data reports 11b-Hydroxymedroxyprogesterone Structure description

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11b-Hydroxymedroxyprogesterone ISSN 2414-3146 Sharifah Nurfazilah Wan Yusop, a,b Sadia Sultan, a,b Bohari M.

Zeller, Purdue University, USA Keywords: crystal structure; medroxyprogesterone; fungal-transformed metabolite.

1 11b-Hydroxymedroxyprogesterone ISSN Sharifah Nurfazilah Wan Yusop, a,b Sadia Sultan, a,b Bohari M. Yamin, c Syed Adnan Ali Shah a,b and Humera Naz a,b * Received 30 May 2016 Accepted 4 July 2016 Edited by M. Zeller, Purdue University, USA Keywords: crystal structure; medroxyprogesterone; fungal-transformed metabolite. CCDC reference: a Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Puncak Alam Campus, Bandar Puncak Alam, Selangor D. E., Malaysia, b Faculty of Pharmacy, Universiti Tecknologi MARA, Puncak Alam, Selangor, Malaysia, and c School of Chemical Sciences and Food Technology, Universiti Kebangsaan Malaysia, Bangi, Selangor D.E., Malaysia. *Correspondence humera@salam.uitm.edu.my The title compound, C 22 H 32 O 4, a fungal-transformed metabolite of medroxyprogesterone, comprises one cyclohexanone ring, two cyclohexane rings and one cyclopentane ring fused together. The cyclohexanone ring has a half-chair conformation, while the cyclohexane rings possess chair conformations and the cyclopentane ring has a twisted conformation on the fused C C bond. In the crystal, molecules are linked by strong O HO and also C HO hydrogen bonds, creating a two-dimensional network parallel to (101). Structural data: full structural data are available from iucrdata.iucr.org Structure description 11-Hydroxymedroxyprogesterone, is a steroid produced by biotransformation of medroxyprogesterone (MP). Medroxyprogesterone is known as a progesterone agonist which is important as a sex hormone. The progesterone agonist activity of MP is less effective than medroxyprogesterone acetate (MPA) (Pullen et al., 2006) which has been used for treatment of endometrial carcinoma (Fujiwara et al., 2012). In a continuation of our work on biotransformation of steroids (Sultan et al., 2014), we aimed to produce unique structurally modified derivatives of medroxyprogesterone that may be more effective than MPA. Herein we report the X-ray study of 11-hydroxymedroxyprogesterone (Fig. 1), a biotransformation product of medroxyprogesterone. The molecule comprises four annelated rings. Ring A (C1 C5/C10) is a cyclohexanone having a half-chair conformation, while rings B (C5 C10) and C (C8/C9/C11 C14) are cyclohexane rings with chair conformations. The cyclopentane ring D (C13 C17) adopts a twisted conformation on the fused C C bond, C13 C of3

Table 1 Hydrogen-bond geometry (Å, ). D HA D H HA DA D HA O3 H3AO1 i 0.81 (3) 2.02 (4) 2.767 (5) 153 (4) O4 H4AO3 ii 0.82 (5) 2.12 (5) 2.910 (5) 165 (6) C18 H18CO1 i 0.96 2.47 3.

2 Table 1 Hydrogen-bond geometry (Å, ). D HA D H HA DA D HA O3 H3AO1 i 0.81 (3) 2.02 (4) (5) 153 (4) O4 H4AO3 ii 0.82 (5) 2.12 (5) (5) 165 (6) C18 H18CO1 i (6) 165 Symmetry codes: (i) x þ 1; y þ 1 2 ; z þ 1; (ii) x; y 1 2 ; z. Table 2 Experimental details. Figure 1 The molecular structure of the title compound, with displacement ellipsoids drawn at the 50% probability level. In the crystal, the molecules are linked by strong O HO hydrogen bonds, O3 H3AO1 i and O4 H4AO3 ii, augmented by a C HO interaction, C18 H18CO1 i, forming a two-dimensional network parallel to (101) (see Fig. 2 and Table 1). Synthesis and crystallization The title compound was obtained from the fungal transformation of medroxyprogesterone via Trichothecium roseum (ATCC 13411) after 8 d of fermentation mg of this compound was purified by recycling preparative HPLC. The compound was crystallized at room temperature from a mixture of chloroform and methanol. Refinement Crystal data, data collection and structure refinement details are summarized in Table 2. The absolute configuration was not determined from the X-ray data but it could be determined Crystal data Chemical formula C 22 H 32 O 4 M r Crystal system, space group Monoclinic, P2 1 Temperature (K) 302 a, b, c (Å) (12), (2), (19) ( ) (5) V (Å 3 ) (3) Z 2 Radiation type Mo K (mm 1 ) 0.09 Crystal size (mm) Data collection Diffractometer Bruker APEXII CCD Absorption correction Multi-scan (SADABS; Bruker, 2009) T min, T max 0.959, No. of measured, independent and 16639, 3527, 3023 observed [I > 2(I)] reflections R int (sin /) max (Å 1 ) Refinement R[F 2 >2(F 2 )], wr(f 2 ), S 0.054, 0.122, 1.09 No. of reflections 3527 No. of parameters 248 No. of restraints 3 H-atom treatment H atoms treated by a mixture of independent and constrained refinement max, min (e Å 3 ) 0.20, 0.21 Computer programs: APEX2 and SAINT (Bruker, 2009), SHELXS97 and SHELXTL (Sheldrick, 2008), SHELXL2013 (Sheldrick, 2015) and PLATON (Spek, 2009). through the comparison of similar compounds (Ouedraogo et al., 2013, Karpinska et al., 2013). Acknowledgements The authors would like to acknowledge the Ministry of Higher Education of Malaysia and Universiti Teknologi MARA for research grants Nos. 600-RMI/FRGS 5/3 (49/2014) and 600- RMI/DANA/5/3/LESTARI(92/2015). Figure 2 The crystal packing of the title compound viewed along the a ax1s. Dashed lines indicate hydrogen bonds. References Bruker (2009). SADABS, APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Fujiwara, H., Jobo, T., Takei, Y., Saga, Y., Imai, M., Arai, T., Taneichi, A., Machida, S., Takahashi, Y. & Suzuki, M. (2012). Oncol. Lett. 3, Karpinska, J., Erxleben, A. & McArdle, P. (2013). Acta Cryst. E69, o60. 2of3 Yusop et al. C 22 H 32 O 4

3 Ouedraogo, Y. P., Huang, L., Torrente, M. P., Proni, G., Chadwick, E., Wehmschulte, R. J. & Nesnas, N. (2013). Chirality, 25, Pullen, M. A., Laping, N., Edwards, R. & Bray, J. (2006). Steroids, 71, Sheldrick, G. M. (2008). Acta Cryst. A64, Sheldrick, G. M. (2015). Acta Cryst. C71, 3 8. Spek, A. L. (2009). Acta Cryst. D65, Sultan, S., Noor, M. Z. B. M., Anouar, el H., Shah, S. A. A., Salim, F., Rahim, R., Al Trabolsy, Z. B. & Weber, J. F. F. (2014). Molecules, 19, Yusop et al. C 22 H 32 O 4 3of3

4 full crystallographic data [ 11β-Hydroxymedroxyprogesterone Sharifah Nurfazilah Wan Yusop, Sadia Sultan, Bohari M. Yamin, Syed Adnan Ali Shah and Humera Naz 11β-Hydroxymedroxyprogesterone Crystal data C 22 H 32 O 4 M r = Monoclinic, P2 1 a = (12) Å b = (2) Å c = (19) Å β = (5) V = (3) Å 3 Z = 2 F(000) = 392 Data collection Bruker APEXII CCD diffractometer Radiation source: fine-focus sealed tube Detector resolution: pixels mm -1 φ and ω scans Absorption correction: multi-scan (SADABS; Bruker, 2009) T min = 0.959, T max = Refinement Refinement on F 2 Least-squares matrix: full R[F 2 > 2σ(F 2 )] = wr(f 2 ) = S = reflections 248 parameters 3 restraints Primary atom site location: structure-invariant direct methods Secondary atom site location: difference Fourier map Hydrogen site location: mixed D x = Mg m 3 Melting point = K Mo Kα radiation, λ = Å Cell parameters from 9916 reflections θ = µ = 0.09 mm 1 T = 302 K Block, colourless mm measured reflections 3527 independent reflections 3023 reflections with I > 2σ(I) R int = θ max = 25.5, θ min = 3.1 h = 8 7 k = l = H atoms treated by a mixture of independent and constrained refinement w = 1/[σ 2 (F o2 ) + (0.0268P) P] where P = (F o 2 + 2F c2 )/3 (Δ/σ) max < Δρ max = 0.20 e Å 3 Δρ min = 0.21 e Å 3 Extinction correction: SHELXL2013 (Sheldrick, 2015), Fc * =kfc[ xfc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: (5) Absolute structure: Flack (1983),???? Friedel pairs Absolute structure parameter: 1.3 (6) data-1

5 Special details 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. Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 ) x y z U iso */U eq O (6) (3) (3) (10) O (5) (3) (3) (9) O (5) (2) (3) (7) O (5) (3) (3) (7) C (7) (3) (3) (10) H1A * H1B * C (8) (4) (4) (11) H2A * H2B * C (8) (4) (4) (11) C (7) (4) (4) (11) H4B * C (6) (3) (4) (10) C (6) (4) (4) (10) H6A * C (6) (4) (4) (10) H7A * H7B * C (6) (3) (3) (9) H8A * C (6) (3) (3) (8) H9A * C (6) (3) (3) (9) C (6) (3) (3) (9) H11A * C (6) (3) (3) (9) H12A * H12B * C (5) (3) (3) (8) C (6) (3) (3) (9) H14A * C (6) (3) (4) (10) H15A * H15B * C (6) (4) (3) (9) H16A * H16B * C (6) (3) (3) (9) data-2

6 C (7) (3) (4) (11) H18A * H18B * H18C * C (6) (3) (4) (9) H19A * H19B * H19C * C (6) (4) (4) (10) C (8) (5) (5) (15) H21A * H21B * H21C * C (9) (4) (5) (15) H22A * H22B * H22C * H3A (6) (4) (2) (13)* H4A (9) (4) (4) 0.07 (2)* Atomic displacement parameters (Å 2 ) U 11 U 22 U 33 U 12 U 13 U 23 O (3) (19) (19) (19) (19) (16) O (2) (2) (18) (17) (16) (16) O (19) (14) (16) (13) (14) (13) O (17) (17) (16) (14) (14) (14) C (3) (2) (19) (19) (19) (17) C (3) (3) (2) (2) (2) (2) C (3) (2) (2) (2) (2) (19) C (3) (2) (2) (2) (2) (2) C (2) (2) (2) (18) (18) (17) C (2) (2) (2) (19) (19) (2) C (2) (2) (2) (19) (19) (19) C (2) (19) (2) (16) (17) (16) C (2) (17) (18) (16) (16) (15) C (2) (19) (2) (17) (17) (16) C (2) (2) (19) (17) (17) (16) C (2) (2) (2) (16) (17) (17) C (18) (18) (19) (16) (16) (16) C (2) (2) (2) (16) (16) (16) C (2) (2) (2) (18) (19) (18) C (2) (2) (2) (18) (17) (18) C (2) (2) (2) (17) (17) (17) C (3) (2) (3) (18) (2) (19) C (2) (2) (2) (17) (18) (17) C (2) (2) (2) (18) (18) (18) C (3) (4) (3) (3) (3) (3) data-3

7 C (3) (3) (3) (3) (3) (2) Geometric parameters (Å, º) O1 C (5) C11 C (5) O2 C (5) C11 H11A O3 C (5) C12 C (5) O3 H3A (14) C12 H12A O4 C (5) C12 H12B O4 H4A (14) C13 C (5) C1 C (6) C13 C (5) C1 C (6) C13 C (5) C1 H1A C14 C (5) C1 H1B C14 H14A C2 C (7) C15 C (6) C2 H2A C15 H15A C2 H2B C15 H15B C3 C (7) C16 C (5) C4 C (6) C16 H16A C4 H4B C16 H16B C5 C (6) C17 C (6) C5 C (5) C18 H18A C6 C (6) C18 H18B C6 C (6) C18 H18C C6 H6A C19 H19A C7 C (5) C19 H19B C7 H7A C19 H19C C7 H7B C20 C (7) C8 C (5) C21 H21A C8 C (5) C21 H21B C8 H8A C21 H21C C9 C (5) C22 H22A C9 C (5) C22 H22B C9 H9A C22 H22C C10 C (6) C11 O3 H3A 105 (3) C11 C12 H12A C17 O4 H4A 105 (4) C13 C12 H12B C2 C1 C (3) C11 C12 H12B C2 C1 H1A H12A C12 H12B C10 C1 H1A C12 C13 C (3) C2 C1 H1B C12 C13 C (3) C10 C1 H1B C19 C13 C (3) H1A C1 H1B C12 C13 C (3) C3 C2 C (4) C19 C13 C (3) C3 C2 H2A C14 C13 C (3) C1 C2 H2A C15 C14 C (3) C3 C2 H2B C15 C14 C (3) data-4

8 C1 C2 H2B C8 C14 C (3) H2A C2 H2B C15 C14 H14A O1 C3 C (4) C8 C14 H14A O1 C3 C (5) C13 C14 H14A C4 C3 C (4) C14 C15 C (3) C5 C4 C (4) C14 C15 H15A C5 C4 H4B C16 C15 H15A C3 C4 H4B C14 C15 H15B C4 C5 C (4) C16 C15 H15B C4 C5 C (4) H15A C15 H15B C6 C5 C (4) C17 C16 C (3) C5 C6 C (4) C17 C16 H16A C5 C6 C (3) C15 C16 H16A C22 C6 C (4) C17 C16 H16B C5 C6 H6A C15 C16 H16B C22 C6 H6A H16A C16 H16B C7 C6 H6A O4 C17 C (3) C8 C7 C (3) O4 C17 C (3) C8 C7 H7A C16 C17 C (3) C6 C7 H7A O4 C17 C (3) C8 C7 H7B C16 C17 C (3) C6 C7 H7B C20 C17 C (3) H7A C7 H7B C10 C18 H18A C7 C8 C (3) C10 C18 H18B C7 C8 C (3) H18A C18 H18B C14 C8 C (3) C10 C18 H18C C7 C8 H8A H18A C18 H18C C14 C8 H8A H18B C18 H18C C9 C8 H8A C13 C19 H19A C8 C9 C (3) C13 C19 H19B C8 C9 C (3) H19A C19 H19B C11 C9 C (3) C13 C19 H19C C8 C9 H9A H19A C19 H19C C11 C9 H9A H19B C19 H19C C10 C9 H9A O2 C20 C (4) C1 C10 C (3) O2 C20 C (4) C1 C10 C (3) C21 C20 C (4) C5 C10 C (3) C20 C21 H21A C1 C10 C (3) C20 C21 H21B C5 C10 C (3) H21A C21 H21B C18 C10 C (3) C20 C21 H21C O3 C11 C (3) H21A C21 H21C O3 C11 C (3) H21B C21 H21C C12 C11 C (3) C6 C22 H22A O3 C11 H11A C6 C22 H22B C12 C11 H11A H22A C22 H22B C9 C11 H11A C6 C22 H22C C13 C12 C (3) H22A C22 H22C data-5

9 C13 C12 H12A H22B C22 H22C C10 C1 C2 C (5) C10 C9 C11 C (3) C1 C2 C3 O (4) O3 C11 C12 C (4) C1 C2 C3 C (5) C9 C11 C12 C (4) O1 C3 C4 C (5) C11 C12 C13 C (4) C2 C3 C4 C5 3.4 (7) C11 C12 C13 C (4) C3 C4 C5 C (4) C11 C12 C13 C (3) C3 C4 C5 C (7) C7 C8 C14 C (5) C4 C5 C6 C (6) C9 C8 C14 C (3) C10 C5 C6 C (4) C7 C8 C14 C (3) C4 C5 C6 C (5) C9 C8 C14 C (4) C10 C5 C6 C (4) C12 C13 C14 C (3) C5 C6 C7 C (5) C19 C13 C14 C (4) C22 C6 C7 C (4) C17 C13 C14 C (4) C6 C7 C8 C (3) C12 C13 C14 C (4) C6 C7 C8 C (5) C19 C13 C14 C (4) C7 C8 C9 C (3) C17 C13 C14 C (3) C14 C8 C9 C (4) C8 C14 C15 C (3) C7 C8 C9 C (4) C13 C14 C15 C (4) C14 C8 C9 C (3) C14 C15 C16 C (4) C2 C1 C10 C (5) C15 C16 C17 O (4) C2 C1 C10 C (4) C15 C16 C17 C (3) C2 C1 C10 C (4) C15 C16 C17 C (4) C4 C5 C10 C (5) C12 C13 C17 O (4) C6 C5 C10 C (4) C19 C13 C17 O (3) C4 C5 C10 C (4) C14 C13 C17 O (3) C6 C5 C10 C (4) C12 C13 C17 C (3) C4 C5 C10 C (4) C19 C13 C17 C (4) C6 C5 C10 C (4) C14 C13 C17 C (4) C8 C9 C10 C (3) C12 C13 C17 C (4) C11 C9 C10 C (4) C19 C13 C17 C (4) C8 C9 C10 C (4) C14 C13 C17 C (3) C11 C9 C10 C (3) O4 C17 C20 O (4) C8 C9 C10 C (4) C16 C17 C20 O (6) C11 C9 C10 C (4) C13 C17 C20 O (4) C8 C9 C11 O (4) O4 C17 C20 C (5) C10 C9 C11 O (4) C16 C17 C20 C (4) C8 C9 C11 C (4) C13 C17 C20 C (5) Hydrogen-bond geometry (Å, º) D H A D H H A D A D H A O3 H3A O1 i 0.81 (3) 2.02 (4) (5) 153 (4) O4 H4A O3 ii 0.82 (5) 2.12 (5) (5) 165 (6) C12 H12A O (5) 105 C14 H14A O (6) 101 C16 H16A O (6) 107 data-6

10 C18 H18C O1 i (6) 165 C19 H19B O (6) 111 Symmetry codes: (i) x+1, y+1/2, z+1; (ii) x, y 1/2, z. data-7

organic compounds (E)-Ethyl N 0 -(3-hydroxybenzylidene)- hydrazinecarboxylate dihydrate

organic compounds (E)-Ethyl N 0 -(3-hydroxybenzylidene)- hydrazinecarboxylate dihydrate organic compounds Acta Crystallographica Section E Structure Reports Online ISSN 1600-5368 (E)-Ethyl N 0 -(3-hydroxybenzylidene)- hydrazinecarboxylate dihydrate Xian-Chao Hu, a,b * Jie Zhang, a Da-Yong