, T.; Kojetin, D. J. Pharmacol. Rev. 2013, 65, 710-778. 12 Katzenellenbogen, J. A.; Muthyala, T.; Katzenellenbogen, B. S. Pure Appl. Chem. 2003, 75, 2397-2403. 13 Tannenbaum, D. M.; Wang, Y.; Williams, S. P.; Sigler, P. B. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 5998-6003. 14 Brzozowski, A. M.; Pike, A. C. W.; Dauter, Z.; Hubbard, R. E.; Bonn, T.; Engström, O.; Öhman, L.; Greene, G. L.; Gustafsson, J.-Å.; Carlquist, M. Nature, 1997, 389, 753-758. 15 Ayan, D.; Roy, J.; Maltais, R.; Poirier, D. J. Steroid Biochem. Mol. Biol. 2011, 127, 324-330. 16 Hill, K. K.; Roemer, S. C.; Churchill, M. E. A.; Edwards, D. P. Mol. Cell. Endocrin. 2012, 348, 418-429. 17 Zhu, M.; Zhang, C.; Nwachukwu, J. C.; Srinivasan, S.; Cavett, V.; Zheng, Y.; Carlson, K. E.; Dong, C.; Katzenellenbogen, J. A.; Nettles, K. W.; Zhou, H.-B. Org. Biomol. Chem. 2012, 10, 86928700. 18 Min, J.; Wang, P.; Srinivasan, S.; Nwachukwu, J. C.; Guo, P.; Huang, M.; Carlson, K. E.; Katzenellenbogen, J. A.; Nettles, K. W.; Zhou, H.-B. J. Med. Chem. 2013, 56, 3346-3366.

19 Liao, Z.-Q.; Dong, C.; Carlson, K. E.; Srinivasan, S.; Nwachukwu, J. C.; Chestnut, R. W.; Sharma, A.; Nettles, K. W.; Katzenellenbogen, J. A.; Zhou, H.-B. J. Med. Chem. 2014, 57, 35323545. 20 Colucci, J. K.; Ortlund, E. A. PLOS One 2013, 8, e80761. 21 Lusher, S. J.; Raaijmakers, H. C. A.; Vu-Pham, D.; Kazemier, B.; Bosch, R.; McGuire, R.; Azevedo, R. ; Hamersma, H.; Dechering, K.; Oubrie, A.; van Duin, M.; de Vlieg, J. J. Biol. Chem. 2012, 287, 20333-20343. 22 Lusher, S. J.; Raaijmakers, H. C. A.; Vu-Pham, D.; Dechering, K.; Lam, T. W.; Brown, A. R.; Hamilton, N. M.; Nimz, O.; Bosch, R.; McGuire, R.; Oubrie, A.; de Vlieg, J. J. Biol. Chem. 2011, 286, 35079-35086. 23 Madauss, K. P.; Grygielko, E. T.; Deng, S.-J.; Sulpizio, A. C.; Stanley, T. B.; Wu, C.; Short, S. A.; Thompson, S. K.; Stewart, E. L.; Laping, N. J.; Williams, S. P.; Bray, J. D. Mol. Endocrin. 2007, 21, 1066-1081. 24 Rachwal, S.; Pop, E.; Brewster, M. E. Steroids, 1996, 61, 524530. 25 Päivärinta, J. T.; Poso, A. T.; Hotokka, M.; Muttonen, E. Cryst, Growth Des. 2002, 2, 121-126. 26 Duax, W. L.; Griffin, J. F.; Rohrer, D. C.; Swenson, D. C.; Weeks, C. M. J. Steroid Biochem. 1981, 15, 41-47. 27 Friščić, T.; Lancaster, R. W.; Fábián, L.; Karamertzanis, P. G. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 13216-13221. 28 James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friščić, T.; Grepioni, F.; Harris, K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse, W. C.; Steed, J. W.; Waddell, D. C. Chem. Soc. Rev. 2012, 41, 413-447. 29 Braga, D.; Giaffreda, S. L.; Grepioni, F.; Pettersen, A.; Maini, L.; Curzi, M.; Polito, M. Dalton Trans. 2006, 1249-1263. 30 Braga, D.; Maini, L.; Grepioni, F. Chem. Soc. Rev. 2013, 42, 7638-7648. 31 Boldyreva, E. Chem. Soc. Rev. 2013, 42, 7719-7738. 32 Etter, M. C. J. Phys. Chem. 1991, 95, 4601-4610. 33 Etter, M. C.; Urbañczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415-8426. 34 Etter, M. C.; Reutzel, S. M. J. Am. Chem. Soc. 1991, 113, 25862598. 35 Chand, B. J. Chem. Crystallogr. 2011, 41, 1901-1926. 36 Duax, W. L.; Griffin, J. F.; Rohrer, D. C. J. Am. Chem. Soc. 1981, 103, 6705-6712. 37 Duax, W. L.; Ghosh, D.; Pletnev, V.; Griffin, J. F. Pure Appl. Chem. 1996, 68, 1297-1302. 38 Lancaster, R. W.; Karamertzanis, P. G.; Hulme, A. T.; Tocher, D. A.; Covey, D. F.; Price, S. L. Chem. Commun. 2006, 4921-4923. 39 Lancaster, R. W. ; Karamertzanis, P. G.; Hulme, A. T.; Tocher, D. A.; Lewis, T. C.; Price, S. L. J. Pharm. Sci. 2007, 96, 3419-3431. 40 Anthony, A.; Jaskólski, M.; Nangia, A. Acta Cryst, 1999, C55, 787-789. 41 Anthony, A.; Jaskólski, M.; Nangia, A. Acta Cryst, 2000, B56, 512-525. 42 Bertolasi, V.; Ferretti, V.; Pretto, L.; Fantin, G.; Fogagnolo, M.; Bortolini, O. Acta Cryst. 2005, B61, 346-356 43 Fábián, L.; Argay, G.; Kálmán, A.; Báthori, M. Acta Cryst, 2002, B58, 710-720. 44 Fábián, L.; Argay, G.; Kálmán, A. Acta Cryst, 1999, B55, 788792. 45 Takata, N.; Shiraki, K.; Takano, R.; Hayashi, Y.; Terada, K. Cryst. Growth Des. 2008, 8, 3032-3037. 46 Springuel, G.; Robeyns, K.; Norberg, B.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2014, 14, 3996-4004. 47 Tilborg, A.; Springuel, G.; Norberg, B.; Wouters, J.; Leyssens, T. Cryst. Growth Des. 2014, 14, 3408-3422.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

48 Parini, C.; Colombi, S.; Casnati, A. J. Incl. Phen. Mol. Rec. Chem. 1994, 18, 341-351 49 Hisaki, I.; Murai, T.; Yabaguchi, H.; Shigemitsu, H.; Tohnai, N.; Miyata, M. Cryst. Growth Des. 2011, 11, 4652-4659. 50 Eger, C.; Norton, D. A. Nature 1965, 208, 997-999. 51 Bhat, P. M.; Desiraju, G. R. CrystEngComm 2008, 10, 17471749. 52 Weeks, C. M.; Rohrer, D. C.; Duax, W. L. Science 1975, 190,1096-1097. 53 Blaustein, J. D. Endocrinology 2008, 149, 2697-2698. 54 Friščić, T. Chem. Soc. Rev. 2012, 41, 3493-3510. 55 Friščić, T.; Jones, W. Cryst. Growth Des. 2009, 9, 1621-1637. 56 Biradha, K.; Santra, R. Chem. Soc. Rev. 2013, 42, 950. 57 Aakeröy, C. B.; Champness, N. R.; Janiak, C. CrystEngComm 2010, 12, 22-43 58 Aakeröy, C. B. Acta Cryst. 1997, B53, 569-586. 59 Moulton, B.; Zaworotko, M. J. Chem. Rev. 2001, 101, 16291658. 60 Desiraju, G. R. Acc. Chem. Res. 2002, 35, 565-573. 61 Biradha, K. CrystEngComm 2003, 5, 374-384. 62 Soldatov, D. V.; Terekhova, I. S. J. Struc. Chem. 2005, 46, S1S8. 63 Desiraju, G. R. Angew. Chem. Int. Ed. 2007, 46, 8342-8356. 64 Tiekink, E. R. Chem. Commun. 2014, 50, 11079-11082. 65 Shan, N.; Perry, M. L.; Weyna, D. R.; Zaworotko, M. J. Expert Opin. Drug Metab. Toxic. 2014, 10, 1255-1271. 66 Delori, A.; Friščić, T.; Jones, W. CrystEngComm 2012, 14, 2350-2362. 67 Brittain, H. G. J. Pharm. Sci. 2013, 102, 311-317. 68 Weyna, D. R.; Cheney, M. L.; Shan, N.; Hanna, M.; Wojtas, Ł.; Zaworotko, M. J. CrystEngComm 2012, 14, 2377-2380. 69 Friščić, T.; Jones, W. J. Pharm. Pharmacol. 2010, 62, 15471559. 70 Trask, A. V. Mol. Pharm. 2007, 4, 301-309. 71 Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Int. J. Pharm. 2011, 419, 1-11. 72 Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodríguez-Hornedo, N. Int. J. Pharm. 2013, 453, 101-125. 73 Tilborg, A.; Norberg, B.; Wouters, J. Eur. J. Med. Chem. 2014, 74, 411-426. 74 Kim, J. H.; Hubig, S. M.; Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2001, 123, 87-95. 75 Kim, J. H.; Lindeman, S. V.; Kochi, J. K. J, Am. Chem. Soc. 2001, 123, 4951-4959. 76 Friščić, T.; Drab, D. M. ; MacGillivray, L. R. Org. Letters, 2004, 6, 4647-4650. 77 Khorasani, S.; Fernandes, M. A. Cryst. Growth Des. 2013, 13, 5499-5505. 78 Black, H. T.; Perepichka, D. F. Angew. Chem. Int. Ed. 2014, 53, 2138-2142. 79 Hutchins, K. M.; Dutta, S.; Loren, B. P.; MacGillivray, L. R. Chem. Mater. 2014, 26, 3042-3044. 80 Ghorai, S.; Sumrak, J. C.; Hutchins, K. M.; Bučar, D.-K.; Tivanski, A. V.; MacGillivray, L. R. Chem. Sci. 2013, 4, 4304-4308. 81 Bushuyev, O. S.; Corkery, T. C.; Barrett, C. J.; Friščić, T. Chem. Sci. 2014, 5, 3158-3164. 82 Atkinson, M. B. J.; Mariappan, S. V. S.; Bučar, D.-K.; Baltrusaitis, J.; Friščić, T.; Sinada, N. G.; MacGillivray, L. R. Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 10974-10979. 83 Liu, P.-H.; Curtis, S. M.; Webb, J. A.; Fowler, F. W.; Lauher, J. W. Org. Lett. 2004, 6, 2081-2083. 84 Etter, M. C.; Baures, P. W. J. Am. Chem. Soc. 1988, 110, 639640. 85 Aakeröy, C. B.; Chopade, P. D.; Ganser, C.; Desper, J. Chem. Commun. 2011, 47, 4688-4690. 86 Aakeröy, C. B.; Wijethunga, T. K.; Haj, M. A.; Desper, J.; Moore, C. CrystEngComm 2014, 16, 7218-7225.

Page 10 of 13

87 Aakeröy, C. B.; Baldrighi, M.; Desper, J.; Metrangolo, P.; Resnati, G. Chem. Eur. J. 2013, 19, 16240-16247. 88 Shan, N.; Batchelor, E.; Jones, W. Tetrahedron Lett. 2002, 43, 8721-8725. 89 Etter, M. C.; Adsmond, D. A. Chem. Commun. 1990, 589591. 90 Užarević, K.; Halasz, I.; Đilović, I.; Bregović, N.; Rubčić, M.; Matković-Čalogović, D.; Tomišić, V. Angew. Chem. Int. Ed. 2013, 52, 5504-5508. 91 Caira, M. R.; Nassimbeni, L. R.; Wildervanck, A. F. J. Chem. Soc. Perkin Trans. 2, 1995, 2213-2216. 92 Eddleston, M. D.; Arhangelskis, M.; Friščić, T.; Jones, W. Chem. Commun. 2012, 48, 11340-11342. 93 Friščić, T.; Childs, S. L.; Rizvi, S. A. A.; Jones, W. CrystEngComm 2009, 11, 418-426. 94 Weyna, D. R.; Shattock, T.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2009, 9, 1106-1123. 95 Childs, S. L.; Rodríguez-Hornedo, N.; Reddy, L. S.; Jayasankar, A.; Maheshwari, C.; McCausland, L.; Shipplett, R.; Stahly, B. C. CrystEngComm 2008, 10, 856-864. 96 Whereas mechanochemical cocrystallization has been demonstrated superior to solution- or melt-based alternatives,9395 it was recently demonstrated that outcomes of mechanochemical cocrystal screening can be affected by kinetic, nucleation effects, see references 97 and 98. 97 Bučar, D.-K.; Day, G. M.; Halasz, I.; Zhang, G. G. Z.; Sander, J. R. G.; Reid, D. G.; MacGillivray, L. R.; Duer, M. J.; Jones, W. Chem. Sci. 2013, 4, 4417-4425. 98 Bučar, D.-K.; Henry, R. F.; Lou, X.; Borchardt, T. B.; Zhang, G. G. Z. Chem. Commun. 2007, 525-527. 99 Examples of commercial drugs that include est as the active ingredient are Estragyn®, Hormonin®, while bes is the active component of a number of products, e.g. Alora®, Climara®, Hormonin®, Minivelle®. 100 Duer, M. J. Introduction to Solid-State NMR Spectroscopy, Blackwell Publishing, Oxford (2008). 101 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J.; Gaussian 09, revision D.01, Gaussian, Inc.: Wallingford, CT, 2009. 102 Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. 103 Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785789. 104 Ditchfield, R.; Hehre, W. J.; Pople, J. A., J. Chem. Phys. 1971, 54, 724-728. 105 GaussView, Version 5, Dennington, R.; Keith, T.; Millam, J.; Semichem Inc., Shawnee Mission, KS, 2009. 106 Debaerdemaeker, T. D. J. Cryst. Struc. Commun. 1972, 1, 39. 107 Busetta, B.; Courseille, C.; Hospital, M. Acta Cryst. 1973, B29, 298-313. 108 Shikii, K.; Sakamoto, S.; Seki, H.; Utsumi, H.; Yamaguchi, K. Tetrahedron 2004, 60, 3487-3492.


Page 11 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


109 Bacchi, S.; Benaglia, M.; Cozzi, F.; Demartin, F.; Filippini, G.; Gavezzotti, A. Chem. Eur. J. 2006, 12, 3538-3546. 110 Loader, J. R.; Libri, S.; Meijer, A. J. H. M.; Perutz, R. N.; Brammer, L. CrystEngComm 2014, 16, 9711-9720. 111 Dunitz, J. D.; Gavezzotti, A. Cryst. Growth Des. 2012, 12, 5873-5877. 112 Patrick, C. R.; Prosser, G. S. Nature 1960, 187, 1021. 113 Coates, G. W.; Dunn, A. R.; Henling, L. M.; Dougherty, D. A.; Grubbs, R. H. Angew. Chem. Int. Ed. Eng. 1997, 36, 248-251. 114 Coates, G. W.; Dunn, A. R.; Henling, L. M.; Ziller, J. W.; Lobkovsky, E. B.; Grubbs, R. H. J. Am. Chem. Soc. 1998, 120, 36413649. 115 Reichenbächer, K.; Süss, H. I.; Hulliger, J. Chem. Soc. Rev. 2005, 34, 22-30. 116 Vishweshwar, P.; Nangia, A.; Lynch, V. M. CrystEngComm 2003, 5, 164-168. 117 Sarma, B.; Sreenivas Reddy, L.; Nangia, A. Cryst. Growth Des. 2008, 8, 4546-4552. 118 Bučar, D.-K.; Henry, R. F.; Zhang, G. G. Z.; MacGillivray, L. R. Cryst. Growth Des. 2014, 14, 5318-5328. 119 Sokolov, A. N.; Friščić, T.; Blais, S.; Ripmeester, J. A.; MacGillivray, L. R. Cryst. Growth Des. 2006, 6, 2427-2428. 120 Lemmerer, A.; Adsmond, D. A.; Esterhuysen, C.; Bernstein, J. Cryst. Growth Des. 2013, 13, 3935-3952. 121 Huang, K.-S.; Britton, D.; Etter, M. C.; Byrn, S. R. J. Mater. Chem. 1997, 7, 713-720. 122 For a previous solid-state NMR study of β-estradiol, see: Li, G.-C.; Wang, D.-R.; Chen, W.; Tzou, D.-L. M. Steroids, 2012, 77, 185-192. 123 Desiraju, G. R. Angew. Chem. Int. Ed. 1995, 34, 2311-2327. 124 Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647-678. 125 Kitaigorodskii, A. I. Molecular Crystals and Molecules, Academic Press, London (1973). 126 Miyata, M.; Tohnai, N.; Hisaki, I. Acc. Chem. Res. 2007, 40, 694-702. 127 Tomašić, V.; Štefanić, Z. CrystEngComm 2007, 9, 1124-1128. 128 Oguchi, T.; Tozuka, Y.; Hanawa, T.; Mizutani, M.; Sasaki, N.; Limmatvapirat, S.; Yamamoto, K. Chem. Pharm. Bull. 2002, 50, 887-891. 129 Szyrszyng, M.; Nowak, E.; Gdaniec, M.; Milewska, M. J.; Połonski, T. Tetrahedron: Asymmetry 2004, 15, 103-107.

130 Caira, M. R.; Nassimbeni, L. R.; Scott, J. L. J. Chem. Cryst. 1994, 24, 783-791. 131 Caira, M. R.; Nassimbeni, L. R.; Scott, J. L. J. Chem. Soc. Perkin Trans. 2, 1994, 1403-1405. 132 Bertolasi, V.; Bortolini, O.; Fantin, G.; Fogagnolo, M.; Pretto, L. Tetrahedron: Asymmetry 2006, 17, 308-312. 133 Caira, M. R.; Nassimbeni, L. R.; Scott, J. L. J. Chem. Soc. Perkin Trans. 2, 1994, 623-628. 134 Shibakami, M.; Tamura, M.; Sekiya, A. J. Am. Chem. Soc. 1995, 117, 4499-4505. 135 Natarajan, R.; Bridgland, L.; Sirikulkajorn, A.; Lee, J.-H.; Haddow, M. F.; Magro, G.; Ali, B.; Narayanan, S.; Strickland, P.; Charmant, J. P. H.; Orpen, A. G.; McKeown, N. B.; Bezzu, C. G.; Davis, A. P. J. Am. Chem. Soc. 2013, 135, 16912-16925. 136 Yoswathananont, N.; Sada, K.; Nakano, K.; Aburaya, K.; Shigesato, M.; Hishikawa, Y.; Tani, K.; Tohnai, N.; Miyata, M. Eur. J. Org. Chem. 2005, 5330-5338. 137 Nakano, K.; Sada, K.; Miyata, M. Polymer J. 2001, 33, 172176. 138 Nakano, K.; Sada, K.; Aburaya, K.; Nakagawa, K.; Yoswathananont, N.; Tohnai, N.; Miyata, M. CrystEngComm 2006, 8, 461-467. 139 Ikonen, S.; Kolehmainen, E. CrystEngComm 2010, 12, 43044311. 140 Scott, J. L. J. Chem. Soc. Perkin Trans 2, 1995, 495-502. 141 Herbstein, F. H. Crystalline Molecular Complexes and Compounds, Vol. 1, 272-291, Oxford University Press, Oxford (2005). 142 Miyata, M.; Sada, K. Deoxycholic acid and related hosts in: Comprehensive Supramolecular Chemistry, Ed. J. L. Atwood, J. E. D. Davies, D. D. MacNicol and F. Vögtle, Pergamon, Oxford, 147176 (1996). 143 Bishop, R. Chem. Soc. Rev. 1996, 311-319. 144 No structures of bile acid inclusion compounds involving pyrene or anthracene have been reported in the CSD. CSD contains two structures with phenanthrene as a guest in lattice inclusion compounds of dexycholic acid (CSD DCPHEN) and ursodeoxycholic acid (CSD IMENIX), see references 145 and 146. 145 Fukami, T.; Yamaguchi, K.; Tozuka, Y.; Moribe, K.; Oguchi, T.; Yamamoto, K. Chem. Pharm. Bull. 2003, 51, 227-229. 146 Candeloro de Sanctis, S.; Giglio, E.; Pavel, V.; Quagliata, C. Acta Cryst. 1972, B28, 3656-3661.



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 13

For table of contents use only Title: Molecular recognition of steroid hormones in the solid state: stark differences in cocrystallization of β-estradiol and estrone Authors: Karen J. Ardila-Fierro, Vânia André, Davin Tan, M. Teresa Duarte, Robert W. Lancaster, Panagiotis G. Karamertzanis, Tomislav Friščić*

SYNOPSIS. Screening for cocrystals of hormones ß-estradiol and estrone reveals that minor changes to their structure, such as switching from 17-hydroxyl to a 17-keto group, can almost entirely shut off the steroid’s ability to cocrystallize with arenes. Such sensitivity of cocrystallization to molecular structure suggests that solid-state behavior of steroids can mirror their highly specialized molecular recognition properties in biological systems.


12

Page 13 of 13

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC graphics


Molecular Recognition of Steroid Hormones in ... - ACS Publications

Recommend Documents