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X-Ray Crystal Structure of 10β-Hydroxy-4β,5β-epoxyestr-1-en-3,17-dione and Antitumor Activity of its Congeners

Dragana R. Milić
Agneš Kapor
Borislava Markov
Bela Ribar
Marianne Strümpel
Zorica Juranić
Miroslav J. Gašić
1,2 and
Bogdan A. Šolaja
Faculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 158, YU-11001 Belgrade, Yugoslavia
Institute of Chemistry, Technology and Metallurgy, Belgrade, Yugoslavia
Institute of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 4, 21000, Novi Sad, Yugoslavia
Institut für Kristallographie, Freie Universität Berlin, Takustr.6, D-14195 Berlin, Germany
Institute for Oncology and Radiology of Serbia, Belgrade, Yugoslavia
Author to whom correspondence should be addressed.
Molecules 1999, 4(12), 338-352;
Submission received: 5 August 1999 / Accepted: 1 November 1999 / Published: 23 November 1999


Based on the biological properties of epoxyquinols from natural sources, the title compound was synthesised as a potential antitumor agent. Its molecular structure was partially confirmed by NMR studies. The detailed structure was established by X-ray analysis revealing two symmetry independent molecules in the asymmetric unit each consisting of four fused rings with the C(10) β-oriented hydroxy group and β-oriented O atom bridging C(4) and C(5). The conformation of A ring in both conformers A and B is boat (B3,6), while rings B and C are chairs (1C4) and the five-membered D ring is in an envelope (E2) conformation. The in vitro antitumor activity of title compound and its 17β-acetoxy analogue against HeLa and Fem-x cells revealed IC50 values of 5.7 and 7.1 μM, and 2.25 and 1.58 μM, respectively. Corresponding quinols were tested on 47 cell lines with 10β-hydroxy-17β-acetoxyestra-1,4-dien-3-one being most active against leukemia SR cells (GI50 = 0.17 μM).


A large number of natural as well as synthetic compounds with an epoxyquinol moiety show various biological activities (Figure 1) [1], being at the same time useful intermediates in the synthesis of cyclitols (conduritols, inositols) [2], which are also of biological importance [3].
The incorporation of such substructures into the steroidal framework could lead to synthetically and biologically important compounds [4]. Synthesis of the steroidal epoxyquinol 3 (along with quinol 2) was achieved in good yield [5], but no direct determination of configuration of the epoxide ring in 3 has been made [6].
The determination of the configuration of 3 was undertaken as a part of our program aimed at fully characterising these and related compounds in an attempt to synthetically expand the structural frame-works of natural compounds in an analogous way for further structure-activity studies.
Here we present the structure determination of epoxyquinol 3 and in vitro antitumor activity of 3 and of 17β-acetoxy analogue 5 (Figure 5) against HeLa and Fem-x cell lines. The antitumor activity of corresponding quinols 2 and 4 will also be presented.

Results and discussion


The epoxyquinol 3 (Scheme 1) was synthesised either from estrone 1 (two step one-pot reaction) or from quinol 2, using the oxidation system consisting of m-CPBA / (BzO)2 / hν as described in [4], [5], [9].

Structure Elucidation

The constitution of the epoxyquinol 3 (mp = 201-203oC (colourless needles, benzene)) was derived from the following data: [α]D24 = +294 (c = 1.0, chl.). IR (KBr) cm-1: 3359(s), 2955(w), 1725(s), 1686(s), 1152(w). MS (CI, isobutane, m/e): 303 (MH+). λmaxMeOH =234 nm(8200). Anal. calc. for C18H22O4 × 2/3 C6H6 (354.45): C 74.55, H 7.39, found: C 74.61, H 7.12.
Molecular modelling indicated that the configuration of oxirane ring cannot be determined using NOE difference spectroscopy: in both α and β configuration of the epoxide, the distance between H-C(4) and all other NOE-related protons (OH, Hα-C(6) and Hβ-C(6) is less than 2.7 Å). Therefore we determined the structure of 3 by X-ray analysis.

X-ray crystallography

Crystals obtained by slow evaporation of a benzene solution at room temperature were studied by X-ray diffraction procedures. Selected geometrical parameters, bond distances, bond angles and torsion angles are listed in Table 6 according to the numbering scheme displayed in Figure 2.
Perspective view of the crystal unit of 3 is depicted in Figure 2 [15]. The structure consists of two symmetry independent molecules in the asymmetric unit, each with four fused rings with β oriented hydroxy group, and β-oriented O atom bridging C(4) and C(5) atoms.
Geometrical analysis confirmed the existence of two C-O double bonds, with distances C(3)-O(3) = 1.217(4)Å (A), 1.217(4)Å (B) and C(17)-O(17) = 1.212(3) Å (A), 1.212(4) Å (B) for molecules A and B, respectively. The analysis of the steroid rings by calculating puckering parameters [7] and asym- metric factors [8] (Table 1) has shown that the symmetry independent molecules A and B are of very similar conformations. This was also confirmed by fitting the molecules into each other.
The A ring in both molecules is in boat B3,6 conformation, B and C steroid rings are chairs with 1C4 conformations, while the five membered D ring is in envelope E2 conformation. The energetically more stable conformation of steroid rings in the molecule under study, compared to the methoxy- quinone derivative [9], indicate a less strained and hence lower energy conformation for this com- pound. The values of relevant torsion angles [O(10)A(B)-C(10)A(B)-C(5)A(B)-O(4)A(B) = 75.7(3)° (A), 74.4(3)° (B)] reveal the cis junction between A/B rings, trans junction [H(9)A(B)-C(9)A(B)-C(8)A(B)-H(8)A(B) = -177.7(2)° (A), 177.9(2)° (B)] between B/C rings and [C(18)A(B)-C(13)A(B)-C(14)A(B)-H(14)A(B) = -179.5(2)° (A), 180.0(2)° (B)] between C/D steroid rings. The best plane through the rings B and C in the molecule A form an angle of 71.35° with the corresponding plane of the molecule B (Figure 2).
Analysis of the molecular packing in the unit cell revealed a weak C-H…O intermolecular hydro- gen contacts (Table 2) and a very strong intermolecular hydrogen bond [O(10) - H(10)…O(17)i = 2.873(3)Å in molecule A and 2.779(3) Å in molecule B]. The above mentioned strong hydrogen bonds lead to the creation of the chains consisting of only one type of molecules, A or B. These chains are stacked alternatively along a-axis and bonded by weaker C-H….O type bonds, which results in a layered packing of the molecules parallel to the ab plane (Figure 3).

NMR analysis

Appearance of the signal at 3.33 ppm (d, J = 2.2 Hz) in 1H NMR spectrum indicates the existence of oxirane moiety in compound 3 (H-C(4)). Doublet at 6.68 ppm (J = 10.6 Hz) belongs to H-C(1), which is coupled to H-C(2); consequently, doublet of doublets at 5.77 ppm (J = 10.6, 2.2 Hz) is assigned to H-C(2), and its J-values are a measure of coupling to H-C(1) ("ortho"-H) and H-C(4) (long-range W scalar coupling through 4 σ-bonds including the carbonyl function). In addition, connection of signals at 6.68, 5.77 and 3.33 ppm was confirmed by HOMO decoupling experiments: irr. at 6.68 ppm → 5.77 ppm, d, J = 2.2 Hz; irr. at 5.77 ppm → 6.68 and 3.33 ppm, both s; irr. at 3.33 ppm → 6.68 and 5.77 ppm, both d, J = 10.6 Hz. Singlet at 5.79 ppm, exchangeable with D2O, belongs to OH, and the one at ppm to the angular methyl group hydrogens.
Assignation of selected spin-active nuclei is obtained by using comparative analysis of DEPT 13C and 2D correlated NMR spectra (H,H and C,H COSY) (Table 3).


In this work, the antiproliferative action of synthetic compounds 3 and 5 derived from estrone on two human neoplastic cell lines, HeLa and Fem-x, in vitro, was determined. Presented are also the activities [10] of corresponding quinols 2 and 4 (Figure 6).
The epoxyquinols 3 and 5 expressed the dose-dependent antiproliferative action toward investigated cell lines. In order to compare the extent of the antiproliferative action between neoplastic cell lines of different origin, IC50 were determined under the same conditions by MTT test. They were very similar for HeLa and Fem-X cells and mean values from three independently performed experiments for 48 h of continuous agent’s action (epoxyquinols 3 and 5, respectively) were 5.7 ± 1.3 and 2.25 ± 0.35 μM for HeLa, and 7.1 ± 2.25 and 1.58 ± 0.04 μM for Fem-x cells (Table 4). Morphological examination of target cells by inverted microscope showed that the cytotoxic action resulted in cells rounding in the presence of agent in concentration higher than 6 μM and / or cell ballooning in the concentration higher than 12 μM.
The title compounds 2 and 4 were in vitro tested by NCI at a minimum of five concentrations at 10- fold dilutions. A 48 hours continuous drug exposure protocol is used, and a SRB (sulforhodamine B) protein assay is used to estimate cell survival or growth. The GI50 is interpolated value representing concentration at which the percentage growth is +50. Presented results indicate that quinol 2 is moder- ately active against both leukemia cell lines, while analogue compound 4 is much more selective.
Both compounds, 2 and 4, were also tested for their antiviral activity. The procedure used in the NCI's test for agents active against HIV virus is designed to detect agents acting at any stage of the vi- rus reproductive cycle. The assay involves the killing of T4 lymphocytes by HIV. Small amounts of HIV are added to cells, and two cycles of virus reproduction are necessary to obtain the required kill- ing. Agents that interact with virions, cells or virus gene-products to interfere with viral activities, will protect cells from cytolysis. All tests are compared with at least one positive (AZT-treated) control performed at the same time under identical conditions. Both quinols are confirmed inactive, having IC50 > 2×10-4 M against CEM-SS cell line.
Although the two pairs of compounds, epoxyquinols 3 and 5 and quinols 2 and 4, were tested on different cell lines, one observation merits comment: In both cases estradiol derived compounds 4 and 5 (possessing 17β-acetoxy group instead of 17-oxo functionality as in 2 and 3) exhibited stronger ac- tivity towards target cell lines. Compound 4 is also highly active against melanoma SK-MEL-5 cell lines with GI50 = 3.14 μM (quinol 2, GI50 = 82.0 μM).
Our further investigation in this area will be focused to the synthesis and antitumor activity evaluation of the influence of the oxirane ring position and its stereochemistry, as well as on the influence of C(17) substituent in estrane derived quinols.



Melting points were determined on a Mikro-Heiztisch Boetius PHMK apparatus and were not corrected. IR and UV spectra were recorded on Perkin-Elmer FT-IR 1725X and Beckman DU-50 spectro- photometers, respectively. 1H and 13C NMR spectra were recorded on Bruker AM-250 spectrometer. Chemical shifts were expressed as ppm (δ) values and coupling constant (J) in Hz. Mass spectra were taken on a Finnigan-MAT 8230 spectrometer.
All compounds were synthesised and the relevant data are presented in refs. [4], [5] and [9].

X-ray crystallography

A colourless plate-like crystal of dimensions 0.5×0.3×0.2 mm was mounted on an STOE four circle diffractometer equipped with CuKα radiation and Ni filter. Cell parameters (Table 5) were determined by least-squares refinement of diffractometer angles for 59 reflections collected in the range 15.0 ≤ θ ≤ 31.0°. Three standard reflections were monitored every 90 min but no considerable intensity variations were recorded. Reflections were recorded with 2θ-ω scan in the range 3.19 ≤ θ ≤ 65.04° and with Miller indices hmin= -11, hmax= 11, kmin= -1, kmax= 14, lmin= -16, lmax= 16. 2954 independent reflections were merged with R = 0.0155 to 2822 unique reflections. The intensity data were corrected for Lorentz and polarisation effect.
The structure was solved by direct methods using SHELX86 [11] and SIR92 [12] program and re- fined by anisotropic full-matrix least squares on F2 (SHELXL93 [13]). The position of the H atoms were generated from assumed geometry, checked on a difference Fourier map and refined isotropically with common displacement parameter U1=0.056(2) Å2, U2=0.066(4) Å2 and U3=0.063(2) Å2, U4=0.100(7) Å2 for all H atoms except H atoms attached to C(15)A(B), C(16)A(B) (peripheral atoms) for molecules A and B, respectively and methyl type atoms C(18)A(B) with isotropic displacement parameters fixed to 1.5 Ueq of the parent atoms. Final R-factor was R = 0.0308 for 404 parameters and 2954 reflections. Scattering factors were taken from SHELXL93. Conformational calculations were performed using the program RING [14]. Molecular graphics were drawn using ORTEP-III [15].
Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no.CCDC- 132357. Copies of the data can be obtained free of charge on application to The Director, CCDC,12 Union Road, Cambridge CB2 1EZ, UK (fax: int.code +(1223) 336-033, E-mail: [email protected]


Materials and methods

Stock solution of investigated compounds were made in DMSO at a concentration of 10.58 mM, and it was diluted by nutritient medium (RPMI 1640 medium supplemented with l-glutamine (3 mmol/L), streptomycin 100 μg/mL and penicillin 100 IU/mL, 10% heat inactivated fetal bovine serum, FBS and 25 mM Hepes, adjusted to pH 7.2 by bicarbonate solution) to various final concentrations. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT); RPMI 1640 cell culture medium and fetal bovine serum (FBS), were purchased from Sigma Chemicals (St. Luis, MO, U.S.A.). MTT was dissolved, 5 mg/mL in phosphate buffer saline pH 7.2, and filtered through Milipore filter, 0.22 μm, before use.

Cell culture

Human malignant melanoma Fem-x cells, and human cervix carcinoma HeLa cells were maintained as a monolayer culture in the same nutritient medium The cells were grown at 37 °C in 5% CO2 and humidified air atmosphere.

Treatment of Fem-x and HeLa cells

Target cells were seeded (2000 cells in 100 μL of nutrient medium per well), into 96-well microtiter flat bottomed plates and twenty hours later, five different concentrations of the investigated compound were added to the wells in triplicate, to various final concentrations, except to the control wells where only a nutritient medium was added to the cells. Nutritient medium with corresponding concentrations of compound, but void of cells was used as blank, in triplicate too. The experiment was repeated three times.

Determination of HeLa and Fem-x cell survival

Cell survival was determined as reported earlier [16] by MTT test 48 h after the drug addition. Briefly, MTT solution (5 mg / mL PBS) was added to each well. Samples were incubated for further four hours at 37 °C in 5% CO2 and humidified air atmosphere. Then, 10% SDS in 0.01 M HCl was added to the wells. Optical density (OD) at 570 nm was red the next day. To get cell survival (%), optical density at 570 nm of a sample with cells grown in the presence of various concentration of investigated agent (OD), was divided with control optical density ODc, (the OD of cells grown only in nutritient medium) °100. Concentration IC50 was defined as the concentration of a drug needed to inhibit cell survival by 50%, compared with vehicle-treated control.


This work was supported by Federal Ministry of Science, project No.OSI 412, and by Serbian Ministry of Science and Technology, project No 01E18.

References and Notes

  1. a) Kamikubo, T.; Ogasawara, K. The enantiocontrolled synthesis of (-)-tricholomenyn A, a novel antimitotic enynylcyclohexenone from Tricholoma acerbum. Chem. Commun. 1996, 1679–1680. [Google Scholar] [CrossRef] ; b) Johnson, C. R.; Miller, M. W. Enzymatic resolution of a C2 symmetric diol derived from p-benzoquinone: synthesis of (+)- and (-)-Bromoxone. J.Org. Chem. 1995, 60, 6674–6675. [Google Scholar] [CrossRef] ; c) Al- caraz, L.; Macdonald, G.; Ragot, J. P.; Lewis, N.; Taylor, R. J. K. M. Manumycin A: Synthesis of the (+)-Enantiomer and Revision of Stereochemical Assignment. J. Org. Chem. 1998, 63, 3526–3527. [Google Scholar] [CrossRef] ; d) Wipf, P.; Kim, Y. Synthesis of the Antitumor Antibiotic LL-C10037α. J. Org. Chem. 1994, 59, 3518–3519. [Google Scholar] [CrossRef]
  2. Results of further transformations of epoxyquinol 3 and quinol 2 will be published elsewhere.
  3. a) Balci, M.; Sütbeyaz, Y.; Seçen, H. Conduritols and Related Compounds. Tetrahedron 1990, 46, 3715–3742. [Google Scholar] [CrossRef] ; b) Angyal, S. J. The Inositols. Q. Rev. Chem. Soc. 1957, 11, 212–226. [Google Scholar] [CrossRef]
  4. Solaja, B. A.; Milie, D. R.; Gasie, M. J. A Novel m-CPBA Oxidation: p-Quinols and Epoxy-quinols from Phenols. Tetrahedron Lett. 1996, 37, 3765–3768. [Google Scholar] [CrossRef]
  5. Milie, D. R.; Gasie, M. J.; Muster, W.; Csanadi, J. J.; Solaja, B. A. The Synthesis and Biological Evaluation of A-ring Substituted Steroidal p-Quinones. Tetrahedron 1997, 53, 14073–14084. [Google Scholar] [CrossRef]
  6. Quinol 2 was treated with Katsuki-Sharpless reagent to give the epoxyquinol 3 (97% yield of (1:1)- mixture of two regioisomers; 20% overall yield in three phases from starting estrone) the structure of which was proposed on the basis of the known mechanism of the reaction. See: Adam, W.; Lupon, P. Quinol Epoxides from p-Cresol and Estrone by Photooxigenation and Tita- nium(IV)- or Vanadium(V)-Catalysed Oxygen Transfer. Chem. Ber. 1988, 121, 21–25. [Google Scholar] [CrossRef]
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  9. Milie, D.R.; Solaja, B.A.; Dosen-Mieovie, Lj.; Ribar, B.; Kapor, A.; Sladie, D.; Gasie, M.J. Structure and reactivity of steroidal quinones. J. Serb. Chem. Soc. 1997, 62, 755–768. [Google Scholar]
  10. Quinol 4 and epoxyquinol 5 were tested in National Cancer Institute, Bethesda, U.S.A. as part of NCI developmental therapeutics program. For detailed synthetic procedure and spectroscopic data of 4 and 5 see refs. 4 and 9.
  11. Sheldrick, G.M. SHELXS86 Program for Solution of Crystal Structure; University of Göttingen: Germany, 1985. [Google Scholar]
  12. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M.C.; Polidori, G.; Camalli, M. SIR92-a program for automatic solution of crystal structures by direct methods. J. Appl. Cryst. 1994, 27, 435–436. [Google Scholar] [CrossRef]
  13. Sheldrick, G.M. SHELXL93 Program for Refinement of Crystal Structure; University of Göttin- gen: Germany, 1993. [Google Scholar]
  14. Párkányi, L. RING, Program for Conformational Analysis; Budapest: Hungary, 1979. [Google Scholar]
  15. Johnoson, C.K.; Burnett, M.N.; Farrugia, L.J. ORTEP III Version 1.0.2 University of Glasgow; Great Britain, 1997. [Google Scholar]
  16. a) Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to prolif- eration and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55–56. [Google Scholar] [CrossRef] ; b) Ohno, M.; Abe, T. Rapid colorimetric assays for the quantification of leukemia inhibitory factor (LIF) and interleu- kin-6 (IL-6). J. Immunol. Methods 1991, 145, 199–203. [Google Scholar] [CrossRef] ; c) Juranie, Z.; Radulovie, S.; Joksimovie, J.; Juranie, I. The Mechanism of 8-Cl-cAMP Action. J. Exp. Clin. Cancer Res. 1998, 17, 269–275. [Google Scholar]
  • Samples Availability: compounds 2, 3 and 5 are available from MDPI.
Figure 1.  
Figure 1.  
Molecules 04 00338 g001
Figure 2. ORTEP [15] drawing of the molecules A (blue) and B (red) with the non-H atom labeling scheme. The displacement ellipsoids are drawn at 25% probability.
Figure 2. ORTEP [15] drawing of the molecules A (blue) and B (red) with the non-H atom labeling scheme. The displacement ellipsoids are drawn at 25% probability.
Molecules 04 00338 g002
Figure 3. The crystal packing for the unit cell projected along the b-axis. The arrows denote hydrogen bonds (two strongest ones).
Figure 3. The crystal packing for the unit cell projected along the b-axis. The arrows denote hydrogen bonds (two strongest ones).
Molecules 04 00338 g003
Figure 4. a) 1H NMR spectrum of compound 3; b) HD 1H NMR spectrum (irradiated signal at 5.77 ppm) of compound 3.
Figure 4. a) 1H NMR spectrum of compound 3; b) HD 1H NMR spectrum (irradiated signal at 5.77 ppm) of compound 3.
Molecules 04 00338 g004
Figure 5. Selected spectra of epoxyquinol 3. a) C,H-COSY; b) H,H-COSY; c)13C NMR-DEPT.
Figure 5. Selected spectra of epoxyquinol 3. a) C,H-COSY; b) H,H-COSY; c)13C NMR-DEPT.
Molecules 04 00338 g005
Figure 6.  
Figure 6.  
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Scheme 1.  
Scheme 1.  
Molecules 04 00338 sch001
Table 1. Puckering parameters and asymmetry factors.
Table 1. Puckering parameters and asymmetry factors.
Molecules 04 00338 i001
Table 2. Geometry (Å,° ) of hydrogen-bond nets and short contact bridged by an hydrogen atom.
Table 2. Geometry (Å,° ) of hydrogen-bond nets and short contact bridged by an hydrogen atom.
Molecules 04 00338 i002
Symmetry code: (i) x–1, y, z (ii) x+1,y,z (iii) –x,y-1/2,-z (iv) -x,y-1/2,-z+1 (v) -x,y+1/2,-z.
Table 3. C- and H-chemical shifts of 10β-hydroxy-4β,5β-epoxyestr-1-en-3,17-dione (3; DMSO-d6).
Table 3. C- and H-chemical shifts of 10β-hydroxy-4β,5β-epoxyestr-1-en-3,17-dione (3; DMSO-d6).
PositionδC (ppm)δH (ppm)
1153.066.68 (d, J = 10.6)
2122.335.77 (dd, J = 10.6, 2.2)
459.563.33 (d, J = 2.2)
628.152.32a (m, Hβ), 1.24 (m, Hα)
833.621.87 (m, Hβ)
954.191.03 (m)
1813.300.81 (s)
OH-5,79 (s)
a Values for presented multiplets are mean of signal in C,H COSY spectrum.
Table 4a. In vitro antitumor activity of epoxyquinols 3 and 5, and quinols 2 and 4.
Table 4a. In vitro antitumor activity of epoxyquinols 3 and 5, and quinols 2 and 4.
CompoundIC50 (μM) bGIC50 (μM) c
2 74.3026.40
4 0.17 d11.90
a 48 h of continuous agent’s action; b IC = Inhibition concentration; c GI = Growth inhibition. Out of 47 cell lines tested, presented are only the ones where highest activity of 2 and 4 was established; d TGI (Total GI) = 1.63 μM, LC50 > 100 μM.
Table 5. Crystal data and structure refinement.
Table 5. Crystal data and structure refinement.
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Table 6. Selected bond lengths [Å] and angles [°].
Table 6. Selected bond lengths [Å] and angles [°].
Molecules 04 00338 i004
Molecules 04 00338 i005

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MDPI and ACS Style

Milić, D.R.; Kapor, A.; Markov, B.; Ribar, B.; Strümpel, M.; Juranić, Z.; Gašić, M.J.; Šolaja, B.A. X-Ray Crystal Structure of 10β-Hydroxy-4β,5β-epoxyestr-1-en-3,17-dione and Antitumor Activity of its Congeners. Molecules 1999, 4, 338-352.

AMA Style

Milić DR, Kapor A, Markov B, Ribar B, Strümpel M, Juranić Z, Gašić MJ, Šolaja BA. X-Ray Crystal Structure of 10β-Hydroxy-4β,5β-epoxyestr-1-en-3,17-dione and Antitumor Activity of its Congeners. Molecules. 1999; 4(12):338-352.

Chicago/Turabian Style

Milić, Dragana R., Agneš Kapor, Borislava Markov, Bela Ribar, Marianne Strümpel, Zorica Juranić, Miroslav J. Gašić, and Bogdan A. Šolaja. 1999. "X-Ray Crystal Structure of 10β-Hydroxy-4β,5β-epoxyestr-1-en-3,17-dione and Antitumor Activity of its Congeners" Molecules 4, no. 12: 338-352.

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