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Supplementary Crystallographic Information for
“Towards understanding P-gp resistance: a case study of the
antitumour drug cabazitaxel”
Ulrich Baisch 1,2 and Liana Vella-Zarb*,1,2
1Department of Chemistry, University of Malta, Msida, Malta
MSD2080. 2School of Chemistry, Bedson Building, Newcastle
University, NE1 7RU, Newcastle-upon-Tyne,
United Kingdom.
E-mail: [email protected] and
[email protected]
The following tables contain methods and crystallographic
information as well as atom coordinates and the main inter- and
intramolecular interactions of various cabazitaxel structures.
Scheme 1 shows the common numbering scheme applied to each of the
cabazitaxel molecules. Where two molecules are situated in the
asymmetric unit, the corresponding number plus 100 was used (e.g.
atom C22 in one molecule is atom C122 in the other molecule in the
asymmetric unit).
Electronic Supplementary Material (ESI) for CrystEngComm.This
journal is © The Royal Society of Chemistry 2014
mailto:[email protected]:[email protected]
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Scheme S1: Numbering scheme for cabazitaxel
Figure S1: Structure figure for anhydrous cabazitaxel (CCDC
structure 940083). The probability for non-hydrogen spheroids is
50%. Hydrogen atoms were refined isotropically and are depicted
with a radius of 0.07 Å.
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Figure S2: Structure figure for cabazitaxel hemihydrate (CCDC
structure 940084). The probability for
non-hydrogen spheroids is 50%. Hydrogen atoms were refined
isotropically and are depicted with a radius of 0.07 Å.
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Figure S3: Structure figure for cabazitaxel hemihydrate ethanol
solvate (CCDC structure 940085). The probability for non-hydrogen
spheroids is 50%. Hydrogen atoms were refined isotropically and are
depicted with a radius of 0.07 Å.
Figure S4: Structure figure for cabazitaxel THF solvate (CCDC
structure 940086). The probability for non-hydrogen spheroids is
50%. Hydrogen atoms were refined isotropically and are depicted
with a radius of 0.07 Å.
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Figure S5: Structure figure for cabazitaxel acetone solvate
(CCDC structure 940087). The probability for non-hydrogen spheroids
is 50%. Hydrogen atoms were refined isotropically and are depicted
with a radius of 0.07 Å.
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Methods
In order to obtain suitable single crystals, 0.020g of
cabazitaxel were dissolved in about 1 ml of solvent at room
temperature. 1 ml of water was then added carefully, ensuring that
cabazitaxel remained completely dissolved. This was repeated with a
variety of solvents and solvent mixtures. In six of the samples,
slow evaporation of the solvent mixture over a number of days
resulted in the formation of crystals suitable for data
collection.
Single crystal X-ray diffraction data were collected at Station
I19 at Diamond Light Source on a Rigaku Saturn724+ diffractometer
at a temperature of 120K. SADABS-2008/119 was used for absorption
correction. The structure was solved by direct methods and refined
on all unique F2 values, with anisotropic non-H atoms and
constrained riding isotropic H atoms. Even though all compounds
crystallised in the non-centrosymmetric space group P21, Flack
parameters did not result in meaningful values because of the short
wavelength used to collect the data (synchrotron radiation, λ =
0.6889Å) and the absence of heavy atoms in the structure. The
crystal structure of cabazitaxel hemihydrate ethanol solvate (CCDC
940085) can also be refinement in the orthorhombic space group
P212121. However, the original monoclinic cell setting was retained
because of the following reasons: i) the R(int) is lower for the
monoclinic cell setting, ii) standard deviation of the β angle of
the cell parameters is too low to add up to 90°, ii) the heavily
disordered ethanol solvent molecules refine better in the
monoclinic cell setting.The software used was Rigaku CrystalClear
for data collection, APEX220 for integration and absorption
correction, OLEX221or SHELXTL22 for structure solution and
refinement, and DIAMOND23 for graphics.
Temperature-resolved X-ray powder diffraction measurements were
carried out on a STOE Stadi P diffractometer equipped with a
position sensitive detector. Temperatures ranged from 50oC to 130oC
at 20o increments. Each measurement covered a range of 2˚ to 70˚
along 2θ in steps of 0.010˚ over 6 hours.
Structure refinement of powder data was carried out using the
programs TOPAS 4.124 and DASH 3.3.125. Powder diffraction patterns
were indexed independently with the singular value decomposition
method as implemented within TOPAS26. The peak profile and precise
lattice parameters were determined by Le Bail fits27 using the
fundamental parameter (FP) approach of TOPAS28. The crystal
structure of cabazitaxel ethanol solvate was refined against the
single crystal structure obtained from synchrotron data using
DASH25. For the final Rietveld refinement, all profile and lattice
parameters were released and all atomic positions were subjected to
refinement using soft bond and angle constraints.
Final agreement factors (R-values) and full crystallographic
experimental details are provided in the following tables, together
with a list of bond distances and angles.
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Table S1: Numerical differences arising from Hirshfeld surface
analyses.
Compound Curvedness Shape IndexMolecularVolume /Å3 Min Max Mean
Min Max Mean
Paclitaxel 1141.5 -4.1519 0.438 -1.0127 -0.999 0.9989
0.1543Docetaxel 1060.74 -4.4925 0.506 -1.018 -0.995 0.996
0.1512Cabazitaxel 1010.97 -3.5757 0.504 -0.9653 -0.999 0.9976
0.1625
Table S2: Selected bond distances and torsion angles.
1 2 3 4 5C17 – C61 /Å C17-C15
···C47-N54 /°C2-C47 /Å O25-C2
···C47-N54 /°Centroids /Å
Cabazi Anh 4.705(2) 7.0(10) 6.932(2) 119.1(10) 8.430(2)Cabazi
Anh 4.510(2) -9.0(9) 6.876(2) 101.5(8) 9.509(2)Cabazi Hemi 4.70(2)
-8.2(10) 7.041(19) -120.7(10) 8.551(4)Cabazi Hemi 4.80(2) 11.2(9)
7.064(16) -102.2(8) 9.543(4)Cabazi THF 5.66(2) -42.7(5) 6.95(1)
66.1(5) 10.152(3)Cabazi Acet 5.839(6) -43.72(16) 7.020(3) 64.75(15)
10.242 (1)Cabazi EtW 7.49(1) -44.7(3) 7.146(6) 65.1(3)
10.715(1)Cabazi EtW 7.494(9) -44.9(3) 7.146(6) 65.3(3)
10.710(1)
Doce Anh 6.608(1) -28.06(1) 6.856(1) 56.09(1) 8.933(1)Doce EtW
7.524(5) -45.43(17) 7.117(3) 63.91(16) 10.709(2)Doce Tri 7.491(9)
-44.8(3) 7.094(5) 64.0(2) 10.720(2)
Pacli Anh -NA- -145(2) 8.26(3) 94(2) 10.576(1)Pacli Anh -NA-
-158(4) 7.49(3) 32(2) 5.978(1)Pacli Dihy -NA- -167.3(14) 8.13(2)
-52.9(11) 10.720(5)Pacli Dihy -NA- 171(2) 7.53(2) -56.3(14)
5.955(3)Pacli Hemi -NA- -179.2(14) 8.301(15) 37.8(11)
11.079(1)Pacli Hemi -NA- 178(2) 7.565(15) 38.8(13) 6.174(1)
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Table S3: Chemical, crystallographic and refinement parameters
of cabazitaxel anhydrous, hemihydrate and hemihydrate ethanol
solvate obtained by single-crystal diffraction using synchrotron
radiation.
Cabazitaxel anhydrous
Cabazitaxelhemihydrate
CabazitaxelHemihydrate ethanol
CCDC deposition number CCDC 940083 CCDC 940084 CCDC
940085Empirical formula C45H57NO14 C45H57.5NO14.25
C47H63NO15.5Formula weight /g mol-1 835.91 840.42 889.15Data
collection
Temperature/K 120.15 120.15 120.15Crystal system monoclinic
monoclinic monoclinicSpace group P21 P21 P21a/Å 8.351(3) 8.506(5)
12.542(2)b/Å 44.438(17) 45.16(2) 8.6716(16)c/Å 11.410(4) 11.675(6)
42.090(8)α/° 90 90 90β/° 98.532(5) 98.362(4) 89.987(2)γ/° 90 90
90Volume/Å3 4187(3) 4438(4) 4577.7(14)Z 4 4 4ρcalcmg/mm3 1.326
1.258 1.291m/mm1 0.092 0.088 0.090F(000) 1784.0 1794.0
1904.0Crystal size/mm3 0.1 × 0.03 × 0.001 0.12 × 0.09 × 0.02 0.2 ×
0.05 × 0.0012Θ range for data collection 1.776 to 48.442° 5.246 to
49.444° 1.876 to 49.726°
Index ranges-8 ≤ h ≤ 9, -52 ≤ k ≤ 52, -13 ≤ l ≤ 1
-10 ≤ h ≤ 10, -47 ≤ k ≤ 53, -9 ≤ l ≤ 1
-15 ≤ h ≤ 15, -8 ≤ k ≤ 10, -51 ≤ l ≤ 51
RefinementReflections collected 30848 20627 36815
Independent reflections 14114[R(int) = 0.0938] 11168[R(int) =
0.0698]
15163[R(int) = 0.0315]
Data/restraints/parameters 14114/1/1106 11168/1/1118
15163/2/1281Goodness-of-fit on F2 1.051 1.034 1.101
Final R indexes [I>=2σ (I)] R1 = 0.0989, wR2 = 0.2557 R1 =
0.1002, wR2 = 0.2622
R1 = 0.0549, wR2 = 0.1430
Final R indexes [all data] R1 = 0.1306, wR2 = 0.2760 R1 =
0.1349, wR2 = 0.2838
R1 = 0.0575,wR2 = 0.1456
Largest diff. peak/hole / e Å-3 0.53/-0.38 0.41/-0.27
0.37/-0.27
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Table S4 Chemical, crystallographic and refinement parameters of
cabazitaxel THF solvate and acetone solvate obtained by
single-crystal diffraction using synchrotron radiation.
Cabazitaxel THF solvate
Cabazitaxelacetone solvate
CCDC deposition number CCDC 940086 CCDC 940087Empirical formula
C45H57NO14 C48H63NO15Formula weight /g mol-1 908.03 893.99Data
collectionTemperature/K 120.15 120.15Crystal system monoclinic
monoclinicSpace group P21 P21a/Å 11.778(5) 11.725(2)b/Å 17.208(7)
17.328(3)c/Å 12.339(5) 12.449(2)α/° 90 90β/° 109.747(5)
110.453(2)γ/° 90 90Volume/Å3 2353.6(18) 2369.9(7)Z 2 2ρcalcmg/mm3
1.180 1.253m/mm1 0.082 0.087F(000) 892.0 956.0Crystal size/mm3 0.1
× 0.05 × 0.001 0.2 × 0.05 × 0.0012Θ range for data collection 4.102
to 51.746° 4.08 to 51.318°
Index ranges-14 ≤ h ≤ 14, -21 ≤ k ≤ 17,-14 ≤ l ≤ 15
-14 ≤ h ≤ 14, -19 ≤ k ≤ 21, -15 ≤ l ≤ 15
RefinementReflections collected 17853 20833
Independent reflections 8370[R(int) = 0.0762] 9446[R(int) =
0.0273]
Data/restraints/parameters 8370/1/635 9446/1/612Goodness-of-fit
on F2 1.126 1.032
Final R indexes [I>=2σ (I)] R1 = 0.0869, wR2 = 0.1698 R1 =
0.0317, wR2 = 0.0805
Final R indexes [all data] R1 = 0.1093 wR2 = 0.1789 R1 = 0.0334,
wR2 = 0.0817
Largest diff. peak/hole / e Å-3 0.28/-0.23 0.26/-0.18
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Table S5: Hydrogen Bonds for anhydrous cabazitaxel.
D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/°O146 H146 O38 0.84 2.10
2.861(12) 150.7O22 H22 O361 0.84 2.10 2.878(13) 154.8
O122 H122 O1362 0.84 2.05 2.818(10) 152.6
1-1+X,+Y,+Z; 21+X,+Y,+Z
Table S6: Hydrogen Bonds for cabazitaxel hemihydrate.
D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/°O146 H146 O38 0.84 2.18
2.877(12) 139.7O122 H122 O1361 0.84 2.18 2.893(10) 142.8O46 H46
O902 0.84 2.17 2.91(3) 147.9
11+X,+Y,+Z; 2-1-X,-1/2+Y,-Z
Table S7: Hydrogen Bonds for cabazitaxel hemihydrate ethanol
solvate.
D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/°O46 H46 O83A1 0.84 2.02
2.700(14) 137.6O122 H122 O1361 0.84 2.13 2.897(4) 151.3O93A H93A
O146 0.84 2.05 2.673(15) 130.6O101 H10H O24 0.87 1.98 2.596(11)
126.5
1+X,-1+Y,+Z
Table S8: Hydrogen Bonds for cabazitaxel THF solvate.
D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/°O46 H46 O44 0.84 2.12
2.619(10) 117.0O22 H22 O361 0.84 2.23 2.948(7) 144.0N54 H54 O212
0.88 2.26 3.050(6) 150.0
12-X,-1/2+Y,1-Z; 2X,Y,1+Z
Table S9: Hydrogen Bonds for cabazitaxel Acetone solvate.
D H A d(D-H)/Å d(H-A)/Å d(D-A)/Å D-H-A/°O46 H46 O44 0.84 2.27
2.676(3) 110.0O46 H46 O100 0.84 2.26 2.970(4) 143.0O22 H22 O361
0.84 2.27 3.009(2) 147.0N54 H54 O212 0.88 2.30 3.098(2) 151.0
11-X,-1/2+Y,-Z; 2X,Y,-1+Z;