yl}-3-oxo-1,2,5-thiadiazolidin-2-ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B)

Transcription

1 journals.iucr.org/e Crystal structure of 5-{4 -[(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-4-methoxy-[1,1 -biphenyl]-3- yl}-3-oxo-1,2,5-thiadiazolidin-2-ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B) Kasi Viswanatharaju Ruddraraju, Roman Hillebrand, Charles L. Barnes and Kent S. Gates Acta Cryst. (2015). E71, IUCr Journals CRYSTALLOGRAPHY JOURNALS ONLINE This open-access article is distributed under the terms of the Creative Commons Attribution Licence which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited. Acta Cryst. (2015). E71, Ruddraraju et al. C 24 H 32 N 4 O 8 S

2 research communications ISSN Received 14 February 2015 Accepted 24 February 2015 Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland Keywords: crystal structure; PTP1B; inhibitor; 1,2,5-thiadiazolidin-3-one 1,1-dioxide; hydrogen bonding CCDC reference: Supporting information: this article has supporting information at journals.iucr.org/e Crystal structure of 5-{4 0 -[(2-{2-[2-(2-ammonioeth- oxy)ethoxy]ethoxy}ethyl)carbamoyl]-4-methoxy- [1,1 0 -biphenyl]-3-yl}-3-oxo-1,2,5-thiadiazolidin-2- ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B) Kasi Viswanatharaju Ruddraraju, Roman Hillebrand, Charles L. Barnes and Kent S. Gates* 125 Chemistry Bldg, University of Missouri Columbia, MO 65211, USA. *Correspondence gatesk@missouri.edu The title compound, C 24 H 32 N 4 O 8 S, (I), crystallizes as a zwitterion. The terminal amine N atom of the [(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl] side chain is protonated, while the 1,2,5-thiadiazolidin-3-one 1,1-dioxide N atom is deprotonated. The side chain is turned over on itself with an intramolecular N HO hydrogen bond. The 1,2,5-thiadiazolidin-3-one 1,1-dioxide ring has an envelope conformation with the aryl-substituted N atom as the flap. Its mean plane is inclined by (8) to the aryl ring to which it is attached, while the aryl rings of the biphenyl unit are inclined to one another by (8). In the crystal, molecules are linked by N HO and N HN hydrogen bonds, forming slabs lying parallel to (010). Within the slabs there are C HO and C HN hydrogen bonds and C H interactions present. 1. Chemical context A variety of 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides have been developed as inhibitors of the enzyme protein tyrosine phosphatase 1B (PTP1B) (Combs, 2010). In this capacity, the 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxide core serves as a structural mimic of the phosphoryl tyrosine unit that is present in the endogenous substrates of the enzyme. The parent compound, 5-phenyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide 1 (Fig. 1), is a rather weak inhibitor of PTP1B, displaying a K i value of approximately 2 mm (Black et al., 2005). Docking studies predicted that this compound must bind to the enzyme active site in a conformation where the planes of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl Figure 1 The parent compound 1 and related compounds. 336 doi: /s Acta Cryst. (2015). E71,

3 research communications rings are twisted, rather than co-planar (Black et al., 2005). It was further anticipated that installation of substituents such as methyl or methoxy groups on the aryl ring at the position ortho to the 1,2,5-thiadiazolidin-3-one 1,1-dioxide substituent would bias the conformation of the free ligand toward the twisted form, thus serving to pre-organize the compounds for binding to the enzyme active site (Black et al., 2005). Indeed, compounds 2 and 3 (K i values of 100 and 70 mm, respectively) display substantially higher affinities for PTP1B than does 1 (Black et al., 2005). X-ray crystal structure analysis confirmed the twisted conformation of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl ring systems in the protein ligand cocrystal structure of 4 bound to PTP1B (Black et al., 2005). The planes of these two rings are nearly perpendicular in the protein ligand complex (dihedral angle of ca 88, see: pdb code 2bgd). The ability of methyl and methoxy substituents to favor the twisted relationship between the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl rings in compounds like 2 and 3 has been studied computationally and the twisted relationship of these rings has been experimentally observed in the protein ligand co-crystal structure of 4 with the enzyme PTP1B. However, to the best of our knowledge no crystal structures of free 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides have been published. Herein, we describe the crystal structure of the title compound (I), shown in the scheme below, a derivative of compound Structural commentary The title compound (I), crystallized as a zwitterion (Fig. 2). The terminal amine N atom, N4, is protonated and the 1,2,5- Table 1 Hydrogen-bond geometry (Å, ). Cg1 is the centroid of the C3 C8 ring. D HA D H HA DA D HA N3 H1N3O3 i 0.82 (2) 2.22 (3) (2) 161 (2) N4 H1N4O1 ii 0.93 (3) 2.29 (3) (2) 133 (2) N4 H1N4O (3) 2.49 (3) (2) 124 (2) N4 H2N4N1 i 1.03 (3) 1.82 (3) (2) 163 (2) N4 H3N4O6 iii 0.98 (3) 1.99 (3) (2) 162 (3) C2 H2BO3 iv (2) 166 C18 H18AN1 i (2) 168 C22 H22AO8 ii (3) 129 C24 H24AO5 iii (2) 129 C21 H21BCg1 ii (2) 165 Symmetry codes: (i) x; y; z þ 1; (ii) x þ 1; y þ 1; z þ 1; (iii) x þ 1; y; z; (iv) x þ 1; y þ 2; z. thiadiazolidin-3-one 1,1-dioxide nitrogen atom, N1, is deprotonated. The [(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl] side chain is folded over on itself with an intramolecular N HO hydrogen bond involving the ammonium group, N4, and an ether O atom, O7 (Table 1 and Fig. 2). The aryl rings of the biphenyl unit (C3 C8 and C9 C14) are inclined to one another by (8). The 1,2,5- thiadiazolidin-3-one 1,1-dioxide ring (S1/N1/N2/C1/C2) has a shallow envelope conformation with nitrogen atom N2 as the flap. Its mean plane is inclined to the benzene ring to which it is attached (C3 C8) by (8). This twisted relationship between the planes of the 1,2,5-thiadiazolidin-3-one 1,1-dioxide and aryl rings is substantially less than that seen in the protein ligand co-crystal structure of 4 bound to PTP1B (Black et al., 2005), where these two rings are nearly perpendicular to one another with a dihedral angle of ca 88 (see: Protein Data Bank entry: code 2bgd). 3. Supramolecular features In the crystal of (I), molecules are linked by N HO and N HN hydrogen bonds, forming slabs lying parallel to the ac plane (Fig. 3 and Table 1). Within the slabs there are also Figure 2 A view of the molecular structure of the title compound (I), showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular N HO hydrogen bond is shown as a dashed line (see Table 1 for details) and C-bound H atoms have been omitted for clarity. Figure 3 A view along the c axis of the crystal packing of the title compound. The N HO and N HO hydrogen bonds are shown as dashed lines (see Table 1 for details) and C-bound H atoms have been omitted for clarity. Acta Cryst. (2015). E71, Ruddraraju et al. C 24 H 32 N 4 O 8 S 337

4 research communications Table 2 Experimental details. Crystal data Chemical formula C 24 H 32 N 4 O 8 S M r Crystal system, space group Triclinic, P1 Temperature (K) 100 a, b, c (Å) (2), (3), (4),, ( ) (1), (2), (1) V (Å 3 ) (6) Z 2 Radiation type Cu K (mm 1 ) 1.67 Crystal size (mm) Data collection Diffractometer Bruker APEXII CCD area detector Absorption correction Multi-scan (SADABS; Bruker, 2008) T min, T max 0.89, 0.97 No. of measured, independent and 15014, 4539, 4292 observed [I > 2(I)] reflections R int (sin /) max (Å 1 ) Refinement R[F 2 >2(F 2 )], wr(f 2 ), S 0.039, 0.111, 1.03 No. of reflections 4539 No. of parameters 351 H-atom treatment H atoms treated by a mixture of independent and constrained refinement max, min (e Å 3 ) 0.56, 0.33 Computer programs: APEX2 and SAINT (Bruker, 2008), SHELXS2013 (Sheldrick, 2008), SHELXL2013 (Sheldrick, 2015) and Mercury (Macrae et al., 2008). 5. Synthesis and crystallization The title compound was synthesized by amide bond formation between tert-butyl (2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethyl)carbamate and 3 0 -(1,1-dioxido-4-oxo-1,2,5-thiadiazolidin-2-yl)-4 0 -methoxy-[1,1 0 -biphenyl]-4-carboxylic acid via (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate. The precursors were synthesized according to published procedures (Black et al., 2005; Schwabacher et al., 1998). Full synthetic details will be published elsewhere. Single crystals of the title compound (I) were obtained by slow evaporation of a solution of (I) in methanol. 6. Refinement details Crystal data, data collection and structure refinement details are summarized in Table 2. The N-bound H atoms were located in a difference Fourier map and freely refined. The C- bound H atoms were included in calculated positions and treated as riding: C H = Å with U iso (H) = 1.5U eq (C) for methyl H atoms and = 1.2U eq (C) for other H atoms. Acknowledgements We are grateful to the National Institutes of Health (CA ) for partial support of this work. C HO and C HN hydrogen bonds and C H interactions present reinforcing the two-dimensional structure (Table 1). 4. Database survey A search of the Cambridge Structural Database (Version 5.36; Groom & Allen, 2014) revealed no crystal structures of free 5-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides. It did reveal the presence of five 1,2,5-thiadiazolidin-3-one 1,1-dioxide compounds substituted at the N atom in the 2-position. In the majority of these compounds, the five-membered 1,2,5-thiadiazolidine rings also have envelope conformations, with the N atom in the 5-position, as in compound (I), as the flap. References Black, E., Breed, J., Breeze, A. L., Embrey, K., Garcia, R., Gero, T. W., Godfrey, L., Kenny, P. W., Morley, A. D., Minshull, C. A., Pannifer, A. D., Read, J., Rees, A., Russell, D. J., Toader, D. & Tucker, J. (2005). Bioorg. Med. Chem. Lett. 15, Bruker (2008). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA. Combs, A. P. (2010). J. Med. Chem. 53, Groom, C. R. & Allen, F. H. (2014). Angew. Chem. Int. Ed. 53, Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, Schwabacher, A. W., Lane, J. W., Schiesher, M. W., Leigh, K. M. & Johnson, C. W. (1998). J. Org. Chem. 63, Sheldrick, G. M. (2008). Acta Cryst. A64, Sheldrick, G. M. (2015). Acta Cryst. C71, Ruddraraju et al. C 24 H 32 N 4 O 8 S Acta Cryst. (2015). E71,

5 supporting information [doi: /s ] Crystal structure of 5-{4 -[(2-{2-[2-(2-ammonioethoxy)ethoxy]ethoxy}ethyl)- carbamoyl]-4-methoxy-[1,1 -biphenyl]-3-yl}-3-oxo-1,2,5-thiadiazolidin-2-ide 1,1-dioxide: a potential inhibitor of the enzyme protein tyrosine phosphatase 1B (PTP1B) Kasi Viswanatharaju Ruddraraju, Roman Hillebrand, Charles L. Barnes and Kent S. Gates Computing details Data collection: APEX2 (Bruker, 2008); cell refinement: SAINT (Bruker, 2008); data reduction: SAINT (Bruker, 2008); program(s) used to solve structure: SHELXS2013 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2013 (Sheldrick, 2015). 5-{4 -[(2-{2-[2-(2-Ammonioethoxy)ethoxy]ethoxy}ethyl)carbamoyl]-4-methoxy-[1,1 -biphenyl]-3-yl}-3-oxo-1,2,5- thiadiazolidin-2-ide 1,1-dioxide Crystal data C 24 H 32 N 4 O 8 S M r = Triclinic, P1 a = (2) Å b = (3) Å c = (4) Å α = (1) β = (2) γ = (1) V = (6) Å 3 Data collection Bruker APEXII CCD area-detector diffractometer Radiation source: Incoatec microfocus Cu tube ω and phi scans Absorption correction: multi-scan (SADABS; Bruker, 2008) T min = 0.89, T max = measured reflections Refinement Refinement on F 2 Least-squares matrix: full R[F 2 > 2σ(F 2 )] = Z = 2 F(000) = 568 D x = Mg m 3 Cu Kα radiation, λ = Å Cell parameters from 8971 reflections θ = µ = 1.67 mm 1 T = 100 K Plate, colourless mm 4539 independent reflections 4292 reflections with I > 2σ(I) R int = θ max = 72.1, θ min = 3.2 h = 8 7 k = l = wr(f 2 ) = S = reflections sup-1

6 351 parameters 0 restraints Hydrogen site location: mixed H atoms treated by a mixture of independent and constrained refinement w = 1/[σ 2 (F o2 ) + (0.0647P) P] where P = (F o 2 + 2F c2 )/3 (Δ/σ) max < Δρ max = 0.56 e Å 3 Δρ min = 0.33 e Å 3 Special details Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes. Refinement. Maximum electron density of 0.56 e is in the vicinity of C21 in the extended chain and may represent very minor disorder. Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 ) x y z U iso */U eq S (5) (3) (3) (13) O (19) (11) (10) (3) O (18) (11) (10) (3) O (18) (10) (9) (3) O (17) (10) (9) (3) O (17) (11) (9) (3) O (18) (11) (9) (3) O (19) (10) (10) (3) O (2) (11) (10) (3) N (2) (12) (10) (3) N (2) (11) (10) (3) N (2) (12) (11) (3) H1N (3) (18) (16) (6)* N (3) (14) (12) (3) H1N (4) (3) (2) (8)* H2N (3) (2) (19) (6)* H3N (5) (2) (2) (8)* C (2) (14) (12) (3) C (2) (13) (11) (3) H2A * H2B * C (2) (13) (12) (3) C (2) (13) (12) (3) C (2) (14) (13) (4) H * C (2) (14) (12) (3) H * C (2) (13) (12) (3) C (2) (13) (12) (3) H * C (2) (13) (12) (3) C (2) (14) (12) (3) sup-2

7 H * C (2) (14) (12) (4) H * C (2) (13) (12) (3) C (3) (16) (13) (4) H * C (3) (16) (13) (4) H * C (3) (19) (15) (4) H15A * H15B * H15C * C (2) (14) (13) (4) C (3) (15) (13) (4) H17A * H17B * C (3) (16) (13) (4) H18A * H18B * C (3) (16) (14) (4) H19A * H19B * C (3) (15) (15) (4) H20A * H20B * C (3) (19) (17) (5) H21A * H21B * C (4) (2) (17) (6) H22A * H22B * C (3) (16) (15) (4) H23A * H23B * C (3) (15) (14) (4) H24A * H24B * Atomic displacement parameters (Å 2 ) U 11 U 22 U 33 U 12 U 13 U 23 S (2) (2) (2) (15) (15) (14) O (8) (6) (7) (5) (6) (5) O (7) (7) (7) (5) (6) (6) O (7) (6) (6) (5) (5) (5) O (6) (6) (6) (5) (5) (5) O (7) (7) (7) (5) (5) (6) O (7) (6) (7) (5) (5) (5) sup-3

8 O (7) (6) (7) (5) (6) (5) O (8) (7) (7) (6) (6) (6) N (8) (7) (7) (6) (6) (6) N (8) (7) (7) (5) (6) (5) N (8) (8) (7) (6) (6) (6) N (10) (8) (8) (7) (7) (6) C (8) (8) (8) (6) (6) (6) C (8) (7) (8) (6) (6) (6) C (8) (7) (8) (6) (6) (6) C (9) (7) (8) (6) (7) (6) C (8) (8) (9) (6) (7) (7) C (9) (8) (8) (6) (7) (6) C (9) (7) (8) (6) (6) (6) C (8) (8) (8) (6) (6) (6) C (9) (8) (8) (6) (6) (6) C (9) (8) (8) (6) (7) (6) C (9) (8) (8) (6) (7) (6) C (9) (8) (8) (6) (6) (6) C (9) (10) (9) (7) (7) (7) C (10) (10) (8) (7) (7) (7) C (9) (12) (10) (8) (8) (9) C (10) (8) (9) (6) (7) (6) C (9) (9) (9) (7) (7) (7) C (9) (10) (8) (7) (7) (7) C (9) (9) (10) (7) (8) (8) C (9) (9) (11) (7) (8) (8) C (12) (12) (12) (9) (10) (10) C (14) (17) (11) (12) (10) (10) C (12) (9) (10) (8) (9) (8) C (11) (9) (9) (7) (8) (7) Geometric parameters (Å, º) S1 O (13) C8 H S1 O (13) C9 C (2) S1 N (14) C9 C (3) S1 N (14) C10 C (2) O3 C (2) C10 H O4 C (2) C11 C (2) O4 C (2) C11 H O5 C (2) C12 C (3) O6 C (2) C12 C (2) O6 C (2) C13 C (3) O7 C (2) C13 H O7 C (2) C14 H O8 C (3) C15 H15A O8 C (2) C15 H15B N1 C (2) C15 H15C sup-4

9 N2 C (2) C17 C (3) N2 C (2) C17 H17A N3 C (2) C17 H17B N3 C (2) C18 H18A N3 H1N (2) C18 H18B N4 C (2) C19 C (3) N4 H1N (3) C19 H19A N4 H2N (3) C19 H19B N4 H3N (3) C20 H20A C1 C (2) C20 H20B C2 H2A C21 C (3) C2 H2B C21 H21A C3 C (2) C21 H21B C3 C (2) C22 H22A C4 C (2) C22 H22B C5 C (2) C23 C (3) C5 H C23 H23A C6 C (2) C23 H23B C6 H C24 H24A C7 C (2) C24 H24B C7 C (2) O2 S1 O (8) C14 C13 H O2 S1 N (8) C12 C13 H O1 S1 N (8) C13 C14 C (17) O2 S1 N (8) C13 C14 H O1 S1 N (8) C9 C14 H N1 S1 N (7) O4 C15 H15A C4 O4 C (14) O4 C15 H15B C19 O6 C (14) H15A C15 H15B C21 O7 C (15) O4 C15 H15C C22 O8 C (18) H15A C15 H15C C1 N1 S (12) H15B C15 H15C C3 N2 C (13) O5 C16 N (16) C3 N2 S (11) O5 C16 C (16) C2 N2 S (11) N3 C16 C (16) C16 N3 C (16) N3 C17 C (15) C16 N3 H1N (16) N3 C17 H17A C17 N3 H1N (15) C18 C17 H17A C24 N4 H1N (17) N3 C17 H17B C24 N4 H2N (14) C18 C17 H17B H1N4 N4 H2N4 107 (2) H17A C17 H17B C24 N4 H3N (17) O6 C18 C (14) H1N4 N4 H3N4 117 (2) O6 C18 H18A H2N4 N4 H3N4 109 (2) C17 C18 H18A O3 C1 N (16) O6 C18 H18B O3 C1 C (15) C17 C18 H18B N1 C1 C (14) H18A C18 H18B sup-5

10 N2 C2 C (13) O6 C19 C (15) N2 C2 H2A O6 C19 H19A C1 C2 H2A C20 C19 H19A N2 C2 H2B O6 C19 H19B C1 C2 H2B C20 C19 H19B H2A C2 H2B H19A C19 H19B C8 C3 C (15) O7 C20 C (15) C8 C3 N (15) O7 C20 H20A C4 C3 N (15) C19 C20 H20A O4 C4 C (16) O7 C20 H20B O4 C4 C (15) C19 C20 H20B C5 C4 C (15) H20A C20 H20B C6 C5 C (16) O7 C21 C (18) C6 C5 H O7 C21 H21A C4 C5 H C22 C21 H21A C5 C6 C (16) O7 C21 H21B C5 C6 H C22 C21 H21B C7 C6 H H21A C21 H21B C6 C7 C (15) O8 C22 C (2) C6 C7 C (15) O8 C22 H22A C8 C7 C (15) C21 C22 H22A C3 C8 C (16) O8 C22 H22B C3 C8 H C21 C22 H22B C7 C8 H H22A C22 H22B C10 C9 C (16) O8 C23 C (16) C10 C9 C (15) O8 C23 H23A C14 C9 C (15) C24 C23 H23A C11 C10 C (16) O8 C23 H23B C11 C10 H C24 C23 H23B C9 C10 H H23A C23 H23B C10 C11 C (16) N4 C24 C (16) C10 C11 H N4 C24 H24A C12 C11 H C23 C24 H24A C11 C12 C (16) N4 C24 H24B C11 C12 C (16) C23 C24 H24B C13 C12 C (16) H24A C24 H24B C14 C13 C (17) O2 S1 N1 C (13) C9 C7 C8 C (14) O1 S1 N1 C (13) C6 C7 C9 C (2) N2 S1 N1 C (14) C8 C7 C9 C (16) O2 S1 N2 C (15) C6 C7 C9 C (16) O1 S1 N2 C (15) C8 C7 C9 C (2) N1 S1 N2 C (14) C14 C9 C10 C (3) O2 S1 N2 C (12) C7 C9 C10 C (15) O1 S1 N2 C (13) C9 C10 C11 C (3) N1 S1 N2 C (13) C10 C11 C12 C (2) S1 N1 C1 O (14) C10 C11 C12 C (15) sup-6

11 S1 N1 C1 C (19) C11 C12 C13 C (3) C3 N2 C2 C (15) C16 C12 C13 C (17) S1 N2 C2 C (16) C12 C13 C14 C9 2.3 (3) O3 C1 C2 N (16) C10 C9 C14 C (3) N1 C1 C2 N2 7.3 (2) C7 C9 C14 C (17) C2 N2 C3 C (17) C17 N3 C16 O5 7.3 (3) S1 N2 C3 C (19) C17 N3 C16 C (14) C2 N2 C3 C (2) C11 C12 C16 O (17) S1 N2 C3 C (16) C13 C12 C16 O (2) C15 O4 C4 C5 3.1 (2) C11 C12 C16 N (2) C15 O4 C4 C (15) C13 C12 C16 N (16) C8 C3 C4 O (14) C16 N3 C17 C (19) N2 C3 C4 O4 0.1 (2) C19 O6 C18 C (15) C8 C3 C4 C5 0.3 (2) N3 C17 C18 O (2) N2 C3 C4 C (15) C18 O6 C19 C (15) O4 C4 C5 C (15) C21 O7 C20 C (17) C3 C4 C5 C6 0.2 (2) O6 C19 C20 O (19) C4 C5 C6 C7 0.6 (3) C20 O7 C21 C (19) C5 C6 C7 C8 1.1 (2) C23 O8 C22 C (2) C5 C6 C7 C (15) O7 C21 C22 O (3) C4 C3 C8 C7 0.3 (2) C22 O8 C23 C (2) N2 C3 C8 C (14) O8 C23 C24 N (2) C6 C7 C8 C3 1.0 (2) Hydrogen-bond geometry (Å, º) Cg1 is the centroid of the C3 C8 ring. D H A D H H A D A D H A N3 H1N3 O3 i 0.82 (2) 2.22 (3) (2) 161 (2) N4 H1N4 O1 ii 0.93 (3) 2.29 (3) (2) 133 (2) N4 H1N4 O (3) 2.49 (3) (2) 124 (2) N4 H2N4 N1 i 1.03 (3) 1.82 (3) (2) 163 (2) N4 H3N4 O6 iii 0.98 (3) 1.99 (3) (2) 162 (3) C2 H2B O3 iv (2) 166 C18 H18A N1 i (2) 168 C22 H22A O8 ii (3) 129 C24 H24A O5 iii (2) 129 C21 H21B Cg1 ii (2) 165 Symmetry codes: (i) x, y, z+1; (ii) x+1, y+1, z+1; (iii) x+1, y, z; (iv) x+1, y+2, z. sup-7