research communications\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890

Crystal structure of 13-(E)-(2-amino­benzyl­­idene)parthenolide

CROSSMARK_Color_square_no_text.svg

aDept. of Pharm. Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA, and bDept. of Chemistry, University of Kentucky, Lexington KY 40506, USA
*Correspondence e-mail: pacrooks@uams.edu

Edited by J. Simpson, University of Otago, New Zealand (Received 12 September 2018; accepted 24 September 2018; online 9 October 2018)

The title compound, C21H25NO3 [systematic name: (1aR,4E,7aS,8E,10aS,10bR)-8-(2-amino­benzyl­idene)-1a,5-dimethyl-2,3,6,7,7a,8,10a,10b-octa­hydro­oxireno[2′,3′:9,10]cyclo­deca­[1,2-b]furan-9(1aH)-one], was synthesized by the reaction of parthenolide [systematic name (1aR,7aS,10aS,10bS,E)-1a,5-dimethyl-8-methyl­ene-2,3,6,7,7a,8,10a,10b-octa­hydro­oxireno[2′,3′:9,10]cyclo­deca­[1,2-b]furan-9(1aH)-one] with 2-iodo­aniline via Heck reaction conditions. The mol­ecule is composed of fused ten-, five- (lactone), and three-membered (epoxide) rings. The lactone ring shows a flattened envelope-type conformation (r.m.s. deviation from planarity = 0.0477 Å), and bears a 2-amino­benzyl­idene substituent that is disordered over two conformations [occupancy factors 0.901 (4) and 0.099 (4)]. The ten-membered ring has an approximate chair–chair conformation. The dihedral angle between the 2-amino­benzyl­idine moiety (major component) and the lactone ring (mean plane) is 59.93 (7)°. There are no conventional hydrogen bonds, but there are a number of weaker C—H⋯O-type inter­actions.

1. Chemical context

Sesquiterpene lactones (SLs) are a large family of natural products that have been widely investigated for their anti­cancer activity. Parthenolide (PTL), a naturally occurring germacranolide SL (Minnaard et al., 1999[Minnaard, A. J., Wijnberg, J. B. P. A. & de Groot, A. (1999). Tetrahedron, 55, 2115-2146.]) isolated from the feverfew plant (Tanacetum parthenium) (Knight, 1995[Knight, D. W. (1995). Nat. Prod. Rep. 12, 271-276.]), has unique biological properties and selectively targets leukemia stem cells (LSC) compared to normal hematopoietic stem cells (Guzman et al., 2005[Guzman, M. L., Rossi, R. M., Karnischky, L., Li, X., Peterson, D. R., Howard, D. S. & Jordan, C. T. (2005). Blood, 105, 4163-4169.]). PTL has been demonstrated to inhibit the NFkB pathway in LSCs, and also increases reactive oxygen species, and inhibits STAT3 (signal transduction and activation of transcription) (Mathema et al., 2012[Mathema, V. B., Koh, Y. S., Thakuri, B. C. & Sillanpää, M. (2012). Inflammation, 35, 560-565.]). Synthetic analogues of SLs are also excellent sources of novel chemical entities for drug discovery, and over the last decade have been developed as efficacious anti­cancer drugs (Ghantous et al., 2010[Ghantous, A., Gali-Muhtasib, H., Vuorela, H., Saliba, N. A. & Darwiche, N. (2010). Drug Discovery Today, 15, 668-678.]). Previous work from our laboratory (Nasim & Crooks, 2008[Nasim, S. & Crooks, P. A. (2008). Bioorg. Med. Chem. Lett. 18, 3870-3873.]) reported the amino analogues of PTL as anti-leukemic agents, and moreover a water-soluble analogue of PTL, di­methyl­amino­parthenolide (DMAPT), has advanced into clinical studies (Ghantous et al., 2010[Ghantous, A., Gali-Muhtasib, H., Vuorela, H., Saliba, N. A. & Darwiche, N. (2010). Drug Discovery Today, 15, 668-678.]). Recently, Kempema et al. (2015[Kempema, A. M., Widen, J. C., Hexum, J. K., Andrews, T. E., Wang, D., Rathe, S. K., Meece, F. A., Noble, K. E., Sachs, Z., Largaespada, D. A. & Harki, D. A. (2015). Bioorg. Med. Chem. 23, 4737-4745.]) have reported C1 to C10-modified PTL analogues as anti-leukemic agents. Han et al. (2009[Han, C., Barrios, F. J., Riofski, M. V. & Colby, D. A. (2009). J. Org. Chem. 74, 7176-7179.]) have also reported Heck products of PTL as anti-cancer agents. In continuing efforts from our group, Penthala et al. (2014a[Penthala, N. R., Bommagani, S., Janganati, V., MacNicol, K. B., Cragle, C. E., Madadi, N. R., Hardy, L. L., MacNicol, A. M. & Crooks, P. A. (2014a). Eur. J. Med. Chem. 85, 517-525.]) reported Heck products of PTL and Melampomagnolide B as anti-cancer agents. Subsequently, Bommagani et al. (2015[Bommagani, S., Penthala, N. R., Parkin, S. & Crooks, P. A. (2015). Acta Cryst. E71, 1536-1538.]) reported the crystal structure of (E)-13-(pyrimidin-5-yl)-parthenolide, an analog of PTL, which was found to have an E-configuration at C-13. The useful biological properties of PTL and its analogs directed our attention to design and synthesize novel bioactive analogs. In order to obtain detailed information on the structural conformation of the current mol­ecule and to determine the geometry of the exocyclic double bond, a single-crystal X-ray structure determination has been carried out.

[Scheme 1]

2. Structural commentary

The title compound (Fig. 1[link]) is built from the PTL substructure, which contains a ten-membered carbocyclic ring (chair–chair conformation) merged to a lactone ring, and an epoxide ring, as previously reported (Castañeda-Acosta et al., 1993[Castañeda-Acosta, J., Fischer, N. H. & Vargas, D. (1993). J. Nat. Prod. 56, 90-98.]). The lactone ring has a flattened envelope-type conformation, wherein atoms C6 and C7 reside 0.093 (4) and −0.105 (4) Å above and below the mean plane through atoms C11, C12, O2, and O3. The mol­ecule also contains a 2-amino­benzyl­idene group attached by an E-exocyclic C11=C13 olefinic bond. The 2-amino­benzyl­idene ring is twisted out of the plane of the furan ring, subtending a dihedral angle of 59.93 (7)°. All other bond lengths and angles are largely unremarkable.

[Figure 1]
Figure 1
The mol­ecular structure of the title compound with ellipsoids drawn at the 50% probability level.

3. Supra­molecular features

There are no conventional hydrogen bonds in the crystal structure, although there are a number of weaker C—H⋯O-type inter­actions (Table 1[link]). The most striking packing feature consists of 21 screw-related (1 − x, [{1\over 2}] + y, −z) stacking of lactone groups parallel to the b axis (Fig. 2[link]). The distance between planes of adjacent lactone rings is therefore half the b-axis length.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
C5—H5⋯O3i 1.00 2.59 3.268 (3) 125
C7—H7⋯O3i 1.00 2.57 3.226 (3) 123
C15—H15A⋯O1ii 0.98 2.40 3.223 (3) 141
Symmetry codes: (i) [-x+1, y-{\script{1\over 2}}, -z]; (ii) [-x, y+{\script{1\over 2}}, -z].
[Figure 2]
Figure 2
A packing plot showing the stacking of 21 screw-related adjacent lactone groups. The stacking direction, shown by a dashed line, is parallel to the crystallographic b axis. For emphasis, lactone-group atoms are depicted as solid balls. For clarity, hydrogen atoms and minor disorder components are omitted.

4. Database survey

A search of the November 2017 release (with three incremental updates) of the Cambridge Structure Database (Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) for the PTL substructure gave 30 hits. Three of these, PARTEN (Quick & Rogers, 1976[Quick, A. & Rogers, D. (1976). J. Chem. Soc. Perkin Trans. 2, pp. 465-469.]), PARTEN01 (Bartsch et al., 1983[Bartsch, H.-H., Jarchow, O. & Schmalle, H. W. (1983). Z. Kristallogr. 162, 15-17.]), and PARTEN02 (Long et al., 2013[Long, J., Ding, Y.-H., Wang, P.-P., Zhang, Q. & Chen, Y. (2013). J. Org. Chem. 78, 10512-10518.]) give the structure of PTL itself. One (EBOLOZ, Jamal et al., 2014[Jamal, W., Bari, A., Mothana, R. A., Basudan, O., Mohammed, M. S. & Ng, S. W. (2014). Asian J. Chem. 26, 5183-5185.]) is flagged in the CSD as a stereoisomer of parthenolide, though from the context it appears to be parthenolide with an incorrectly assigned absolute configuration. The remaining 26 are substituted variants of PTL. Of these, only six entries: HORZOF (Penthala et al., 2014b[Penthala, N. R., Bommagani, S., Janganati, V., Parkin, S. & Crooks, P. A. (2014b). Acta Cryst. E70, o1092-o1093.]), HUKLAB, HUKLEF (Han et al., 2009[Han, C., Barrios, F. J., Riofski, M. V. & Colby, D. A. (2009). J. Org. Chem. 74, 7176-7179.]), QILGEZ (Penthala et al., 2013[Penthala, N. R., Janganati, V., Parkin, S., Varughese, K. I. & Crooks, P. A. (2013). Acta Cryst. E69, o1709-o1710.]), RUTPON (Bommagani et al., 2015[Bommagani, S., Penthala, N. R., Parkin, S. & Crooks, P. A. (2015). Acta Cryst. E71, 1536-1538.]), and BEMHIN (El Bouakher et al., 2017[El Bouakher, A., Jismy, B., Allouchi, H., Duverger, E., Barkaoui, L., El Hakmaoui, A., Daniellou, R., Guillaumet, G. & Akssira, M. (2017). Planta Med. 83, 661-671.]) are substituted at the exocyclic double bond.

5. Synthesis and crystallization

Synthetic procedures: The title compound, containing the PTL substructure, was synthesized by the previously reported literature procedure (Han et al., 2009[Han, C., Barrios, F. J., Riofski, M. V. & Colby, D. A. (2009). J. Org. Chem. 74, 7176-7179.]). In brief, parthenolide (1 mmol), 2-iodo­aniline (1.2 mmol), tri­ethyl­amine (3.0 mmol) and 5 mol% of palladium acetate were charged into di­methyl­formamide (2 ml) at room temperature. The reactants were stirred at 333–343 K for 24 h. After completion of the reaction, water was added to the reaction mass at room temperature, and the mixture was extracted into diethyl ether (2 × 30 mL). The combined organic layers were dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography.

Crystallization: The title compound was recrystallized from a mixture of hexane and acetone (9:1), which gave colorless crystals upon slow evaporation of the solution at room temperature over 24 h. Melting point 457–459 K. 1H NMR (400 MHz, CDCl3d): δ 7.63 (s, 1H), 7.17 (d, J = 6.4 Hz, 2H), 6.78 (dd, J = 7.6 Hz, J = 18.4 Hz, 2H), 5.26 (d, J = 11.6 Hz, 1H), 3.97 (s, 2H), 3.92 (t, J = 7.6 Hz, J = 15.6 Hz, 1H), 2.87–2.83 (m, 2H), 2.42–2.38 (m, 1H), 2.20–2.08 (m, 4H), 2.08–1.96 (m, 1H), 1.74 (d, J = 18.0 Hz, 1H), 1.63 (s, 3H), 1.36–1.26 (m, 4H) ppm; 13C NMR (100 MHz, CDCl3d) δ 171.17, 145.47, 135.37, 133.98, 131.11, 130.06, 129.05, 124.82, 118.93, 118.25, 116.21, 83.33, 66.91, 61.85, 47.42, 41.54, 36.49, 29.76, 24.42, 17.62, 17.54 ppm; (ESI): m/z C21H26NO3 [M + H] 340.28.

6. Refinement details

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. H atoms were found in difference-Fourier maps. Carbon-bound hydrogens were subsequently placed at idealized positions with constrained distances of 0.98 Å (RCH3), 0.99 Å (R2CH2), 1.00 Å (R3CH) and 0.95 Å (Csp2H). Nitro­gen-bound hydrogens on the major disorder component were refined freely, while those on the minor component were heavily restrained. Uiso(H) values were set to either 1.2Ueq or 1.5Ueq (RCH3) of the attached atom.

Table 2
Experimental details

Crystal data
Chemical formula C21H25NO3
Mr 339.42
Crystal system, space group Monoclinic, P21
Temperature (K) 90
a, b, c (Å) 11.6136 (3), 6.2403 (1), 12.6875 (3)
β (°) 104.385 (1)
V3) 890.67 (3)
Z 2
Radiation type Cu Kα
μ (mm−1) 0.67
Crystal size (mm) 0.16 × 0.12 × 0.08
 
Data collection
Diffractometer Bruker X8 Proteum
Absorption correction Multi-scan (SADABS; Krause et al., 2015[Krause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3-10.])
Tmin, Tmax 0.840, 0.942
No. of measured, independent and observed [I > 2σ(I)] reflections 24004, 2592, 2559
Rint 0.041
(sin θ/λ)max−1) 0.602
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.032, 0.084, 1.08
No. of reflections 2592
No. of parameters 238
No. of restraints 2
H-atom treatment H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3) 0.18, −0.14
Absolute structure Flack x determined using 811 quotients [(I+)−(I)]/[(I+)+(I)] (Parsons et al., 2013[Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249-259.]), as calculated by PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).
Absolute structure parameter 0.07 (7)
Computer programs: APEX2 and SAINT (Bruker, 2006[Bruker (2006). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]), XP in SHELXTL and SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), SHELXL2013 (Sheldrick, 2015[Sheldrick, G. M. (2015). Acta Cryst. C71, 3-8.]) and CIFFIX (Parkin, 2013[Parkin, S. (2013). CIFFIX. https://xray.uky.edu/people/parkin/programs/ciffix]).

To ensure satisfactory refinement of disordered groups in the structure, a combination of constraints and restraints were employed. The constraints (SHELXL commands EXYZ and EADP) were used to fix parameters of superimposed or partially overlapping fragments. Restraints (SHELXL command SADI) were used to maintain the integrity of ill-defined or disordered groups. Refinement progress was checked using PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) and by an R-tensor (Parkin, 2000[Parkin, S. (2000). Acta Cryst. A56, 157-162.]).

The minor component of disorder of the amine was apparent in a difference map. Given the small occupancy factor (only about 10%), the geometry of the minor component is approximate, and its hydrogen atoms were included merely to achieve the correct atom count.

The conventionally calculated Flack parameter does not convincingly indicate the proper assignment of absolute configuration. An alternative formulation of the chirality parameter using Parsons quotients (Parsons et al., 2013[Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249-259.]) [the so-called 'z′ parameter = 0.07 (7)] as calculated by PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) is much more definitive.

Supporting information


Computing details top

Data collection: APEX2 (Bruker, 2006); cell refinement: SAINT (Bruker, 2006); data reduction: SAINT (Bruker, 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELX (Sheldrick, 2008) and CIFFIX (Parkin, 2013).

(1aR,4E,7aS,8E,10aS,10bR)-8-(2-Aminobenzylidene)-1a,5-dimethyl-2,3,6,7,7a,8,10a,10b-octahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-9(1aH)-one top
Crystal data top
C21H25NO3F(000) = 364
Mr = 339.42Dx = 1.266 Mg m3
Monoclinic, P21Cu Kα radiation, λ = 1.54178 Å
a = 11.6136 (3) ÅCell parameters from 9958 reflections
b = 6.2403 (1) Åθ = 3.9–68.2°
c = 12.6875 (3) ŵ = 0.67 mm1
β = 104.385 (1)°T = 90 K
V = 890.67 (3) Å3Block, colourless
Z = 20.16 × 0.12 × 0.08 mm
Data collection top
Bruker X8 Proteum
diffractometer
2592 independent reflections
Radiation source: fine-focus rotating anode2559 reflections with I > 2σ(I)
Detector resolution: 5.6 pixels mm-1Rint = 0.041
φ and ω scansθmax = 68.2°, θmin = 3.6°
Absorption correction: multi-scan
(SADABS; Krause et al., 2015)
h = 1313
Tmin = 0.840, Tmax = 0.942k = 67
24004 measured reflectionsl = 1515
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.032H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.084 w = 1/[σ2(Fo2) + (0.0449P)2 + 0.1894P]
where P = (Fo2 + 2Fc2)/3
S = 1.08(Δ/σ)max < 0.001
2592 reflectionsΔρmax = 0.18 e Å3
238 parametersΔρmin = 0.14 e Å3
2 restraintsAbsolute structure: Flack x determined using 811 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013), as calculated by PLATON (Spek, 2009).
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.07 (7)
Special details top

Experimental. The crystal was mounted with polyisobutene oil on the tip of a fine glass fibre, fastened in a copper mounting pin with electrical solder. It was placed directly into the cold stream of a liquid nitrogen based cryostat, according to published methods (Hope, 1994; Parkin & Hope, 1998).

Diffraction data were collected with the crystal at 90K, which is standard practice in this laboratory for the majority of flash-cooled crystals.

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Refinement. Refinement progress was checked using Platon (Spek, 2009) and by an R-tensor (Parkin, 2000). The final model was further checked with the IUCr utility checkCIF.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
O10.15259 (14)0.2877 (3)0.01598 (12)0.0449 (5)
O20.37973 (12)0.4845 (3)0.01116 (10)0.0310 (3)
O30.57392 (13)0.4878 (3)0.08619 (10)0.0338 (3)
C10.0887 (2)0.3088 (4)0.34185 (17)0.0352 (5)
H10.13760.18840.34560.042*
C20.0258 (2)0.2614 (4)0.31056 (19)0.0398 (6)
H2A0.06720.14150.35550.048*
H2B0.07810.38870.32560.048*
C30.0032 (2)0.2016 (5)0.18904 (19)0.0408 (6)
H3A0.07970.19740.16800.049*
H3B0.03310.05730.17690.049*
C40.07850 (19)0.3630 (4)0.11934 (17)0.0353 (5)
C50.20641 (18)0.3246 (4)0.10509 (17)0.0328 (5)
H50.22510.19050.14070.039*
C60.29816 (17)0.4982 (4)0.09641 (14)0.0288 (4)
H60.25870.64180.10640.035*
C70.37413 (16)0.4677 (4)0.18048 (14)0.0262 (4)
H70.36260.31710.20800.031*
C80.34284 (18)0.6194 (4)0.28030 (15)0.0287 (5)
H8A0.30810.75300.25960.034*
H8B0.41670.65780.30140.034*
C90.25450 (18)0.5184 (4)0.37888 (14)0.0314 (5)
H9A0.25210.60760.44390.038*
H9B0.28400.37480.39240.038*
C100.12982 (17)0.4963 (4)0.36473 (13)0.0286 (4)
C110.49909 (17)0.4865 (4)0.11042 (13)0.0255 (4)
C120.49328 (19)0.4875 (4)0.00462 (15)0.0280 (4)
C130.60415 (17)0.5038 (4)0.13427 (14)0.0282 (4)
H130.67110.52070.07420.034*
C140.0631 (2)0.7032 (4)0.37465 (19)0.0395 (6)
H14A0.01940.67520.37270.059*
H14B0.06440.77250.44360.059*
H14C0.10050.79760.31410.059*
C150.0281 (2)0.5807 (5)0.1117 (2)0.0436 (6)
H15A0.03760.57050.07620.065*
H15B0.00130.64020.18500.065*
H15C0.09010.67450.06900.065*
C160.62889 (16)0.5001 (4)0.24275 (14)0.0279 (4)
C170.58739 (18)0.3343 (4)0.31796 (15)0.0301 (4)0.901 (4)
N10.52374 (18)0.1616 (4)0.29365 (15)0.0308 (5)0.901 (4)
H1N0.524 (3)0.047 (5)0.334 (2)0.046*0.901 (4)
H2N0.530 (3)0.136 (6)0.225 (2)0.046*0.901 (4)
C17'0.58739 (18)0.3343 (4)0.31796 (15)0.0301 (4)0.099 (4)
H17'0.54500.21600.29920.036*0.099 (4)
C180.61026 (19)0.3482 (5)0.42116 (16)0.0349 (5)
H180.58300.23770.47280.042*
C190.67180 (19)0.5197 (5)0.44896 (16)0.0382 (6)
H190.68430.52790.52010.046*
C200.71561 (19)0.6804 (4)0.37407 (18)0.0372 (5)
H200.75880.79730.39320.045*
C210.69556 (18)0.6680 (4)0.27111 (17)0.0315 (5)0.901 (4)
H210.72750.77510.21880.038*0.901 (4)
C21'0.69556 (18)0.6680 (4)0.27111 (17)0.0315 (5)0.099 (4)
N1'0.7329 (16)0.843 (3)0.2219 (13)0.0308 (5)0.099 (4)
H1N'0.72090.83890.15380.046*0.099 (4)
H2N'0.81190.85710.21750.046*0.099 (4)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O10.0318 (8)0.0637 (13)0.0419 (8)0.0018 (9)0.0144 (6)0.0236 (8)
O20.0381 (7)0.0293 (8)0.0295 (6)0.0003 (8)0.0160 (5)0.0015 (7)
O30.0452 (8)0.0288 (8)0.0258 (6)0.0091 (8)0.0060 (6)0.0006 (7)
C10.0382 (12)0.0304 (13)0.0368 (10)0.0021 (11)0.0093 (9)0.0045 (9)
C20.0356 (12)0.0331 (14)0.0491 (12)0.0049 (10)0.0075 (9)0.0010 (10)
C30.0324 (11)0.0388 (15)0.0542 (13)0.0006 (11)0.0162 (9)0.0129 (11)
C40.0310 (11)0.0456 (15)0.0331 (10)0.0096 (11)0.0154 (8)0.0133 (10)
C50.0325 (10)0.0298 (12)0.0401 (10)0.0067 (10)0.0166 (8)0.0112 (10)
C60.0311 (10)0.0266 (11)0.0314 (9)0.0056 (10)0.0130 (7)0.0072 (9)
C70.0269 (9)0.0251 (11)0.0279 (8)0.0011 (9)0.0096 (7)0.0014 (8)
C80.0277 (10)0.0315 (12)0.0282 (9)0.0012 (9)0.0094 (7)0.0052 (8)
C90.0381 (11)0.0335 (13)0.0246 (8)0.0022 (10)0.0114 (7)0.0011 (9)
C100.0314 (10)0.0319 (12)0.0205 (8)0.0005 (11)0.0029 (7)0.0023 (9)
C110.0320 (10)0.0204 (10)0.0251 (8)0.0004 (9)0.0090 (7)0.0003 (8)
C120.0389 (10)0.0178 (10)0.0287 (8)0.0027 (10)0.0110 (7)0.0005 (9)
C130.0277 (9)0.0281 (11)0.0276 (8)0.0002 (10)0.0048 (7)0.0002 (9)
C140.0334 (11)0.0383 (15)0.0446 (12)0.0063 (11)0.0058 (9)0.0133 (11)
C150.0393 (12)0.0528 (17)0.0417 (12)0.0142 (12)0.0161 (9)0.0052 (11)
C160.0221 (8)0.0335 (12)0.0285 (8)0.0047 (10)0.0071 (7)0.0024 (9)
C170.0266 (9)0.0338 (12)0.0314 (9)0.0032 (10)0.0103 (7)0.0003 (9)
N10.0382 (11)0.0292 (12)0.0270 (9)0.0012 (9)0.0122 (7)0.0032 (8)
C17'0.0266 (9)0.0338 (12)0.0314 (9)0.0032 (10)0.0103 (7)0.0003 (9)
C180.0333 (10)0.0435 (15)0.0299 (9)0.0041 (11)0.0119 (8)0.0012 (10)
C190.0331 (10)0.0509 (17)0.0332 (10)0.0071 (11)0.0134 (8)0.0107 (11)
C200.0274 (10)0.0412 (15)0.0456 (12)0.0013 (11)0.0140 (8)0.0125 (11)
C210.0225 (9)0.0351 (13)0.0371 (10)0.0021 (9)0.0075 (7)0.0011 (9)
C21'0.0225 (9)0.0351 (13)0.0371 (10)0.0021 (9)0.0075 (7)0.0011 (9)
N1'0.0382 (11)0.0292 (12)0.0270 (9)0.0012 (9)0.0122 (7)0.0032 (8)
Geometric parameters (Å, º) top
O1—C51.440 (2)C9—H9B0.9900
O1—C41.456 (2)C10—C141.496 (3)
O2—C121.342 (3)C11—C131.332 (3)
O2—C61.458 (2)C11—C121.478 (2)
O3—C121.211 (3)C13—C161.474 (2)
C1—C101.323 (4)C13—H130.9500
C1—C21.508 (3)C14—H14A0.9800
C1—H10.9500C14—H14B0.9800
C2—C31.544 (3)C14—H14C0.9800
C2—H2A0.9900C15—H15A0.9800
C2—H2B0.9900C15—H15B0.9800
C3—C41.510 (4)C15—H15C0.9800
C3—H3A0.9900C16—C211.402 (3)
C3—H3B0.9900C16—C171.409 (3)
C4—C51.471 (3)C17—N11.384 (3)
C4—C151.492 (4)C17—C181.402 (3)
C5—C61.504 (3)N1—H1N0.88 (3)
C5—H51.0000N1—H2N0.87 (3)
C6—C71.556 (2)C18—C191.381 (4)
C6—H61.0000C18—H180.9500
C7—C111.506 (3)C19—C201.388 (4)
C7—C81.550 (3)C19—H190.9500
C7—H71.0000C20—C211.385 (3)
C8—C91.541 (3)C20—H200.9500
C8—H8A0.9900C21—H210.9500
C8—H8B0.9900N1'—H1N'0.9100
C9—C101.509 (3)N1'—H2N'0.9100
C9—H9A0.9900
C5—O1—C461.05 (13)C10—C9—H9B108.8
C12—O2—C6111.18 (13)C8—C9—H9B108.8
C10—C1—C2128.4 (2)H9A—C9—H9B107.7
C10—C1—H1115.8C1—C10—C14125.06 (19)
C2—C1—H1115.8C1—C10—C9121.1 (2)
C1—C2—C3111.59 (19)C14—C10—C9113.8 (2)
C1—C2—H2A109.3C13—C11—C12119.54 (17)
C3—C2—H2A109.3C13—C11—C7132.42 (16)
C1—C2—H2B109.3C12—C11—C7108.03 (16)
C3—C2—H2B109.3O3—C12—O2120.69 (17)
H2A—C2—H2B108.0O3—C12—C11128.95 (19)
C4—C3—C2110.5 (2)O2—C12—C11110.35 (16)
C4—C3—H3A109.6C11—C13—C16127.78 (17)
C2—C3—H3A109.6C11—C13—H13116.1
C4—C3—H3B109.6C16—C13—H13116.1
C2—C3—H3B109.6C10—C14—H14A109.5
H3A—C3—H3B108.1C10—C14—H14B109.5
O1—C4—C558.93 (13)H14A—C14—H14B109.5
O1—C4—C15112.9 (2)C10—C14—H14C109.5
C5—C4—C15122.7 (2)H14A—C14—H14C109.5
O1—C4—C3117.2 (2)H14B—C14—H14C109.5
C5—C4—C3115.6 (2)C4—C15—H15A109.5
C15—C4—C3116.50 (19)C4—C15—H15B109.5
O1—C5—C460.02 (12)H15A—C15—H15B109.5
O1—C5—C6119.7 (2)C4—C15—H15C109.5
C4—C5—C6124.6 (2)H15A—C15—H15C109.5
O1—C5—H5114.0H15B—C15—H15C109.5
C4—C5—H5114.0C21—C16—C17119.53 (17)
C6—C5—H5114.0C21—C16—C13118.4 (2)
O2—C6—C5108.06 (16)C17—C16—C13122.1 (2)
O2—C6—C7106.71 (15)N1—C17—C18119.5 (2)
C5—C6—C7111.96 (18)N1—C17—C16122.18 (18)
O2—C6—H6110.0C18—C17—C16118.4 (2)
C5—C6—H6110.0C17—N1—H1N115 (2)
C7—C6—H6110.0C17—N1—H2N117 (2)
C11—C7—C8115.51 (17)H1N—N1—H2N115 (3)
C11—C7—C6102.31 (14)C19—C18—C17121.1 (2)
C8—C7—C6115.32 (17)C19—C18—H18119.4
C11—C7—H7107.7C17—C18—H18119.4
C8—C7—H7107.7C18—C19—C20120.67 (19)
C6—C7—H7107.7C18—C19—H19119.7
C9—C8—C7112.77 (18)C20—C19—H19119.7
C9—C8—H8A109.0C21—C20—C19119.1 (2)
C7—C8—H8A109.0C21—C20—H20120.4
C9—C8—H8B109.0C19—C20—H20120.4
C7—C8—H8B109.0C20—C21—C16121.1 (2)
H8A—C8—H8B107.8C20—C21—H21119.4
C10—C9—C8113.94 (16)C16—C21—H21119.4
C10—C9—H9A108.8H1N'—N1'—H2N'109.5
C8—C9—H9A108.8
C10—C1—C2—C3107.8 (3)C8—C9—C10—C1103.1 (2)
C1—C2—C3—C449.0 (3)C8—C9—C10—C1474.6 (2)
C5—O1—C4—C15115.5 (2)C8—C7—C11—C1343.4 (4)
C5—O1—C4—C3104.9 (2)C6—C7—C11—C13169.5 (3)
C2—C3—C4—O1151.63 (19)C8—C7—C11—C12135.47 (19)
C2—C3—C4—C585.0 (2)C6—C7—C11—C129.4 (2)
C2—C3—C4—C1570.2 (2)C6—O2—C12—O3176.5 (2)
C4—O1—C5—C6115.1 (3)C6—O2—C12—C114.5 (3)
C15—C4—C5—O198.8 (2)C13—C11—C12—O35.6 (4)
C3—C4—C5—O1107.7 (2)C7—C11—C12—O3175.3 (2)
O1—C4—C5—C6107.3 (2)C13—C11—C12—O2175.4 (2)
C15—C4—C5—C68.5 (3)C7—C11—C12—O23.6 (3)
C3—C4—C5—C6145.1 (2)C12—C11—C13—C16178.2 (2)
C12—O2—C6—C5131.12 (19)C7—C11—C13—C163.0 (4)
C12—O2—C6—C710.6 (3)C11—C13—C16—C21127.5 (3)
O1—C5—C6—O244.4 (3)C11—C13—C16—C1752.3 (3)
C4—C5—C6—O2116.6 (2)C21—C16—C17—N1178.3 (2)
O1—C5—C6—C7161.60 (18)C13—C16—C17—N11.9 (3)
C4—C5—C6—C7126.2 (2)C21—C16—C17—C182.7 (3)
O2—C6—C7—C1111.8 (2)C13—C16—C17—C18177.11 (19)
C5—C6—C7—C11129.85 (19)N1—C17—C18—C19179.0 (2)
O2—C6—C7—C8138.03 (19)C16—C17—C18—C190.1 (3)
C5—C6—C7—C8103.9 (2)C17—C18—C19—C201.8 (3)
C11—C7—C8—C9146.42 (18)C18—C19—C20—C210.8 (3)
C6—C7—C8—C994.4 (2)C19—C20—C21—C162.0 (3)
C7—C8—C9—C1071.1 (2)C17—C16—C21—C203.8 (3)
C2—C1—C10—C146.3 (4)C13—C16—C21—C20176.0 (2)
C2—C1—C10—C9171.1 (2)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
C5—H5···O3i1.002.593.268 (3)125
C7—H7···O3i1.002.573.226 (3)123
C15—H15A···O1ii0.982.403.223 (3)141
Symmetry codes: (i) x+1, y1/2, z; (ii) x, y+1/2, z.
 

Funding information

This work was supported by NIH/NCI grant CA158275. SP thanks the National Science Foundation (NSF) MRI program for grants CHE0319176 and CHE1625732.

References

First citationCastañeda-Acosta, J., Fischer, N. H. & Vargas, D. (1993). J. Nat. Prod. 56, 90–98.  PubMed Web of Science Google Scholar
First citationBartsch, H.-H., Jarchow, O. & Schmalle, H. W. (1983). Z. Kristallogr. 162, 15–17.  Google Scholar
First citationBommagani, S., Penthala, N. R., Parkin, S. & Crooks, P. A. (2015). Acta Cryst. E71, 1536–1538.  CrossRef IUCr Journals Google Scholar
First citationBruker (2006). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.  Google Scholar
First citationEl Bouakher, A., Jismy, B., Allouchi, H., Duverger, E., Barkaoui, L., El Hakmaoui, A., Daniellou, R., Guillaumet, G. & Akssira, M. (2017). Planta Med. 83, 661–671.  Web of Science PubMed Google Scholar
First citationGhantous, A., Gali-Muhtasib, H., Vuorela, H., Saliba, N. A. & Darwiche, N. (2010). Drug Discovery Today, 15, 668–678.  Web of Science CrossRef PubMed Google Scholar
First citationGroom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171–179.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationGuzman, M. L., Rossi, R. M., Karnischky, L., Li, X., Peterson, D. R., Howard, D. S. & Jordan, C. T. (2005). Blood, 105, 4163–4169.  Web of Science CrossRef PubMed CAS Google Scholar
First citationHan, C., Barrios, F. J., Riofski, M. V. & Colby, D. A. (2009). J. Org. Chem. 74, 7176–7179.  Web of Science CSD CrossRef PubMed CAS Google Scholar
First citationJamal, W., Bari, A., Mothana, R. A., Basudan, O., Mohammed, M. S. & Ng, S. W. (2014). Asian J. Chem. 26, 5183–5185.  Google Scholar
First citationKempema, A. M., Widen, J. C., Hexum, J. K., Andrews, T. E., Wang, D., Rathe, S. K., Meece, F. A., Noble, K. E., Sachs, Z., Largaespada, D. A. & Harki, D. A. (2015). Bioorg. Med. Chem. 23, 4737–4745.  Web of Science CrossRef PubMed Google Scholar
First citationKnight, D. W. (1995). Nat. Prod. Rep. 12, 271–276.  CrossRef PubMed Web of Science Google Scholar
First citationKrause, L., Herbst-Irmer, R., Sheldrick, G. M. & Stalke, D. (2015). J. Appl. Cryst. 48, 3–10.  Web of Science CSD CrossRef CAS IUCr Journals Google Scholar
First citationLong, J., Ding, Y.-H., Wang, P.-P., Zhang, Q. & Chen, Y. (2013). J. Org. Chem. 78, 10512–10518.  Web of Science CrossRef PubMed Google Scholar
First citationMathema, V. B., Koh, Y. S., Thakuri, B. C. & Sillanpää, M. (2012). Inflammation, 35, 560–565.  Web of Science CrossRef PubMed Google Scholar
First citationMinnaard, A. J., Wijnberg, J. B. P. A. & de Groot, A. (1999). Tetrahedron, 55, 2115–2146.  Web of Science CrossRef Google Scholar
First citationNasim, S. & Crooks, P. A. (2008). Bioorg. Med. Chem. Lett. 18, 3870–3873.  Web of Science CSD CrossRef PubMed CAS Google Scholar
First citationParkin, S. (2000). Acta Cryst. A56, 157–162.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationParkin, S. (2013). CIFFIX. https://xray.uky.edu/people/parkin/programs/ciffix  Google Scholar
First citationParsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249–259.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationPenthala, N. R., Bommagani, S., Janganati, V., MacNicol, K. B., Cragle, C. E., Madadi, N. R., Hardy, L. L., MacNicol, A. M. & Crooks, P. A. (2014a). Eur. J. Med. Chem. 85, 517–525.  Web of Science CrossRef CAS PubMed Google Scholar
First citationPenthala, N. R., Bommagani, S., Janganati, V., Parkin, S. & Crooks, P. A. (2014b). Acta Cryst. E70, o1092–o1093.  CSD CrossRef IUCr Journals Google Scholar
First citationPenthala, N. R., Janganati, V., Parkin, S., Varughese, K. I. & Crooks, P. A. (2013). Acta Cryst. E69, o1709–o1710.  CSD CrossRef CAS IUCr Journals Google Scholar
First citationQuick, A. & Rogers, D. (1976). J. Chem. Soc. Perkin Trans. 2, pp. 465–469.  CSD CrossRef Web of Science Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar
First citationSheldrick, G. M. (2015). Acta Cryst. C71, 3–8.  Web of Science CrossRef IUCr Journals Google Scholar
First citationSpek, A. L. (2009). Acta Cryst. D65, 148–155.  Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Follow Acta Cryst. E
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds