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

Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 74| Part 3| March 2018| Pages 400-405
https://doi.org/10.1107/S2056989018002955

Crystal structure and conformational analysis of doxorubicin nitrate

CROSSMARK_Color_square_no_text.svg
Logesh Mathivathanan,a* Guang Yang,a,b Fenfei Lenga and Raphael G. Raptisa

aDepartment of Chemistry and Biochemistry and Biomolecular Sciences Institute, Florida International University, 11200 SW 8th St, Miami, FL 33199, USA, and bCollege of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, Henan, 450001, People's Republic of China
*Correspondence e-mail: logesh.mathivathanan@fiu.edu

Edited by M. Weil, Vienna University of Technology, Austria (Received 2 February 2018; accepted 19 February 2018; online 28 February 2018)

Crystal structure determination of doxorubicin nitrate, (DoxH)NO3, systematic name (7S,9S)-7-{[(2R,4S,5S,6S)-4-azaniumyl-5-hy­droxy-6-methyl­oxan-2-yl]­oxy}-6,9,11-trihy­droxy-9-(2-hy­droxy­acet­yl)-4-meth­oxy-8,10-di­hydro-7H-tetra­cen-5,12-dione nitrate, shows two formula units present in the asymmetric unit. In the crystal lattice, hydrogen-bonded pairs of (DoxH+) cations and segregation of the aglycone and sugar moieties are observed. Inspection of mol­ecular overlays reveals that the conformation of (DoxH)NO3 resembles that of DNA-inter­calated, but not of protein-docked (DoxH)+. The structure was refined as a two-component twin.

CCDC reference: 1815074

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1. Chemical context

Since its discovery and isolation by genetic mutation of Streptomyces peucetius in 1969 (Arcamone et al., 1969[Arcamone, F., Cassinelli, G., Fantini, G., Grein, A., Orezzi, P., Pol, C. & Spalla, C. (1969). Biotechnol. Bioeng. 11, 1101-1110.]), the anthracycline anti­biotic doxorubicin [(Dox); trade name adriamycin] has become one of the most potent and widely used drugs in cancer chemotherapy (Denel-Bobrowska & Marczak, 2017[Denel-Bobrowska, M. & Marczak, A. (2017). Life Sci. 178, 1-8.]; Cagel et al., 2017[Cagel, M., Grotz, E., Bernabeu, E., Moretton, M. A. & Chiappetta, D. A. (2017). Drug Discov. Today, 22, 270-281.]; Cappetta et al., 2018[Cappetta, D., Rossi, F., Piegari, E., Quaini, F., Berrino, L., Urbanek, K. & De Angelis, A. (2018). Pharmacol. Res. 127, 4-14.]). Extensive studies of the anti­cancer activities of doxorubicin (Weiss, 1992[Weiss, R. B. (1992). Semin. Oncol. 19, 670-686.]; Shafei et al., 2017[Shafei, A., El-Bakly, W., Sobhy, A., Wagdy, O., Reda, A., Aboelenin, O., Marzouk, A., El Habak, K., Mostafa, R., Ali, M. A. & Ellithy, M. (2017). Biomed. Pharmacother. 95, 1209-1218.]) have led to FDA approval for the treatment of cancer forms, such as breast (Shafei et al., 2017[Shafei, A., El-Bakly, W., Sobhy, A., Wagdy, O., Reda, A., Aboelenin, O., Marzouk, A., El Habak, K., Mostafa, R., Ali, M. A. & Ellithy, M. (2017). Biomed. Pharmacother. 95, 1209-1218.]), ovarian (Duggan & Keating, 2011[Duggan, S. T. & Keating, G. M. (2011). Drugs, 71, 2531-2558.]) and small-cell lung cancer (López-González et al., 2013[López-González, A., Diz, P., Gutierrez, L., Almagro, E., Palomo, A. G. & Provencio, M. (2013). Ann. Transl. Med. 1, 5.]). The anti­cancer action of doxorubicin is a consequence of its inter­calation into base pairs of double-stranded DNA and subsequent inhibition of human DNA topoisomerase II (Arcamone, 1981[Arcamone, F. (1981). Doxorubicin: Anticancer Antibiotics. Academic Press.]; Liu, 1989[Liu, L. F. (1989). Annu. Rev. Biochem. 58, 351-375.]; Chaires, 1998[Chaires, J. B. (1998). Curr. Opin. Struct. Biol. 8, 314-320.]; Yang & Wang, 1999[Yang, X.-L. & Wang, A. H.-J. (1999). Pharmacol. Ther. 83, 181-215.]; Jung & Reszka, 2001[Jung, K. & Reszka, R. (2001). Adv. Drug Deliv. Rev. 49, 87-105.]). Although a few crystal structures of doxorubicin bound to DNA, enzymes and proteins have been reported, to the best of our knowledge, there is no crystal structure determination of doxorubicin itself in the literature. A Cambridge Structural Database (CSD version 5.38; Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]) search for the doxorubicin skeleton structure gave only two hits for hydro­chloride salts of N- and O-substituted variants [CSD entries ADRMVL (Eckle & Stezowski, 1980[Eckle, E. & Stezowski, J. J. (1980). European Crystallographic Meeting, 6, 296.]) and BUJZIP (Eckle & Stezowski, 1983[Eckle, E. & Stezowski, J. J. (1983). Z. Kristallogr. 162, 63.])]. Even for daunorubicin (also known as daunomycin), a closely related anthracycline anti­biotic, only the crystal structures of its hydro­chloride solvates have been reported (Neidle & Taylor, 1977[Neidle, S. & Taylor, G. (1977). Biochim. Biophys. Acta, 479, 450-459.]; Courseille et al., 1979[Courseille, C., Busetta, B., Geoffre, S. & Hospital, M. (1979). Acta Cryst. B35, 764-767.]). In the absence of a high-resolution crystal structure, researchers have so far relied on computational and solution studies to ascertain the preferred conformational geometry of (Dox) (Zhu et al., 2010[Zhu, S., Yan, L., Ji, X. & Lu, W. (2010). J. Mol. Struct. Theochem, 951, 60-68.]; Agrawal et al., 2009[Agrawal, P., Barthwal, S. K. & Barthwal, R. (2009). Eur. J. Med. Chem. 44, 1437-1451.]; Barthwal et al., 2008[Barthwal, R., Agrawal, P., Tripathi, A. N., Sharma, U., Jagannathan, N. R. & Govil, G. (2008). Arch. Biochem. Biophys. 474, 48-64.]).

[Scheme 1]

In order to probe and improve the activity of (Dox), several derivatives have been studied (Post et al., 2005[Post, G. C., Barthel, B. L., Burkhart, D. J., Hagadorn, J. R. & Koch, T. H. (2005). J. Med. Chem. 48, 7648-7657.]). Metal complexation to doxorubicin is known to alter its pharmaceutical activity and several Fe, Mn, Pt and Sn derivatives of the anthracycline have been studied with regard to their anti­cancer activities (Ming, 2003[Ming, L.-J. (2003). Med. Res. Rev. 23, 697-762.]). (DoxH)+-functionalized iron oxide nanoparticles have been studied as cancer thera­nostics (Yu et al., 2008[Yu, M. K., Jeong, Y. Y., Park, J., Park, S., Kim, J. W., Min, J. J., Kim, K. & Jon, S. (2008). Angew. Chem. Int. Ed. 47, 5362-5365.]). With a similar objective, we have attempted to coordinate Ag+ to (Dox). However, mixing stoichiometric amounts of (DoxH)Cl and AgNO3 in the presence of Et3N yielded only the nitrate derivative of (Dox) as (DoxH)NO3 in crystalline form. In this article, we report the 0.80 Å resolution crystal structure determination of doxorubicin nitrate and analyze and compare conformational details.

2. Structural commentary

The title compound crystallizes in the chiral monoclinic P21 space group with two protonated doxorubicin cations (DoxH+) and two nitrate anions in the asymmetric unit. The (DoxH)+ cations consist of an aglycone, containing three approximately planar fused rings (the root-mean-square deviations of the six rings in the asymmetric unit are between 0.009 and 0.027 Å, B–D; the atom-numbering scheme and ring labels are shown in the scheme), and a sugar moiety in a chair conformation attached to ring A. Two nitrate ions hold pairs of cations with their fused rings at an approximately right angle to each other [86.4 (4)° between C1–C20 and N62(O64–O66)]. The two cations present in the asymmetric unit are rather similar, exhibiting insignificant differences (Fig. 1[link]).

[Figure 1]
Figure 1
Mol­ecular structure of (DoxH)+ showing the atom-labeling scheme. Only one of the mol­ecules present in the asymmetric unit is shown, with displacement ellipsoids drawn at the 40% probability level. H atoms are not presented for clarity. Inset: Mol­ecular overlay of the two crystallographically independent (DoxH)+ moieties present in the asymmetric unit. The molecular overlay was performed using the function available within the Discovery Studio Visualizer Suite. The target chosen was one of the (Dox) units from the crystal structure, with the H atoms ignored.

In 2010, Zhu and co-workers published a detailed conformational analysis of anthracycline anti­biotics, including doxorubicin, based on previously published (Dox)–protein and (Dox)–DNA complexes as well as DFT calculations (Zhu et al., 2010[Zhu, S., Yan, L., Ji, X. & Lu, W. (2010). J. Mol. Struct. Theochem, 951, 60-68.]). The analysis identified three important doxorubicin conformational domains: (1) the aromatic ring system, (2) the functional group at C9 and (3) at C7 relating to the aminal linkage:

(1) The aromatic anthracycline ring system does not vary significantly in any of the DNA-bound (Dox) structures and in the structure in this study. A somewhat more pronounced variation is encountered in protein-bound-(Dox), such as the one in 4dx7 or 4mra (vide infra). Based on the B3LYP level of theory, Zhu et al. have proposed four types of stable conformational isomers, with type I tautomer – forming two hydrogen bonds between C5—O and C6—OH and between C12—O and C11—OH – being the preferred one. The crystal structure in the present report confirms this prediction.

(2) The C8 carbon can either be above or below the anthracycline planes; in this structure, C8 is above the plane and the C19—C20—C7—C8 torsion angles are 16.6 (6)° and 17.5 (7)° (Table 1[link]). This is in the expected range for an inter­calating (Dox), but significantly deviates from that found in a protein-bound (Dox). The conformation at C9 is similar to that at C8, as C9 is almost coplanar the anthracycline plane [C20—C19—C10—C9 torsion angles are 18.9 (6) and 19.2 (6)°]. More dramatic variations between the conformations of C8 and C9 are observed in the protein-bound (Dox) (5mra), where their torsion angles are 47.75 and −49.70°, respectively. According to a study based on resonant mol­ecular dynamic calculations and NMR experiments, the conformation with a C7—O7—C1*—C2* torsion angle of 142–143° was found to be biologically relevant (Barthwal et al., 2008[Barthwal, R., Agrawal, P., Tripathi, A. N., Sharma, U., Jagannathan, N. R. & Govil, G. (2008). Arch. Biochem. Biophys. 474, 48-64.]; Agrawal et al., 2009[Agrawal, P., Barthwal, S. K. & Barthwal, R. (2009). Eur. J. Med. Chem. 44, 1437-1451.]). However, this seems to be only applicable to DNA-inter­calated (Dox). Protein-bound (Dox) have a wider range of torsion angles, for example, 88.43° in sorcin-bound (Dox), to 150.82° in AcrB-bound (Dox). The (Dox) structure in the present study has torsion angles of 161.6 (5) and 162.6 (4)°.

Table 1
Conformational parameters (°) of one of the (DoxH)+ cations present in the title compound, (DoxH)NO3, and representative examples from the literature

  (DoxH)NO3 AcrB-(Dox) (4dx7)a Sorcin-(Dox) (5mra)b DNA-(Dox) (1p20)c
C7—O7—C1*—C2* 161.6 (5), 162.6 (4) 150.82 88.43 144.36
C8 conformation C19—C20—C7—C8 16.6 (6), 17.5 (7) −18.93 47.75 8.92
C9 conformation C20—C19—C10—C9 18.9 (6), 19.2 (6) −9.27 −49.70 22.91
O7—N3* 7.947 (1), 8.042 (1) 7.636 6.433 6.481
Notes: (a) Eicher et al. (2012[Eicher, T., Cha, H., Seeger, M. A., Brandstätter, L., El-Delik, J., Bohnert, J. A., Kern, W. V., Verrey, F., Grütter, M. G., Diederichs, K. & Pos, K. M. (2012). Proc. Natl Acad. Sci. 109, 5687-5692.]); b Genovese et al. (2017[Genovese, I., Fiorillo, A., Ilari, A., Masciarelli, S., Fazi, F. & Colotti, G. (2017). Cell Death Dis. 8, e2950.]); c Howerton et al. (2003[Howerton, S. B., Nagpal, A. & Dean Williams, L. (2003). Biopolymers, 69, 87-99.]).

(3) The C7-connected daunosamine is the most flexible conformational entity in (Dox). The N3*—O7(C5) distance (2.74–8.50 Å) determines the conformational diversity. In the present structure, the corresponding distances are 7.947 (1) and 8.042 (2) Å, which are on the longer end of the spectrum. The presence of the nitrate ions between the two (Dox) fragments of the asymmetric unit influences this distance greatly.

3. Supra­molecular features

The ammonium group forms hydrogen bonds with nitrate counter-ions with N⋯O distances of 2.836 (8), 2.876 (9) and 2.865 (8) Å (Table 2[link]). The crystal structure is further stabilized by an extensive network of inter- and intra­molecular O—H⋯O and N—H⋯O hydrogen bonds (Table 2[link]), in addition to two inter­molecular π–π inter­actions between the C and D rings of the aglycone moiety [centroid-to-centroid distances: 3.526 (3) and 3.694 (4) Å, Figs. 2[link] and 3[link]] and a C—H⋯π inter­action with Cg2 [Cg2 is the centroid of the C1–C4/C15/C16 ring; C⋯Cg distance 3.556 (7) Å].

Table 2
Hydrogen-bond geometry (Å, °)

Cg2 is the centroid of the C1–C4/C15/C16 ring.
D—H⋯A D—H H⋯A D⋯A D—H⋯A
O6—H6⋯O5 0.82 1.81 2.526 (6) 146
O11—H11⋯O12 0.82 1.80 2.526 (6) 146
O14—H14⋯O65i 0.82 2.07 2.779 (9) 145
N3*—H3*A⋯O13ii 0.89 2.00 2.874 (7) 167
N3*—H3*C⋯O63 0.89 1.99 2.865 (8) 168
O41—H41⋯O42 0.82 1.82 2.537 (6) 146
O44—H44⋯O14iii 0.82 2.08 2.888 (6) 168
O55—H55⋯O4* 0.82 1.93 2.724 (6) 163
N54—H54A⋯O43iv 0.89 2.18 2.890 (7) 136
N54—H54A⋯O44iv 0.89 2.05 2.843 (7) 147
N54—H54B⋯O62 0.89 1.99 2.836 (8) 159
N54—H54C⋯O64 0.89 2.05 2.876 (9) 155
C38—H38B⋯Cg2v 0.97 2.64 3.556 (7) 157
Symmetry codes: (i) x-1, y, z+1; (ii) x, y, z-1; (iii) x+2, y, z; (iv) x-1, y, z-1; (v) [-x+1, y+{\script{1\over 2}}, -z+1].
[Figure 2]
Figure 2
Mol­ecular packing diagram of (DoxH)NO3 viewed parallel to the crystallographic a axis.
[Figure 3]
Figure 3
Representation highlighting the π–π inter­actions between C and D rings of the aglycone moieties. Turquoise spheres indicate centroids.

4. Database survey

Table 3[link] lists the published crystal structures of macromolecules with (Dox) as the ligand (DM2 ligand code in PDB; Berman et al., 2000[Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. & Bourne, P. E. (2000). Nucleic Acids Res. 28, 235-242.]). To analyze the significance of the new (DoxH)NO3 crystal structure, structural comparisons were made by performing mol­ecular overlays (Dassault Systèmes BIOVIA, 2017[Dassault Systèmes BIOVIA (2017). Discovery Studio Visualizer. San Diego, CA, USA.]) of the current structure with published (Dox)-bound protein/DNA structures, which resulted in the following observations: (1) The most important functional groups are, understandably, the amino group of the daunosamine moiety and the hydroxyl group of the glycolic site; (2) (Dox) binds in the DNA minor groove and (3) while the crystal structure reported here is by and large quite similar to the one of (Dox) bound in DNA, significant conformational differences are prominent in comparison to protein-bound (Dox), mainly because of differences in hydrogen-bond donors present in proteins.

Table 3
Selected RCSB-PDB entries with (Dox) (DM2) as the ligand

PDB accession (Reference) Macromolecule(s) Resolution (Å)
5MRA (Genovese et al., 2017[Genovese, I., Fiorillo, A., Ilari, A., Masciarelli, S., Fazi, F. & Colotti, G. (2017). Cell Death Dis. 8, e2950.]) Sorcin (protein) 3.74
4ZVM (Leung & Shilton, 2015[Leung, K. K. K. & Shilton, B. H. (2015). Biochemistry, 54, 7438-7448.]) Ribsyldi­hydro­nicotinamide de­hydrogenase 1.97
4DX7 (Eicher et al., 2012[Eicher, T., Cha, H., Seeger, M. A., Brandstätter, L., El-Delik, J., Bohnert, J. A., Kern, W. V., Verrey, F., Grütter, M. G., Diederichs, K. & Pos, K. M. (2012). Proc. Natl Acad. Sci. 109, 5687-5692.]) Acriflavine resistance protein B (protein) DARPIN (protein) 2.25
2DR6 (Murakami et al., 2006[Murakami, S., Nakashima, R., Yamashita, E., Matsumoto, T. & Yamaguchi, A. (2006). Nature, 443, 173-179.]) AcrB (protein) 3.3
1P20 (Howerton et al., 2003[Howerton, S. B., Nagpal, A. & Dean Williams, L. (2003). Biopolymers, 69, 87-99.]) DNA 1.34
1I1E (Eswaramoorthy et al., 2001[Eswaramoorthy, S., Kumaran, D. & Swaminathan, S. (2001). Acta Cryst. D57, 1743-1746.]) Botulinium Neurotoxin Type B (protein) 2.5
151D (Lipscomb et al., 1994[Lipscomb, L. A., Peek, M. E., Zhou, F. X., Bertrand, J. A., VanDerveer, D. & Williams, L. D. (1994). Biochemistry, 33, 3649-3659.]) DNA 1.4
1DA9 (Leonard et al., 1993[Leonard, G. A., Hambley, T. W., McAuley-Hecht, K., Brown, T. & Hunter, W. N. (1993). Acta Cryst. D49, 458-467.]) DNA 1.7
1D12 (Frederick et al., 1990[Frederick, C. A., Williams, L. D., Ughetto, G., Van der Marel, G. A., Van Boom, J. H., Rich, A. & Wang, A. H. J. (1990). Biochemistry, 29, 2538-2549.]) DNA 1.7

Binding of (Dox) to sorcin, a calcium-binding protein that causes multidrug resistance (MDR) in human tumors, impairs cell death. Sorcin is overexpressed in human tumors and MDR cancers. Two sites, designated as pocket 1 and pocket 2, were found to bind (Dox), which was modeled satisfactorily at pocket 1, but not at pocket 2. The mol­ecular overlay in Fig. 4[link]a shows the significant differences in the conformation: meth­oxy and the glycolic units are significantly rotated from their native state. On the contrary, DNA-bound (inter­calated) (Dox) and (Dox) in this study do not differ significantly in their conformations, as shown in (Dox)-1p20 in Fig. 4[link] below.

[Figure 4]
Figure 4
Representative mol­ecular overlays of doxorubicin from this study (purple) and the ones from the literature.

In another study, three mol­ecules of (Dox) were found to bind the AcrB protein (PDB accession 4dx7; Eicher et al., 2012[Eicher, T., Cha, H., Seeger, M. A., Brandstätter, L., El-Delik, J., Bohnert, J. A., Kern, W. V., Verrey, F., Grütter, M. G., Diederichs, K. & Pos, K. M. (2012). Proc. Natl Acad. Sci. 109, 5687-5692.]). Although the conformational differences are not as stark as they were in sorcin, the rotation now being about the bond between glycol-O carbon and the A ring [(Dox)-4dx7 in Fig. 5]. In the neurotoxin BoNT/B-(Dox) complex, O13 and O14 of the aglycone inter­act with the toxin and is stacked between Trp1261 and His1240 (Eswaramoorthy et al., 2001[Eswaramoorthy, S., Kumaran, D. & Swaminathan, S. (2001). Acta Cryst. D57, 1743-1746.]). All the O and H atoms of the structure are hydrogen-bonded with various amino acid residues of the neurotoxin. The conformational changes in this complex are minimal, similar to DNA-bound (Dox).

5. Synthesis and crystallization

By mixing an ethano­lic solution of doxorubicin hydro­chloride (3 mg, 0.005 mmol), abbreviated as (DoxH)Cl, Et3N and an MeCN solution of AgNO3 (1.7 mg, 0.01 mmol), an orange solution was obtained. This was allowed to evaporate to near dryness to afford an orange powder. The orange powder was then dissolved in EtOH. After filtration, the filtrate was layered with Et2O. Red sheet-like crystals of (DoxH)NO3 were obtained in two weeks.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 4[link]. All H atoms were positioned geometrically and refined using a riding model: O—H = 0.82, N—H = 0.89 and C—H = 0.93–0.98 Å with Uiso(H) = 1.2 or 1.5Ueq(parent atom). The structure was refined as a two-component twin (matrix to transform one domain into the other: ([\overline{1}] 0 0 0 [\overline{1}] 0 1 0 1); BASF = 0.3072). Atoms marked with a star correspond to the pyran­ose ring, following a numbering convention previously described for (Dox) (Eswaramoorthy et al., 2001[Eswaramoorthy, S., Kumaran, D. & Swaminathan, S. (2001). Acta Cryst. D57, 1743-1746.]).

Table 4
Experimental details

Crystal data
Chemical formula C27H30NO11·NO3
Mr 606.53
Crystal system, space group Monoclinic, P21
Temperature (K) 298
a, b, c (Å) 8.3169 (12), 34.280 (5), 10.1010 (14)
β (°) 114.293 (4)
V (Å3) 2624.8 (6)
Z 4
Radiation type Mo Kα
μ (mm−1) 0.13
Crystal size (mm) 0.24 × 0.10 × 0.05
 
Data collection
Diffractometer Bruker D8 Quest CMOS
Absorption correction Multi-scan (SADABS; Bruker, 2016[Bruker (2016). APEX3, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.])
Tmin, Tmax 0.685, 0.745
No. of measured, independent and observed [I > 2σ(I)] reflections 33597, 10764, 7299
Rint 0.049
(sin θ/λ)max (Å−1) 0.626
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.050, 0.093, 1.01
No. of reflections 10764
No. of parameters 792
No. of restraints 1
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.24, −0.18
Absolute structure Flack x determined using 2632 quotients [(I+)−(I−)]/[(I+)+(I−)] (Parsons et al., 2013[Parsons, S., Flack, H. D. & Wagner, T. (2013). Acta Cryst. B69, 249-259.]).
Absolute structure parameter −0.3 (4)
Computer programs: APEX3 and SAINT (Bruker, 2016[Bruker (2016). APEX3, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), SHELXL (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]) and CrystalMaker (Palmer, 2017[Palmer, D. (2017). CrystalMaker. Begbroke, Oxfordshire, England: CrystalMaker Software Ltd.]).

Supporting information

CCDC reference: 1815074

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2056989018002955/wm5435sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989018002955/wm5435Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989018002955/wm5435Isup3.cdx

checkCIF report


Computing details top

Data collection: APEX3 (Bruker, 2016); cell refinement: SAINT (Bruker, 2016); data reduction: SAINT (Bruker, 2016); program(s) used to solve structure: SHELXT (Sheldrick, 2015b); program(s) used to refine structure: SHELXL (Sheldrick, 2015a); molecular graphics: OLEX2 (Dolomanov et al., 2009) and CrystalMaker (Palmer, 2017); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

(7S,9S)-7-{[(2R,4S,5S,6S)-4-Azaniumyl-5-hydroxy-6-methyloxan-2-yl]oxy}-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracen-5,12-dione nitrate top
Crystal data top
C27H30NO11+·NO3−F(000) = 1272
Mr = 606.53Dx = 1.535 Mg m−3
Monoclinic, P21Mo Kα radiation, λ = 0.71073 Å
a = 8.3169 (12) ÅCell parameters from 9978 reflections
b = 34.280 (5) Åθ = 2.9–26.4°
c = 10.1010 (14) ŵ = 0.13 mm−1
β = 114.293 (4)°T = 298 K
V = 2624.8 (6) Å3Sheet, red
Z = 40.24 × 0.10 × 0.05 mm
Data collection top
Bruker D8 Quest CMOS
diffractometer		7299 reflections with I > 2σ(I)
Detector resolution: 10.42 pixels mm-1Rint = 0.049
φ and ω scansθmax = 26.4°, θmin = 2.8°
Absorption correction: multi-scan
(SADABS; Bruker, 2016)		h = −10→10
Tmin = 0.685, Tmax = 0.745k = −42→42
33597 measured reflectionsl = −12→12
10764 independent reflections
Refinement top
Refinement on F2Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.050 w = 1/[σ2(Fo2) + (0.0405P)2]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.093(Δ/σ)max = 0.001
S = 1.01Δρmax = 0.24 e Å−3
10764 reflectionsΔρmin = −0.18 e Å−3
792 parametersAbsolute structure: Flack x determined using 2632 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013).
1 restraintAbsolute structure parameter: −0.3 (4)
Primary atom site location: dual
Special details top

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. Refined as a 2-component twin.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
O4−0.0502 (7)0.18514 (13)0.0931 (5)0.0585 (13)
O4*0.6155 (6)0.48108 (13)0.5178 (5)0.0481 (11)
H4*0.6456860.4657630.4699770.072*
O50.1037 (6)0.24134 (12)0.2718 (5)0.0513 (12)
O5*0.5027 (5)0.42141 (11)0.6516 (4)0.0373 (10)
O60.2581 (5)0.29480 (12)0.4514 (4)0.0385 (10)
H60.2490290.2771630.3939040.058*
O70.2617 (5)0.38118 (10)0.5142 (4)0.0305 (9)
O90.0248 (6)0.42485 (12)0.6025 (4)0.0404 (10)
H90.0082040.4133750.5267790.061*
O11−0.3440 (5)0.31738 (12)0.5332 (5)0.0456 (12)
H11−0.4256730.3036970.4794580.068*
O12−0.4933 (6)0.26575 (13)0.3438 (5)0.0518 (12)
O130.1964 (6)0.41696 (14)0.9652 (5)0.0592 (13)
O14−0.0341 (8)0.47530 (13)0.9372 (5)0.0622 (13)
H14−0.0031560.4631691.0137200.093*
N3*0.3633 (7)0.46242 (16)0.2253 (6)0.0500 (14)
H3*A0.2975070.4478370.1494140.060*
H3*B0.4751490.4616700.2365270.060*
H3*C0.3247740.4869340.2104060.060*
C1−0.5146 (9)0.21495 (18)0.1278 (7)0.0444 (17)
H1−0.6189290.2211600.1361190.053*
C1*0.4370 (7)0.39312 (17)0.5417 (7)0.0370 (15)
H1*0.5139360.3701880.5722630.044*
C2−0.5114 (10)0.18808 (19)0.0281 (7)0.0497 (18)
H2−0.6172550.176785−0.0340840.060*
C2*0.4371 (9)0.40795 (16)0.4007 (7)0.0420 (16)
H2*A0.5577850.4097990.4103500.050*
H2*B0.3755530.3894060.3238760.050*
C3−0.3624 (10)0.17727 (19)0.0160 (7)0.0468 (18)
H3−0.3672120.158116−0.0507360.056*
C3*0.3507 (8)0.44697 (18)0.3592 (6)0.0374 (15)
H3*0.2256660.4441000.3394570.045*
C4−0.2009 (9)0.19443 (17)0.1022 (7)0.0403 (16)
C4*0.4339 (8)0.47586 (18)0.4843 (6)0.0384 (15)
H4*A0.3722920.5009590.4590760.046*
C5−0.0353 (8)0.24605 (16)0.2879 (6)0.0321 (14)
C5*0.4159 (8)0.45854 (16)0.6152 (6)0.0353 (14)
H5*0.2902260.4546300.5910930.042*
C60.1027 (7)0.29952 (16)0.4623 (6)0.0286 (13)
C6*0.4922 (10)0.48356 (18)0.7488 (7)0.0515 (18)
H6*A0.4648050.4723490.8241160.077*
H6*B0.4427080.5092840.7266270.077*
H6*C0.6179120.4850330.7809420.077*
C70.2549 (7)0.35565 (15)0.6252 (6)0.0283 (13)
H70.3605790.3391800.6610490.034*
C80.2488 (7)0.37850 (16)0.7521 (6)0.0291 (13)
H8A0.2780660.3611050.8345270.035*
H8B0.3378430.3988040.7794610.035*
C90.0706 (7)0.39708 (16)0.7192 (6)0.0307 (14)
C10−0.0675 (8)0.36543 (16)0.6807 (7)0.0358 (15)
H10A−0.0568230.3524170.7692230.043*
H10B−0.1833390.3774060.6378840.043*
C11−0.2010 (8)0.31119 (17)0.5054 (6)0.0315 (14)
C12−0.3558 (8)0.26088 (16)0.3247 (6)0.0343 (14)
C130.0784 (8)0.42099 (16)0.8475 (7)0.0328 (14)
C14−0.0640 (10)0.4493 (2)0.8234 (7)0.061 (2)
H14A−0.0827960.4642090.7366020.074*
H14B−0.1717870.4350430.8050930.074*
C15−0.3541 (8)0.23265 (16)0.2165 (7)0.0335 (14)
C16−0.1969 (8)0.22379 (16)0.2027 (6)0.0325 (14)
C17−0.1987 (7)0.28312 (16)0.4090 (6)0.0290 (13)
C18−0.0431 (7)0.27627 (15)0.3858 (6)0.0277 (12)
C19−0.0547 (7)0.33577 (15)0.5783 (6)0.0288 (13)
C200.0949 (7)0.32995 (16)0.5542 (6)0.0264 (12)
C21−0.0478 (11)0.1538 (2)0.0032 (9)0.076 (3)
H21A−0.1339170.158353−0.0939370.115*
H21B−0.0750120.1300130.0395180.115*
H21C0.0671980.1518900.0029260.115*
O340.9753 (7)0.82204 (16)−0.0230 (6)0.0754 (16)
O351.0122 (6)0.76876 (14)0.1649 (5)0.0599 (14)
O361.0308 (5)0.71127 (12)0.3215 (5)0.0456 (12)
H360.9893010.6892620.3138510.068*
O371.1071 (5)0.62664 (11)0.3901 (4)0.0343 (10)
O391.4642 (7)0.58445 (12)0.5127 (5)0.0506 (12)
H391.3865750.5916260.4354180.076*
O411.7277 (5)0.69683 (12)0.4310 (5)0.0428 (11)
H411.7557400.7111190.3788570.064*
O421.6881 (6)0.75101 (12)0.2491 (5)0.0470 (12)
O431.6156 (7)0.60300 (13)0.8710 (5)0.0591 (14)
O441.8716 (6)0.55690 (13)0.8977 (4)0.0508 (12)
H441.8954920.5337420.8960900.076*
O550.7047 (6)0.53757 (13)0.3706 (5)0.0498 (11)
H550.6982980.5188090.4185730.075*
O560.9570 (5)0.59384 (11)0.5073 (4)0.0373 (10)
N540.7120 (7)0.54394 (16)0.0945 (5)0.0469 (14)
H54A0.7216580.5532010.0157850.056*
H54B0.6077960.5507450.0926770.056*
H54C0.7206120.5180530.0958900.056*
C311.4914 (9)0.80230 (17)0.0381 (7)0.0429 (16)
H311.6072550.7975680.0517850.052*
C321.3907 (11)0.8297 (2)−0.0621 (7)0.0523 (19)
H321.4401450.843813−0.1147450.063*
C331.2187 (11)0.83629 (19)−0.0847 (7)0.0527 (19)
H331.1517000.854418−0.1539450.063*
C341.1447 (9)0.81639 (18)−0.0061 (7)0.0453 (17)
C351.1642 (9)0.76388 (18)0.1767 (7)0.0394 (15)
C361.2008 (8)0.70888 (16)0.3421 (6)0.0324 (14)
C371.2158 (8)0.65236 (16)0.5045 (6)0.0329 (14)
H371.1381420.6679030.5350570.040*
C381.3426 (8)0.63079 (18)0.6346 (6)0.0361 (14)
H38A1.2812830.6090830.6548250.043*
H38B1.3813800.6481110.7179010.043*
C391.5042 (8)0.61522 (16)0.6169 (6)0.0341 (14)
C401.5997 (8)0.64825 (18)0.5799 (7)0.0387 (15)
H40A1.6689660.6624100.6682910.046*
H40B1.6809110.6372170.5433650.046*
C411.5543 (8)0.70137 (16)0.3987 (6)0.0312 (14)
C421.5295 (9)0.75381 (16)0.2251 (7)0.0344 (15)
C431.6279 (8)0.59617 (17)0.7599 (7)0.0345 (14)
C441.7663 (9)0.56963 (18)0.7555 (7)0.0424 (16)
H44A1.7120990.5473900.6938980.051*
H44B1.8386420.5832010.7155930.051*
C451.4174 (8)0.78187 (17)0.1183 (6)0.0345 (14)
C461.2408 (9)0.78777 (18)0.0958 (6)0.0381 (15)
C471.4527 (8)0.72972 (16)0.3014 (6)0.0316 (14)
C481.2731 (8)0.73373 (15)0.2749 (6)0.0291 (13)
C491.4795 (8)0.67671 (15)0.4689 (6)0.0301 (14)
C501.3049 (8)0.67947 (15)0.4398 (6)0.0308 (14)
C510.8621 (12)0.8447 (3)−0.1417 (9)0.085 (3)
H51A0.8623630.834571−0.2301580.128*
H51B0.9025390.871270−0.1289920.128*
H51C0.7444270.843774−0.1465020.128*
C520.9421 (8)0.61882 (18)0.3907 (7)0.0393 (15)
H520.8922730.6436360.4041340.047*
C530.8221 (8)0.60273 (18)0.2455 (7)0.0451 (17)
H53A0.7007370.6056720.2331080.054*
H53B0.8368980.6177290.1698110.054*
C540.8571 (8)0.56056 (18)0.2284 (6)0.0384 (15)
H540.9686320.5585370.2175360.046*
C550.8725 (8)0.53706 (18)0.3605 (6)0.0367 (15)
H55A0.9051570.5101030.3504540.044*
C561.0138 (8)0.55541 (16)0.4903 (6)0.0341 (14)
H561.1213790.5574990.4734200.041*
C571.0544 (9)0.5327 (2)0.6275 (7)0.0515 (18)
H57A1.1397000.5467150.7082670.077*
H57B1.1012450.5076650.6198010.077*
H57C0.9483840.5293540.6422420.077*
O610.3752 (8)0.59449 (18)0.2043 (7)0.0812 (17)
O620.3580 (7)0.5458 (2)0.0653 (6)0.092 (2)
O630.2521 (7)0.54165 (16)0.2223 (6)0.0678 (14)
N610.3272 (8)0.5614 (2)0.1620 (6)0.0525 (15)
O640.6646 (9)0.4626 (2)0.1392 (8)0.102 (2)
O650.9171 (9)0.4433 (3)0.1708 (8)0.138 (3)
O660.7773 (11)0.4163 (2)0.2802 (8)0.119 (3)
N620.7890 (10)0.4409 (2)0.1966 (7)0.0611 (17)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
O40.058 (3)0.054 (3)0.070 (3)−0.007 (2)0.032 (3)−0.031 (3)
O4*0.046 (3)0.046 (3)0.049 (3)−0.020 (2)0.016 (2)−0.005 (2)
O50.046 (3)0.051 (3)0.068 (3)−0.007 (2)0.034 (3)−0.022 (2)
O5*0.038 (2)0.032 (2)0.035 (2)−0.010 (2)0.0085 (19)−0.005 (2)
O60.034 (3)0.039 (3)0.046 (3)−0.003 (2)0.020 (2)−0.013 (2)
O70.029 (2)0.0262 (19)0.037 (2)−0.0035 (17)0.0146 (19)0.0007 (18)
O90.050 (3)0.036 (2)0.033 (2)0.004 (2)0.014 (2)−0.001 (2)
O110.034 (3)0.044 (3)0.068 (3)−0.010 (2)0.030 (3)−0.019 (2)
O120.035 (3)0.053 (3)0.072 (3)−0.012 (2)0.027 (2)−0.021 (3)
O130.061 (3)0.070 (3)0.033 (3)0.010 (3)0.005 (3)−0.014 (2)
O140.083 (4)0.049 (3)0.061 (3)0.000 (3)0.036 (3)−0.022 (3)
N3*0.050 (3)0.054 (3)0.041 (3)−0.010 (3)0.013 (3)−0.001 (3)
C10.045 (4)0.038 (4)0.040 (4)−0.013 (3)0.008 (3)−0.001 (3)
C1*0.027 (3)0.032 (3)0.056 (4)−0.003 (3)0.021 (3)0.002 (3)
C20.054 (5)0.040 (4)0.045 (4)−0.013 (4)0.011 (4)−0.007 (3)
C2*0.053 (4)0.030 (3)0.055 (4)−0.009 (3)0.035 (4)−0.008 (3)
C30.064 (5)0.042 (4)0.032 (4)−0.010 (4)0.016 (4)−0.009 (3)
C3*0.035 (4)0.046 (4)0.031 (3)−0.008 (3)0.013 (3)−0.004 (3)
C40.059 (5)0.026 (3)0.037 (4)−0.001 (3)0.022 (4)−0.002 (3)
C4*0.037 (4)0.036 (3)0.036 (4)−0.001 (3)0.009 (3)−0.005 (3)
C50.037 (4)0.029 (3)0.033 (3)−0.002 (3)0.018 (3)−0.001 (3)
C5*0.036 (4)0.028 (3)0.041 (4)−0.011 (3)0.015 (3)−0.007 (3)
C60.027 (3)0.031 (3)0.029 (3)0.000 (3)0.013 (3)0.004 (3)
C6*0.065 (5)0.039 (4)0.053 (4)−0.015 (4)0.026 (4)−0.013 (3)
C70.030 (3)0.021 (3)0.036 (3)−0.001 (3)0.016 (3)0.001 (3)
C80.026 (3)0.029 (3)0.027 (3)−0.002 (3)0.005 (3)−0.001 (3)
C90.033 (4)0.030 (3)0.028 (3)−0.001 (3)0.011 (3)−0.002 (3)
C100.037 (4)0.030 (3)0.043 (4)−0.007 (3)0.020 (3)−0.014 (3)
C110.030 (4)0.029 (3)0.039 (3)0.002 (3)0.017 (3)−0.001 (3)
C120.041 (4)0.024 (3)0.040 (4)−0.007 (3)0.018 (3)−0.001 (3)
C130.039 (4)0.023 (3)0.038 (4)−0.001 (3)0.017 (3)0.000 (3)
C140.067 (5)0.066 (5)0.050 (4)0.006 (4)0.022 (4)−0.024 (4)
C150.041 (4)0.023 (3)0.034 (3)−0.003 (3)0.013 (3)0.002 (3)
C160.047 (4)0.020 (3)0.032 (3)−0.002 (3)0.017 (3)0.000 (3)
C170.029 (3)0.022 (3)0.035 (3)−0.006 (3)0.012 (3)−0.002 (3)
C180.029 (3)0.022 (3)0.032 (3)−0.004 (3)0.013 (3)−0.002 (3)
C190.030 (3)0.017 (3)0.039 (3)−0.007 (3)0.014 (3)−0.005 (3)
C200.025 (3)0.022 (3)0.030 (3)−0.006 (2)0.009 (3)−0.001 (3)
C210.077 (6)0.079 (6)0.070 (5)0.009 (5)0.025 (5)−0.035 (5)
O340.073 (4)0.090 (4)0.065 (3)0.034 (3)0.030 (3)0.042 (3)
O350.044 (3)0.065 (3)0.072 (3)0.020 (3)0.025 (3)0.034 (3)
O360.032 (3)0.041 (3)0.068 (3)0.002 (2)0.024 (2)0.012 (3)
O370.033 (2)0.029 (2)0.042 (2)−0.0055 (19)0.017 (2)0.002 (2)
O390.067 (3)0.041 (2)0.035 (2)0.015 (2)0.012 (2)−0.002 (2)
O410.033 (3)0.045 (3)0.055 (3)0.006 (2)0.023 (2)0.016 (2)
O420.040 (3)0.053 (3)0.051 (3)−0.006 (2)0.021 (2)0.009 (2)
O430.081 (4)0.063 (3)0.037 (3)0.029 (3)0.028 (3)0.010 (2)
O440.057 (3)0.051 (3)0.040 (3)0.012 (2)0.017 (2)0.012 (2)
O550.043 (3)0.057 (3)0.051 (3)−0.011 (2)0.022 (2)0.019 (2)
O560.039 (3)0.034 (2)0.044 (2)−0.001 (2)0.022 (2)0.005 (2)
N540.047 (3)0.053 (3)0.039 (3)−0.006 (3)0.016 (3)0.005 (3)
C310.056 (4)0.030 (3)0.045 (4)−0.008 (3)0.024 (4)0.003 (3)
C320.068 (5)0.046 (4)0.042 (4)−0.014 (4)0.022 (4)0.007 (4)
C330.069 (5)0.037 (4)0.042 (4)0.002 (4)0.012 (4)0.012 (3)
C340.053 (5)0.035 (4)0.049 (4)0.010 (3)0.022 (4)0.005 (3)
C350.040 (4)0.034 (4)0.043 (4)0.003 (3)0.016 (3)0.002 (3)
C360.026 (3)0.029 (3)0.043 (4)−0.001 (3)0.016 (3)−0.006 (3)
C370.039 (4)0.028 (3)0.035 (3)0.004 (3)0.019 (3)0.002 (3)
C380.041 (4)0.041 (4)0.033 (3)0.001 (3)0.023 (3)0.006 (3)
C390.044 (4)0.028 (3)0.028 (3)0.005 (3)0.013 (3)0.003 (3)
C400.035 (4)0.047 (4)0.038 (3)0.010 (3)0.018 (3)0.009 (3)
C410.034 (4)0.024 (3)0.038 (3)0.000 (3)0.017 (3)0.000 (3)
C420.042 (4)0.028 (3)0.037 (4)−0.008 (3)0.019 (3)−0.009 (3)
C430.044 (4)0.028 (3)0.032 (3)0.002 (3)0.016 (3)0.002 (3)
C440.054 (4)0.036 (3)0.035 (4)0.007 (3)0.016 (3)0.001 (3)
C450.040 (4)0.032 (3)0.031 (3)−0.003 (3)0.014 (3)0.002 (3)
C460.048 (4)0.035 (4)0.030 (3)0.002 (3)0.015 (3)0.001 (3)
C470.038 (4)0.024 (3)0.035 (3)0.000 (3)0.016 (3)0.001 (3)
C480.035 (4)0.018 (3)0.033 (3)0.001 (3)0.013 (3)0.002 (3)
C490.041 (4)0.019 (3)0.034 (3)0.004 (3)0.019 (3)0.002 (3)
C500.038 (4)0.019 (3)0.038 (3)0.003 (3)0.017 (3)−0.002 (3)
C510.081 (6)0.109 (7)0.056 (5)0.041 (5)0.019 (5)0.014 (5)
C520.030 (4)0.036 (3)0.054 (4)0.005 (3)0.020 (3)0.015 (3)
C530.037 (4)0.042 (4)0.047 (4)−0.003 (3)0.008 (3)0.019 (3)
C540.036 (4)0.044 (4)0.037 (3)−0.001 (3)0.016 (3)0.008 (3)
C550.036 (4)0.034 (3)0.046 (4)0.002 (3)0.022 (3)0.004 (3)
C560.032 (3)0.035 (3)0.037 (4)0.002 (3)0.016 (3)0.013 (3)
C570.055 (4)0.051 (4)0.054 (4)0.011 (4)0.028 (4)0.009 (4)
O610.093 (5)0.055 (4)0.092 (4)0.003 (3)0.034 (4)0.016 (3)
O620.062 (4)0.158 (6)0.062 (3)0.001 (4)0.032 (3)−0.026 (4)
O630.062 (3)0.072 (3)0.075 (3)−0.001 (3)0.034 (3)0.009 (3)
N610.042 (4)0.065 (4)0.045 (4)0.007 (3)0.012 (3)0.012 (3)
O640.081 (4)0.079 (4)0.128 (6)0.012 (4)0.025 (4)−0.004 (4)
O650.065 (4)0.254 (10)0.112 (6)−0.004 (5)0.053 (4)−0.001 (6)
O660.170 (8)0.114 (6)0.084 (5)−0.013 (5)0.062 (5)0.005 (5)
N620.069 (5)0.064 (4)0.049 (4)0.001 (4)0.023 (4)−0.008 (4)
Geometric parameters (Å, º) top
O4—C41.332 (8)O36—H360.8200
O4—C211.411 (8)O36—C361.344 (7)
O4*—H4*0.8200O37—C371.438 (7)
O4*—C4*1.417 (7)O37—C521.400 (7)
O5—C51.243 (7)O39—H390.8200
O5*—C1*1.405 (7)O39—C391.429 (7)
O5*—C5*1.435 (7)O41—H410.8200
O6—H60.8200O41—C411.351 (7)
O6—C61.351 (7)O42—C421.243 (7)
O7—C1*1.427 (7)O43—C431.190 (7)
O7—C71.441 (6)O44—H440.8200
O9—H90.8200O44—C441.409 (7)
O9—C91.439 (7)O55—H550.8200
O11—H110.8200O55—C551.440 (7)
O11—C111.347 (7)O56—C521.420 (7)
O12—C121.247 (7)O56—C561.434 (7)
O13—C131.198 (7)N54—H54A0.8900
O14—H140.8200N54—H54B0.8900
O14—C141.394 (7)N54—H54C0.8900
N3*—H3*A0.8900N54—C541.506 (8)
N3*—H3*B0.8900C31—H310.9300
N3*—H3*C0.8900C31—C321.382 (9)
N3*—C3*1.495 (7)C31—C451.391 (8)
C1—H10.9300C32—H320.9300
C1—C21.373 (9)C32—C331.372 (10)
C1—C151.403 (8)C33—H330.9300
C1*—H1*0.9800C33—C341.370 (10)
C1*—C2*1.513 (9)C34—C461.408 (8)
C2—H20.9300C35—C461.474 (8)
C2—C31.346 (10)C35—C481.461 (8)
C2*—H2*A0.9700C36—C481.373 (8)
C2*—H2*B0.9700C36—C501.427 (8)
C2*—C3*1.494 (8)C37—H370.9800
C3—H30.9300C37—C381.499 (8)
C3—C41.395 (9)C37—C501.496 (8)
C3*—H3*0.9800C38—H38A0.9700
C3*—C4*1.529 (8)C38—H38B0.9700
C4—C161.420 (8)C38—C391.524 (8)
C4*—H4*A0.9800C39—C401.515 (8)
C4*—C5*1.512 (8)C39—C431.533 (8)
C5—C161.476 (8)C40—H40A0.9700
C5—C181.452 (8)C40—H40B0.9700
C5*—H5*0.9800C40—C491.512 (8)
C5*—C6*1.501 (8)C41—C471.393 (8)
C6—C181.390 (8)C41—C491.403 (8)
C6—C201.416 (8)C42—C451.460 (8)
C6*—H6*A0.9600C42—C471.445 (8)
C6*—H6*B0.9600C43—C441.482 (8)
C6*—H6*C0.9600C44—H44A0.9700
C7—H70.9800C44—H44B0.9700
C7—C81.521 (7)C45—C461.405 (9)
C7—C201.508 (7)C47—C481.412 (8)
C8—H8A0.9700C49—C501.361 (8)
C8—H8B0.9700C51—H51A0.9600
C8—C91.519 (8)C51—H51B0.9600
C9—C101.510 (8)C51—H51C0.9600
C9—C131.512 (8)C52—H520.9800
C10—H10A0.9700C52—C531.499 (9)
C10—H10B0.9700C53—H53A0.9700
C10—C191.485 (8)C53—H53B0.9700
C11—C171.375 (8)C53—C541.499 (9)
C11—C191.412 (8)C54—H540.9800
C12—C151.464 (8)C54—C551.518 (8)
C12—C171.448 (8)C55—H55A0.9800
C13—C141.472 (9)C55—C561.493 (8)
C14—H14A0.9700C56—H560.9800
C14—H14B0.9700C56—C571.501 (8)
C15—C161.404 (8)C57—H57A0.9600
C17—C181.426 (8)C57—H57B0.9600
C19—C201.377 (8)C57—H57C0.9600
C21—H21A0.9600O61—N611.221 (7)
C21—H21B0.9600O62—N611.228 (7)
C21—H21C0.9600O63—N611.237 (7)
O34—C341.361 (8)O64—N621.212 (8)
O34—C511.414 (9)O65—N621.200 (9)
O35—C351.231 (7)O66—N621.223 (8)
C4—O4—C21119.3 (5)C39—O39—H39109.5
C4*—O4*—H4*109.5C41—O41—H41109.5
C1*—O5*—C5*114.8 (4)C44—O44—H44109.5
C6—O6—H6109.5C55—O55—H55109.5
C1*—O7—C7112.8 (4)C52—O56—C56112.0 (4)
C9—O9—H9109.5H54A—N54—H54B109.5
C11—O11—H11109.5H54A—N54—H54C109.5
C14—O14—H14109.5H54B—N54—H54C109.5
H3*A—N3*—H3*B109.5C54—N54—H54A109.5
H3*A—N3*—H3*C109.5C54—N54—H54B109.5
H3*B—N3*—H3*C109.5C54—N54—H54C109.5
C3*—N3*—H3*A109.5C32—C31—H31120.4
C3*—N3*—H3*B109.5C32—C31—C45119.3 (7)
C3*—N3*—H3*C109.5C45—C31—H31120.4
C2—C1—H1121.4C31—C32—H32119.7
C2—C1—C15117.2 (7)C33—C32—C31120.6 (6)
C15—C1—H1121.4C33—C32—H32119.7
O5*—C1*—O7112.7 (4)C32—C33—H33119.7
O5*—C1*—H1*108.3C34—C33—C32120.5 (7)
O5*—C1*—C2*111.2 (5)C34—C33—H33119.7
O7—C1*—H1*108.3O34—C34—C33123.0 (6)
O7—C1*—C2*108.0 (5)O34—C34—C46116.0 (6)
C2*—C1*—H1*108.3C33—C34—C46121.0 (7)
C1—C2—H2118.4O35—C35—C46122.1 (6)
C3—C2—C1123.2 (7)O35—C35—C48119.1 (6)
C3—C2—H2118.4C48—C35—C46118.7 (5)
C1*—C2*—H2*A109.2O36—C36—C48122.1 (5)
C1*—C2*—H2*B109.2O36—C36—C50116.8 (5)
H2*A—C2*—H2*B107.9C48—C36—C50121.1 (5)
C3*—C2*—C1*112.2 (5)O37—C37—H37108.0
C3*—C2*—H2*A109.2O37—C37—C38112.6 (4)
C3*—C2*—H2*B109.2O37—C37—C50106.9 (4)
C2—C3—H3119.6C38—C37—H37108.0
C2—C3—C4120.9 (6)C50—C37—H37108.0
C4—C3—H3119.6C50—C37—C38113.2 (5)
N3*—C3*—H3*108.3C37—C38—H38A108.8
N3*—C3*—C4*110.0 (5)C37—C38—H38B108.8
C2*—C3*—N3*111.5 (5)C37—C38—C39114.0 (5)
C2*—C3*—H3*108.3H38A—C38—H38B107.7
C2*—C3*—C4*110.3 (5)C39—C38—H38A108.8
C4*—C3*—H3*108.3C39—C38—H38B108.8
O4—C4—C3123.2 (6)O39—C39—C38113.3 (5)
O4—C4—C16118.2 (6)O39—C39—C40110.9 (5)
C3—C4—C16118.6 (6)O39—C39—C43104.0 (4)
O4*—C4*—C3*110.8 (5)C38—C39—C43108.7 (5)
O4*—C4*—H4*A110.1C40—C39—C38110.2 (5)
O4*—C4*—C5*108.7 (5)C40—C39—C43109.5 (5)
C3*—C4*—H4*A110.1C39—C40—H40A108.7
C5*—C4*—C3*107.1 (5)C39—C40—H40B108.7
C5*—C4*—H4*A110.1H40A—C40—H40B107.6
O5—C5—C16122.0 (5)C49—C40—C39114.3 (5)
O5—C5—C18119.1 (5)C49—C40—H40A108.7
C18—C5—C16118.8 (5)C49—C40—H40B108.7
O5*—C5*—C4*110.6 (5)O41—C41—C47121.9 (5)
O5*—C5*—H5*108.4O41—C41—C49117.4 (5)
O5*—C5*—C6*107.1 (5)C47—C41—C49120.7 (5)
C4*—C5*—H5*108.4O42—C42—C45119.9 (5)
C6*—C5*—C4*113.8 (5)O42—C42—C47121.2 (6)
C6*—C5*—H5*108.4C47—C42—C45118.8 (5)
O6—C6—C18122.1 (5)O43—C43—C39121.3 (5)
O6—C6—C20116.4 (5)O43—C43—C44121.2 (6)
C18—C6—C20121.5 (5)C44—C43—C39117.5 (5)
C5*—C6*—H6*A109.5O44—C44—C43108.9 (5)
C5*—C6*—H6*B109.5O44—C44—H44A109.9
C5*—C6*—H6*C109.5O44—C44—H44B109.9
H6*A—C6*—H6*B109.5C43—C44—H44A109.9
H6*A—C6*—H6*C109.5C43—C44—H44B109.9
H6*B—C6*—H6*C109.5H44A—C44—H44B108.3
O7—C7—H7108.7C31—C45—C42117.5 (6)
O7—C7—C8111.6 (4)C31—C45—C46121.1 (6)
O7—C7—C20107.1 (4)C46—C45—C42121.5 (5)
C8—C7—H7108.7C34—C46—C35123.2 (6)
C20—C7—H7108.7C45—C46—C34117.4 (6)
C20—C7—C8111.9 (5)C45—C46—C35119.4 (6)
C7—C8—H8A108.9C41—C47—C42120.1 (5)
C7—C8—H8B108.9C41—C47—C48119.3 (5)
H8A—C8—H8B107.7C48—C47—C42120.6 (5)
C9—C8—C7113.5 (5)C36—C48—C35120.0 (5)
C9—C8—H8A108.9C36—C48—C47119.4 (5)
C9—C8—H8B108.9C47—C48—C35120.7 (5)
O9—C9—C8111.2 (5)C41—C49—C40117.9 (5)
O9—C9—C10110.3 (5)C50—C49—C40121.8 (5)
O9—C9—C13104.3 (4)C50—C49—C41120.3 (5)
C10—C9—C8109.0 (4)C36—C50—C37118.2 (5)
C10—C9—C13111.7 (5)C49—C50—C36119.2 (5)
C13—C9—C8110.2 (5)C49—C50—C37122.6 (5)
C9—C10—H10A108.8O34—C51—H51A109.5
C9—C10—H10B108.8O34—C51—H51B109.5
H10A—C10—H10B107.7O34—C51—H51C109.5
C19—C10—C9114.0 (5)H51A—C51—H51B109.5
C19—C10—H10A108.8H51A—C51—H51C109.5
C19—C10—H10B108.8H51B—C51—H51C109.5
O11—C11—C17121.9 (5)O37—C52—O56111.6 (5)
O11—C11—C19116.3 (5)O37—C52—H52107.8
C17—C11—C19121.8 (5)O37—C52—C53109.0 (5)
O12—C12—C15119.7 (5)O56—C52—H52107.8
O12—C12—C17120.1 (5)O56—C52—C53112.7 (5)
C17—C12—C15120.2 (5)C53—C52—H52107.8
O13—C13—C9121.1 (5)C52—C53—H53A109.1
O13—C13—C14121.0 (6)C52—C53—H53B109.1
C14—C13—C9117.9 (5)H53A—C53—H53B107.8
O14—C14—C13115.3 (6)C54—C53—C52112.6 (5)
O14—C14—H14A108.5C54—C53—H53A109.1
O14—C14—H14B108.5C54—C53—H53B109.1
C13—C14—H14A108.5N54—C54—H54108.6
C13—C14—H14B108.5N54—C54—C55109.6 (5)
H14A—C14—H14B107.5C53—C54—N54110.3 (5)
C1—C15—C12117.6 (6)C53—C54—H54108.6
C1—C15—C16121.5 (6)C53—C54—C55111.1 (5)
C16—C15—C12120.8 (5)C55—C54—H54108.6
C4—C16—C5122.1 (6)O55—C55—C54108.8 (5)
C15—C16—C4118.4 (6)O55—C55—H55A109.7
C15—C16—C5119.5 (5)O55—C55—C56111.6 (5)
C11—C17—C12120.8 (5)C54—C55—H55A109.7
C11—C17—C18120.6 (5)C56—C55—C54107.4 (5)
C18—C17—C12118.5 (5)C56—C55—H55A109.7
C6—C18—C5121.0 (5)O56—C56—C55108.3 (5)
C6—C18—C17117.2 (5)O56—C56—H56108.9
C17—C18—C5121.8 (5)O56—C56—C57109.0 (5)
C11—C19—C10118.6 (5)C55—C56—H56108.9
C20—C19—C10123.4 (5)C55—C56—C57112.9 (5)
C20—C19—C11117.9 (5)C57—C56—H56108.9
C6—C20—C7118.2 (5)C56—C57—H57A109.5
C19—C20—C6120.7 (5)C56—C57—H57B109.5
C19—C20—C7121.1 (5)C56—C57—H57C109.5
O4—C21—H21A109.5H57A—C57—H57B109.5
O4—C21—H21B109.5H57A—C57—H57C109.5
O4—C21—H21C109.5H57B—C57—H57C109.5
H21A—C21—H21B109.5O61—N61—O62122.5 (7)
H21A—C21—H21C109.5O61—N61—O63119.6 (7)
H21B—C21—H21C109.5O62—N61—O63117.8 (7)
C34—O34—C51118.6 (6)O64—N62—O66117.4 (8)
C36—O36—H36109.5O65—N62—O64120.8 (9)
C52—O37—C37114.0 (5)O65—N62—O66121.8 (9)
Hydrogen-bond geometry (Å, º) top
Cg2 is the centroid of the C1–C4/C15/C16 ring.
D—H···AD—HH···AD···AD—H···A
O6—H6···O50.821.812.526 (6)146
O11—H11···O120.821.802.526 (6)146
O14—H14···O65i0.822.072.779 (9)145
N3*—H3*A···O13ii0.892.002.874 (7)167
N3*—H3*C···O630.891.992.865 (8)168
O41—H41···O420.821.822.537 (6)146
O44—H44···O14iii0.822.082.888 (6)168
O55—H55···O4*0.821.932.724 (6)163
N54—H54A···O43iv0.892.182.890 (7)136
N54—H54A···O44iv0.892.052.843 (7)147
N54—H54B···O620.891.992.836 (8)159
N54—H54C···O640.892.052.876 (9)155
C38—H38B···Cg2v0.972.643.556 (7)157
Symmetry codes: (i) x−1, y, z+1; (ii) x, y, z−1; (iii) x+2, y, z; (iv) x−1, y, z−1; (v) −x+1, y+1/2, −z+1.
Conformational parameters (°) of one of the (DoxH)+ cations present in the title compound, (DoxH)NO3, and representative examples from the literature top
(DoxH)NO3AcrB-(Dox) (4dx7)aSorcin-(Dox) (5mra)bDNA-(Dox) (1p20)c
C7—O7—C1*—C2*161.6 (5), 162.6 (4)150.8288.43144.36
C8 conformation C19—C20—C7—C816.6 (6), 17.5 (7)-18.9347.758.92
C9 conformation C20—C19—C10—C918.9 (6), 19.2 (6)-9.27-49.7022.91
O7—N3*7.947 (1), 8.042 (1)7.6366.4336.481
Notes: (a) Eicher et al. (2012); b Genovese et al. (2017); c Howerton et al. (2003).
Entries in RCSB-PDB with (Dox) (DM2) as the ligand top
PDB accession (Reference)Macromolecule(s)Resolution (Å)
5MRA (Genovese et al., 2017)Sorcin (protein)3.74
4ZVM (Leung & Shilton, 2015)Ribsyldihydronicotinamide dehydrogenase1.97
4DX7 (Eicher et al., 2012)Acriflavine resistance protein B (protein) DARPIN (protein)2.25
2DR6 (Murakami et al., 2006)AcrB (protein)3.3
1P20 (Howerton et al., 2003)DNA1.34
1I1E (Eswaramoorthy et al., 2001)Botulinium Neurotoxin Type B (protein)2.5
151D (Lipscomb et al., 1994)DNA1.4
1DA9 (Leonard et al., 1993)DNA1.7
1D12 (Frederick et al., 1990)DNA1.7
 

Acknowledgements

The authors thank Dr Elumalai Pavadai for helpful technical inputs on mol­ecular overlays.

Funding information

GY acknowledges the support from the program of China Scholarship Council (No. 201707045007).

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Journal logoCRYSTALLOGRAPHIC
COMMUNICATIONS
ISSN: 2056-9890
Volume 74| Part 3| March 2018| Pages 400-405
https://doi.org/10.1107/S2056989018002955
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