Crystal structure of ammonium 3′-azido-3′-de­oxy­thymidine-5′-amino­carbonyl­phospho­nate hemi­hydrate: an anti-HIV agent

Jasko, M.V.; Gurskaya, G.V.; Kukhanova, M.K.; Bushmarinov, I.S.

doi:10.1107/S1600536814022405

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ISSN: 2056-9890

Volume 70| Part 11| November 2014| Pages 396-399

doi:10.1107/S1600536814022405

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Crystal structure of ammonium 3′-azido-3′-deoxythymidine-5′-aminocarbonylphosphonate hemihydrate: an anti-HIV agent

Maxim V. Jasko,^a Galina V. Gurskaya,^a Marina K. Kukhanova ^a and Ivan S. Bushmarinov ^b ^*

^aEngelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Vavilov St 32, Moscow, Russian Federation, and ^bA.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991, Vavilov St 28, Moscow, Russian Federation
^*Correspondence e-mail: ib@ineos.ac.ru

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 25 September 2014; accepted 11 October 2014; online 24 October 2014)

The asymmetric unit of the title compound, NH₄⁺·C₁₁H₁₄N₆O₇P⁻·0.5H₂O, contains one 3′-azido-3′-deoxythymidine-5′aminocarbonylphosphonate (ACP–AZT) anion, half of an NH₄⁺ cation lying on a twofold rotation axis and in another position, occupied with equal probabilities of 0.5, an NH₄⁺ cation and a water molecule. The amide group of the ACP–AZT anion is disordered (occupancy ratio 0.5:0.5), with one part forming an N—H⋯O (involving C=O⋯H₄N⁺) hydrogen bond and the other an O—H⋯N (involving C—NH₂⋯OH₂) hydrogen bond with the components of the split NH₄⁺/H₂O position. The pseudorotation parameters of ACP–AZT set it apart from previously studied AZT and thymidine. In the crystal, the various components are linked by N—H⋯O, O—H⋯O, N—H⋯N, C—H⋯O and C—H⋯N hydrogen bonds, forming a three-dimensional framework.

Keywords: crystal structure; anti-HIV agent; deoxythymidine; aminocarbonylphosphonate; ammonium salt.

CCDC reference: 1028847

1. Chemical context

Nucleoside analogues play an important role in clinics as antiviral drugs. At present, seven nucleoside analogues have been approved by the US FDA for the treatment of HIV-infected patients, the first of which was 3′-azido-3′-deoxythymidine (AZT) (DeClercq, 2010 ). Despite progress in the treatment of HIV-infected patients, these drugs possess some drawbacks: AZT lifetime in patients is only one h, requiring frequent dose administration; long-term usage of AZT causes toxic side effects, viz anaemia, bone-marrow suppression, neuropathy and emergence of HIV-resistant strains (Stańczak et al., 2006 ; Beaumont et al., 2003 ). Various forms of nucleosides and nucleotides have been developed in order to reduce the toxic effects of anti-HIV drugs, to increase their oral bioavailability and to improve their pharmacokinetic properties (Kukhanova & Shirokova, 2005 ). Out of a large number of potential HIV drugs, only one compound has been approved by the FDA for the treatment of HIV-infected patients, namely, tenofovir disoproxil fumarate (Viread^®; DeClercq, 2010), and one prodrug of AZT (5′-hydrogenphosphonate AZT, Nikavir^®) has been used in clinical trials in Russia (Ivanova et al., 2010 ; Kukhanova & Shirokova, 2005). In a continuation of the search for compounds with improved medicinal properties, we have synthesized a novel derivative form of AZT, 5′-aminocarbonylphosphonate 3′-azido-3′-deoxythymidine (ACP–AZT). Biological testing of ACP–AZT in cell cultures infected with HIV-1 showed that this compound inhibited virus replication and its toxicity was much lower compared to that of AZT and Nikavir. ACP–AZT displayed improved pharmacokinetic characteristics compared to AZT (Khandazhinskaya et al., 2009 ; Kukhanova, 2012 ; Shirokova et al., 2006 ). Accumulation of ACP–AZT in animal blood was slower than the accumulation of AZT, leading to a decrease in the toxic side effects displayed by AZT. The half-life of ACP–AZT in animal blood is three to four times longer than that of AZT, making it a perspective candidate as an anti-HIV drug for clinical usage. At present, the title compound is undergoing clinical trials as a potential anti-HIV drug.

2. Structural commentary

The molecular structure of the title compound, ACP–AZT, is illustrated in Fig. 1. The comparative analysis of the crystal structure conformation of the title ACP–AZT molecule with the conformation of AZT and natural thymidine molecules (Young et al., 1969 ) is discussed below. The main differences are observed in the carbohydrate fragments of the molecules. In terms of pseudorotation (IUPAC–IUB, 1983 ), the conformation of the furanose ring in the ACP–AZT molecule is described by the phase angle of pseudorotation, P = 25.2°, and the degree of pucker, Ψ_m = 35.0°. These results correspond to a C3′-endo-C4′-exo (³T₄) conformation of the sugar cycle. Atoms C3′ and C4′ deviate from the plane of atoms C1′/O4′/C2′ by 0.458 and −0.101 Å, respectively. Unlike the AZT molecules and the molecule of thymidine, which exhibit a C3′-exo- class of pucker, the ACP–AZT molecule exhibits a C3′-endo pucker. The orientation of the thymine base relative to the deoxyribose ring in the ACP–AZT molecule is anti, similar to that in natural thymidine and AZT, the glycosyl torsion angle χ_ACP–AZT(O4′—C1′—N1—C2) = −147.75 (16)°. The geometric parameters of the azido residue and the orientation relative to the deoxyribose ring in ACP–AZT and AZT coincide within experimental error.

Figure 1
A view of the molecular structure of the title salt, showing the atom numbering. Displacement ellipsoids are drawn at the 50% probability level. The ammonium cation, N1S, lies on a twofold rotation axis.

3. Supramolecular features

The C(O)NH₂ group of ACP–AZT is disordered, one part forming a C=O⋯H₄N⁺ hydrogen bond and the other a C—NH₂⋯OH₂ hydrogen bond with the components of the NH₄⁺/H₂O position (Table 1 and Fig. 2). In the crystal, the various components are linked by N—H⋯O, O—H⋯O, N—H⋯N, C—H⋯O and C—H⋯N hydrogen bonds (Table 1), forming a three-dimensional framework. The structure can be described by an ordered supercell doubled in the c direction (Fig. 2); however, this was not observed in the diffraction experiment.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1S—H1SA⋯O4ⁱ	0.85 (2)	2.01 (2)	2.8565 (19)	173 (2)
N1S—H1SB⋯O6	0.94 (3)	1.86 (3)	2.780 (2)	168 (2)
N3—H3⋯O5ⁱⁱ	0.90 (3)	1.90 (3)	2.781 (2)	167 (3)
O2S—H2SA⋯O5ⁱⁱⁱ	0.87 (2)	2.00 (2)	2.868 (11)	176 (3)
N2S—H2SA⋯O5ⁱⁱⁱ	0.93 (2)	2.00 (2)	2.857 (11)	154 (3)
N2S—H2SC⋯O6	0.94 (3)	2.21 (4)	3.013 (12)	143 (5)
N2S—H2SC⋯O7	0.94 (3)	2.20 (5)	2.901 (16)	130 (5)
O2S—H2SB⋯O2^iv	0.93 (2)	1.91 (2)	2.822 (11)	166 (3)
N2S—H2SB⋯O2^iv	0.95 (2)	1.91 (2)	2.818 (12)	159 (3)
N2S—H2SD⋯O7^v	0.95 (3)	1.99 (3)	2.902 (16)	162 (5)
N7—H7A⋯N7^vi	0.91 (3)	1.93 (5)	2.67 (3)	136 (5)
N7—H7B⋯N2S^vii	0.92 (3)	2.66 (6)	3.265 (17)	124 (5)
N7A—H7AA⋯O2S^v	0.90 (3)	2.00 (3)	2.887 (18)	167 (6)
N7A—H7AB⋯O2S	0.91 (3)	2.03 (3)	2.856 (15)	150 (4)
C1′—H1′⋯O6^viii	0.90 (3)	2.53 (2)	3.100 (2)	122.3 (19)
C3′—H3′⋯N4^iv	0.92 (2)	2.65 (2)	3.274 (3)	125.1 (19)
C4′—H4′⋯O4^ix	1.00	2.51	3.257 (2)	131
C6—H6⋯O5′	0.95	2.47	3.402 (2)	168
Symmetry codes: (i) $[-x+{\script{3\over 2}}, y-{\script{1\over 2}}, -z+{\script{5\over 4}}]$ ; (ii) $[y+{\script{1\over 2}}, -x+{\script{3\over 2}}, z+{\script{3\over 4}}]$ ; (iii) $[-y+1, -x+1, -z+{\script{1\over 2}}]$ ; (iv) $[-y+{\script{3\over 2}}, x-{\script{1\over 2}}, z+{\script{1\over 4}}]$ ; (v) y, x, -z+1; (vi) y, x, -z; (vii) $[-x+1, -y+1, z-{\script{1\over 2}}]$ ; (viii) $[y+{\script{1\over 2}}, -x+{\script{3\over 2}}, z-{\script{1\over 4}}]$ ; (ix) x, y, z-1.

Figure 2
The hydrogen bonds involving the disordered water and ammonia molecules in the crystal packing of ACP–AZT (see Table 1

for details). A fragment of the hypothetically ordered `supercell' is shown.

4. Database survey

Earlier, in 1986, we studied the crystal and molecular structures of AZT and then some other HIV replication inhibitors by X-ray analysis (Gurskaya et al., 1986 , 1990 , 1991 , 1992 ). AZT structures obtained later by four other laboratories were similar to our structure (Camerman et al., 1987 ; Birnbaum et al., 1987 ; Parthasarathy et al., 1988 ; Van Roey et al., 1988 ).

5. Synthesis and crystallization

The title compound was synthesized as described earlier (Shirokova et al., 2004 ). The crystals for X-ray analysis were selected from a highly dispersed (fine crystals) batch of ACP–AZT prepared for clinical usage.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2. The C-bound H atoms were included in calculated positions and treated as riding, with C—H = 0.95–1.00 Å and U_iso(H) = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) for other H atoms. The other distance restraints and SIMU parameters are given below: DFIX 1.234 0.005 O7A C6′ O7 C6′; DFIX 0.9 N7 H7a N7 H7b; DFIX 0.95 N2S H2Sc N2S H2Sd N2S H2Sa N2S H2Sb O2S H2Sb O2S H2Sa; DFIX 1.325 0.005 N7 C6′ N7A C6′; DFIX 0.9 N7A H7Aa N7A H7Ab; SIMU 0.01 0.005 1.7 N2S O2S; SIMU 0.01 0.005 1.7 N7A O7 O7A N7. The split NH₄⁺/H₂O position was refined with an occupancy of 0.5 for each atom.

Table 2
Experimental details

Crystal data
Chemical formula	NH₄⁺·C₁₁H₁₄N₆O₇P⁻·0.5H₂O
M_r	400.30
Crystal system, space group	Tetragonal, P4₁2₁2
Temperature (K)	100
a, c (Å)	18.5564 (6), 10.1139 (4)
V (Å³)	3482.6 (3)
Z	8
Radiation type	Mo Kα
μ (mm⁻¹)	0.21
Crystal size (mm)	0.21 × 0.20 × 0.20

Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	Multi-scan (SADABS; Bruker, 2009 )
T_min, T_max	0.670, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	47562, 5322, 4822
R_int	0.047
(sin θ/λ)_max (Å⁻¹)	0.714

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.032, 0.079, 1.09
No. of reflections	5322
No. of parameters	315
No. of restraints	32
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.29
Absolute structure	Flack x determined using 1919 quotients [(I⁺)−(I⁻)]/[(I⁺)+(I⁻)] (Parsons et al., 2013 )
Absolute structure parameter	0.00 (3)
Computer programs: APEX2 and SAINT (Bruker, 2009), SHELXS2014 and SHELXL2014 (Sheldrick, 2008 ) and OLEX2 (Dolomanov et al., 2009 ).

Supporting information

CCDC reference: 1028847

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536814022405/su2792sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536814022405/su2792Isup2.hkl

checkCIF report

Chemical context top

Nucleoside analogues play an important role in clinics as antiviral drugs. At present, seven nucleoside analogues have been approved by the US FDA for the treatment of HIV-infected patients, the first of which was 3'-azido-3'-deoxythymidine (AZT) (DeClercq, 2010). Despite progress in the treatment of HIV-infected patients, these drugs possess some drawbacks: AZT lifetime in patients is only one hour, requiring frequent dose administration; long-term usage of AZT causes toxic side effects, viz anaemia, bone-marrow suppression, neuropathy and emergence of HIV-resistant strains (Stańczak et al., 2006; Beaumont et al., 2003). Various forms of nucleosides and nucleotides have been developed in order to reduce the toxic effects of anti-HIV drugs, to increase their oral bioavailability and to improve their pharmacokinetic properties (Kukhanova & Shirokova, 2005). Out of a large number of potential HIV drugs, only one compound has been approved by the FDA for the treatment of HIV-infected patients, namely, tenofovir disoproxil fumarate (Viread®; DeClercq, 2010), and one prodrug of AZT (5'-hydrogenphosphonate AZT, Nikavir®) has been used in clinical trials in Russia (Ivanova et al., 2010; Kukhanova & Shirokova, 2005). Continuing the search for compounds with improved medicinal properties, we have synthesized a novel derivative form of AZT, 5'-aminocarbonylphosphonate 3'-azido-3'-deoxythymidine (ACP–AZT). Biological testing of ACP–AZT in cell cultures infected with HIV-1 showed that this compound inhibited virus replication and its toxicity was much lower compared to that of AZT and Nikavir. ACP–AZT displayed improved pharmacokinetic characteristics compared to AZT (Khandazhinskaya et al., 2009; Kukhanova, 2012; Shirokova et al., 2006). Accumulation of ACP–AZT in animal blood was slower than the accumulation of AZT, leading to a decrease in the toxic side effects displayed by AZT. The half-life of ACP–AZT in animal blood is three to four times longer than that of AZT, making it a perspective candidate as an anti-HIV drug for clinical usage. At present, the title compound is undergoing clinical trials as a potential anti-HIV drug.

Structural commentary top

The molecular structure of the title compound, ACP–AZT, is illustrated in Fig. 1. The comparative analysis of the crystal structure conformation of the title ACP–AZT molecule with the conformation of AZT and natural thymidine molecules (Young et al., 1969) is discussed below. The main differences are observed in the carbohydrate fragments of the molecules. In terms of pseudorotation (IUPAC–IUB, 1983), the conformation of the furanose ring in the ACP–AZT molecule is described by the phase angle of pseudorotation, P = 25.2°, and the degree of pucker, Ψ_m = 35.0°. These results correspond to a C3'-endo-C4'-exo (³T₄) conformation of the sugar cycle. Atoms C3' and C4' deviate from the plane of atoms C1'/O4'/C2' by 0.458 and -0.101 Å, respectively. Unlike the AZT molecules and the molecule of thymidine, which exhibit a C3'-exo- class of pucker, the ACP–AZT molecule exhibits a C3'-endo one. The orientation of the thymine base relative to the deoxyribose ring in the ACP–AZT molecule is anti, similar to that in natural thymidine and AZT, the glycosyl torsion angle χ_ACP–AZT(O4'—C1'—N1—C2) = -147.75 (16)°. The geometric parameters of the azido residue and the orientation relative to the deoxyribose ring in ACP–AZT and AZT coincide within experimental error.

Supramolecular features top

The C(O)NH₂ group of ACP–AZT is disordered, one part forming a C═ O···H₄N⁺ hydrogen bond and the other a C—NH₂···OH₂ hydrogen bond with the components of the NH₄⁺/H₂O position (Table 1 and Fig. 2). In the crystal, the various components are linked by N—H···O, O—H···O, N—H···N, C—H···O and C—H···N hydrogen bonds (Table 1), forming a three-dimensional framework. The structure can be described by an ordered supercell doubled in the c direction (Fig. 2); however, this was not observed in the diffraction experiment.

Database survey top

Earlier, in 1986, we studied the crystal and molecular structures of AZT and then some other HIV replication inhibitors by X-ray analysis (Gurskaya et al., 1986, 1990, 1991, 1992). AZT structures obtained later by four other laboratories were similar to our structure (Camerman et al., 1987; Birnbaum et al., 1987; Parthasarathy et al., 1988; Van Roey et al., 1988).

Synthesis and crystallization top

The title compound was synthesized as described earlier (Shirokova et al., 2004). The crystals for X-ray analysis were selected from a highly dispersed (fine crystals) batch of ACP–AZT prepared for clinical usage.

Refinement top

Crystal data, data collection and structure refinement details are summarized in Table 2. The C-bound H atoms were included in calculated positions and treated as riding, with C—H = 0.95–1.00 Å and U_iso(H) = 1.5U_eq(C) for methyl H atoms and 1.2U_eq(C) for other H atoms. The other distance restraints and SIMU parameters are given below: DFIX 1.234 0.005 O7A C6' O7 C6'; DFIX 0.9 N7 H7a N7 H7b; DFIX 0.95 N2S H2Sc N2S H2Sd N2S H2Sa N2S H2Sb O2S H2Sb O2S H2Sa; DFIX 1.325 0.005 N7 C6' N7A C6'; DFIX 0.9 N7A H7Aa N7A H7Ab; SIMU 0.01 0.005 1.7 N2S O2S; SIMU 0.01 0.005 1.7 N7A O7 O7A N7. The split NH₄⁺/H₂O position was refined with an occupancy of 0.5 for each atom.

Related literature top

For the synthesis, see Shirokova et al., 2004. For crystallographic data on related compounds, see Gurskaya et al., 1986; Gurskaya et al., 1990; Gurskaya et al., 1991; Gurskaya et al., 1992. For pseudorotation definition, see IUPAC-IUB, 1983.

For synthetic and pharmaceutical data, see: Beaumont et al. (2003); Birnbaum et al. (1987); Camerman et al. (1987); DeClercq (2010); Ivanova et al. (2010); Khandazhinskaya et al. (2009); Kukhanova (2012); Kukhanova & Shirokova (2005); Parthasarathy & Kim (1988); Shirokova et al. (2006); Stańczak & Ferra (2006); Van Roey, Salerno, Duax, Chu, Ahin & Schinazi (1988); Young et al. (1969).

Computing details top

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXS2014 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2008); molecular graphics: OLEX2 (Dolomanov et al., 2009); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009).

Figures top

A view of the molecular structure of the title salt, showing the atom numbering. Displacement ellipsoids are drawn at the 50% probability level. The ammonium cation, N1S, lies on a twofold rotation axis.

The hydrogen bonds involving the disordered water and ammonia molecules in the crystal packing of ACP–AZT (see Table 1 for details). A fragment of the hypothetically ordered `supercell' is shown.

Ammonium 3'-azido-3'-deoxythymidine-5'-aminocarbonylphosphonate hemihydrate top

Crystal data top

NH₄⁺·C₁₁H₁₄N₆O₇P⁻·0.5H₂O	D_x = 1.527 Mg m⁻³
M_r = 400.30	Mo Kα radiation, λ = 0.71073 Å
Tetragonal, P4₁2₁2	Cell parameters from 9998 reflections
a = 18.5564 (6) Å	θ = 2.3–30.3°
c = 10.1139 (4) Å	µ = 0.21 mm⁻¹
V = 3482.6 (3) Å³	T = 100 K
Z = 8	Prism, colourless
F(000) = 1672	0.21 × 0.20 × 0.20 mm

Data collection top

Bruker APEXII CCD diffractometer	5322 independent reflections
Radiation source: sealed tube	4822 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.047
Detector resolution: 8 pixels mm^-1	θ_max = 30.5°, θ_min = 2.2°
ϕ and ω scans	h = −26→26
Absorption correction: multi-scan (SADABS; Bruker, 2009)	k = −26→26
T_min = 0.670, T_max = 0.746	l = −14→14
47562 measured reflections

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F² > 2σ(F²)] = 0.032	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.079	w = 1/[σ²(F_o²) + (0.0415P)² + 0.5648P] where P = (F_o² + 2F_c²)/3
S = 1.09	(Δ/σ)_max = 0.001
5322 reflections	Δρ_max = 0.34 e Å⁻³
315 parameters	Δρ_min = −0.29 e Å⁻³
32 restraints	Absolute structure: Flack x determined using 1919 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.00 (3)

Crystal data top

NH₄⁺·C₁₁H₁₄N₆O₇P⁻·0.5H₂O	Z = 8
M_r = 400.30	Mo Kα radiation
Tetragonal, P4₁2₁2	µ = 0.21 mm⁻¹
a = 18.5564 (6) Å	T = 100 K
c = 10.1139 (4) Å	0.21 × 0.20 × 0.20 mm
V = 3482.6 (3) Å³

Data collection top

Bruker APEXII CCD diffractometer	5322 independent reflections
Absorption correction: multi-scan (SADABS; Bruker, 2009)	4822 reflections with I > 2σ(I)
T_min = 0.670, T_max = 0.746	R_int = 0.047
47562 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.032	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.079	Δρ_max = 0.34 e Å⁻³
S = 1.09	Δρ_min = −0.29 e Å⁻³
5322 reflections	Absolute structure: Flack x determined using 1919 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
315 parameters	Absolute structure parameter: 0.00 (3)
32 restraints

Special details top

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq	Occ. (<1)
P1	0.68921 (3)	0.49006 (3)	0.20527 (5)	0.01645 (10)
O2	0.92567 (8)	0.79475 (9)	0.50029 (14)	0.0247 (3)
O2S	0.5859 (5)	0.4368 (6)	0.5786 (9)	0.0241 (17)	0.5
O4	0.79798 (8)	0.68215 (7)	0.82247 (13)	0.0194 (3)
O4'	0.81753 (7)	0.69188 (7)	0.21627 (13)	0.0172 (3)
O5	0.68747 (8)	0.45502 (8)	0.07236 (14)	0.0229 (3)
O5'	0.74688 (8)	0.55407 (8)	0.20885 (14)	0.0234 (3)
O6	0.70278 (9)	0.44576 (8)	0.32578 (14)	0.0257 (3)
O7	0.5715 (9)	0.5389 (8)	0.3380 (10)	0.026 (2)	0.5
O7A	0.5847 (6)	0.5815 (6)	0.1427 (10)	0.0303 (19)	0.5
N1	0.85030 (9)	0.70295 (9)	0.43868 (15)	0.0156 (3)
N1S	0.69819 (9)	0.30181 (9)	0.2500	0.0156 (4)
H1SA	0.7013 (13)	0.2684 (13)	0.308 (2)	0.018 (6)*
H1SB	0.7014 (14)	0.3480 (14)	0.287 (3)	0.025 (6)*
H3	0.8853 (15)	0.7633 (15)	0.719 (3)	0.029*
H2SA	0.5720 (15)	0.3982 (11)	0.536 (3)	0.029*
H2SC	0.619 (3)	0.461 (3)	0.478 (4)	0.029*	0.5
H2SB	0.6270 (12)	0.4260 (15)	0.628 (2)	0.029*
H2SD	0.570 (3)	0.477 (3)	0.590 (5)	0.029*	0.5
N2S	0.5985 (7)	0.4395 (7)	0.5538 (11)	0.028 (2)	0.5
N3	0.86108 (9)	0.73708 (9)	0.65883 (15)	0.0163 (3)
N4	0.94590 (10)	0.55785 (9)	0.10114 (18)	0.0229 (4)
N5	0.92571 (10)	0.49900 (10)	0.05676 (19)	0.0266 (4)
N6	0.91507 (14)	0.44520 (13)	0.0082 (3)	0.0464 (6)
N7	0.5716 (7)	0.5749 (8)	0.1320 (14)	0.0259 (17)	0.5
H7A	0.597 (3)	0.578 (3)	0.055 (4)	0.037 (16)*	0.5
H7B	0.531 (2)	0.604 (3)	0.133 (6)	0.038 (16)*	0.5
N7A	0.5747 (10)	0.5256 (10)	0.3488 (11)	0.0199 (17)	0.5
H7AA	0.532 (2)	0.549 (3)	0.361 (6)	0.033 (17)*	0.5
H7AB	0.593 (2)	0.494 (2)	0.407 (4)	0.011 (11)*	0.5
C1'	0.87645 (10)	0.70731 (10)	0.30064 (18)	0.0166 (3)
H1'	0.8922 (13)	0.7528 (14)	0.290 (2)	0.016 (6)*
C2	0.88180 (10)	0.74798 (10)	0.52988 (18)	0.0164 (3)
C2'	0.93586 (11)	0.65280 (11)	0.26815 (19)	0.0206 (4)
H2'A	0.9735	0.6747	0.2116	0.025*
H2'B	0.9586	0.6341	0.3498	0.025*
C3'	0.89591 (10)	0.59331 (10)	0.19471 (19)	0.0168 (3)
H3'	0.8762 (13)	0.5614 (14)	0.255 (2)	0.018 (6)*
C4	0.81153 (10)	0.68706 (10)	0.70369 (17)	0.0154 (3)
C4'	0.83606 (10)	0.63509 (10)	0.12478 (17)	0.0163 (3)
H4'	0.8557	0.6569	0.0419	0.020*
C5	0.77850 (11)	0.64287 (11)	0.60195 (19)	0.0204 (4)
C5'	0.76867 (12)	0.59301 (11)	0.09211 (19)	0.0211 (4)
H5'A	0.7298	0.6262	0.0640	0.025*
H5'B	0.7784	0.5589	0.0189	0.025*
C6	0.79969 (11)	0.65210 (10)	0.47609 (19)	0.0198 (4)
H6	0.7790	0.6224	0.4097	0.024*
C6'	0.60339 (12)	0.53904 (11)	0.23020 (18)	0.0207 (4)
C7	0.72211 (16)	0.58965 (16)	0.6417 (2)	0.0416 (7)
H7C	0.7422	0.5562	0.7070	0.062*
H7D	0.7061	0.5627	0.5638	0.062*
H7E	0.6810	0.6152	0.6805	0.062*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
P1	0.0215 (2)	0.0144 (2)	0.01346 (19)	−0.00265 (18)	−0.00230 (17)	−0.00192 (16)
O2	0.0285 (8)	0.0300 (8)	0.0157 (6)	−0.0136 (6)	−0.0020 (6)	0.0018 (6)
O2S	0.024 (3)	0.033 (3)	0.015 (2)	0.017 (2)	0.0025 (18)	−0.0010 (17)
O4	0.0261 (7)	0.0193 (6)	0.0127 (6)	0.0011 (5)	0.0019 (5)	−0.0005 (5)
O4'	0.0213 (6)	0.0177 (6)	0.0125 (5)	0.0009 (5)	−0.0039 (5)	−0.0014 (5)
O5	0.0287 (8)	0.0212 (7)	0.0189 (6)	−0.0021 (6)	0.0005 (6)	−0.0088 (5)
O5'	0.0289 (8)	0.0269 (7)	0.0143 (6)	−0.0122 (6)	−0.0027 (6)	0.0011 (6)
O6	0.0348 (8)	0.0200 (7)	0.0223 (7)	−0.0033 (6)	−0.0079 (6)	0.0049 (5)
O7	0.026 (2)	0.033 (5)	0.018 (2)	0.008 (3)	−0.0044 (19)	0.0120 (19)
O7A	0.041 (5)	0.031 (3)	0.019 (2)	0.012 (3)	0.007 (3)	0.000 (2)
N1	0.0213 (7)	0.0161 (7)	0.0095 (6)	−0.0030 (6)	−0.0009 (6)	−0.0001 (5)
N1S	0.0175 (6)	0.0175 (6)	0.0119 (9)	−0.0014 (8)	0.0005 (6)	0.0005 (6)
N2S	0.025 (4)	0.018 (2)	0.042 (6)	0.006 (2)	−0.015 (4)	−0.008 (3)
N3	0.0190 (8)	0.0190 (8)	0.0110 (6)	−0.0029 (6)	−0.0028 (6)	−0.0001 (6)
N4	0.0264 (9)	0.0184 (8)	0.0239 (8)	−0.0024 (7)	0.0071 (7)	−0.0026 (7)
N5	0.0293 (9)	0.0229 (9)	0.0276 (9)	−0.0021 (7)	0.0081 (8)	−0.0030 (7)
N6	0.0528 (14)	0.0334 (11)	0.0529 (14)	−0.0122 (10)	0.0144 (12)	−0.0194 (11)
N7	0.016 (3)	0.039 (3)	0.023 (3)	−0.002 (2)	−0.0084 (18)	0.008 (3)
N7A	0.022 (3)	0.028 (5)	0.009 (2)	0.009 (3)	0.005 (2)	0.006 (2)
C1'	0.0214 (8)	0.0183 (8)	0.0101 (7)	−0.0043 (7)	0.0002 (6)	−0.0005 (6)
C2	0.0182 (8)	0.0173 (8)	0.0138 (8)	−0.0007 (7)	−0.0025 (7)	0.0002 (7)
C2'	0.0184 (9)	0.0276 (10)	0.0158 (8)	−0.0021 (7)	−0.0014 (7)	−0.0026 (7)
C3'	0.0189 (8)	0.0182 (8)	0.0132 (7)	−0.0005 (7)	0.0022 (7)	0.0014 (7)
C4	0.0171 (8)	0.0142 (7)	0.0148 (7)	0.0017 (7)	−0.0009 (7)	0.0002 (6)
C4'	0.0227 (9)	0.0156 (8)	0.0107 (7)	−0.0021 (7)	−0.0011 (7)	−0.0001 (6)
C5	0.0241 (10)	0.0205 (9)	0.0165 (8)	−0.0068 (8)	0.0012 (7)	−0.0017 (7)
C5'	0.0260 (10)	0.0251 (10)	0.0123 (7)	−0.0080 (8)	−0.0019 (7)	0.0012 (7)
C6	0.0226 (9)	0.0186 (9)	0.0182 (9)	−0.0066 (7)	0.0015 (7)	−0.0037 (7)
C6'	0.0277 (10)	0.0203 (9)	0.0140 (8)	−0.0016 (7)	−0.0016 (7)	−0.0009 (7)
C7	0.0536 (16)	0.0472 (15)	0.0242 (11)	−0.0338 (13)	0.0121 (11)	−0.0092 (11)

Geometric parameters (Å, º) top

P1—O5	1.4936 (14)	N4—C3'	1.480 (3)
P1—O5'	1.5991 (14)	N5—N6	1.130 (3)
P1—O6	1.4916 (15)	N7—H7A	0.91 (3)
P1—C6'	1.851 (2)	N7—H7B	0.92 (3)
O2—C2	1.227 (2)	N7—C6'	1.333 (6)
O2S—H2SA	0.874 (19)	N7A—H7AA	0.90 (3)
O2S—H2SB	0.93 (2)	N7A—H7AB	0.91 (3)
O4—C4	1.231 (2)	N7A—C6'	1.336 (5)
O4'—C1'	1.416 (2)	C1'—H1'	0.90 (3)
O4'—C4'	1.444 (2)	C1'—C2'	1.532 (3)
O5'—C5'	1.442 (2)	C2'—H2'A	0.9900
O7—C6'	1.241 (6)	C2'—H2'B	0.9900
O7A—C6'	1.234 (5)	C2'—C3'	1.523 (3)
N1—C1'	1.480 (2)	C3'—H3'	0.92 (2)
N1—C2	1.375 (2)	C3'—C4'	1.528 (3)
N1—C6	1.384 (2)	C4—C5	1.452 (3)
N1S—H1SA	0.85 (2)	C4'—H4'	1.0000
N1S—H1SB	0.94 (3)	C4'—C5'	1.511 (3)
N2S—H2SA	0.93 (2)	C5—C6	1.343 (3)
N2S—H2SC	0.94 (3)	C5—C7	1.494 (3)
N2S—H2SB	0.95 (2)	C5'—H5'A	0.9900
N2S—H2SD	0.95 (3)	C5'—H5'B	0.9900
N3—H3	0.90 (3)	C6—H6	0.9500
N3—C2	1.375 (2)	C7—H7C	0.9800
N3—C4	1.383 (2)	C7—H7D	0.9800
N4—N5	1.239 (2)	C7—H7E	0.9800

O5—P1—O5'	110.99 (8)	C3'—C2'—C1'	103.47 (15)
O5—P1—C6'	108.53 (9)	C3'—C2'—H2'A	111.1
O5'—P1—C6'	102.01 (9)	C3'—C2'—H2'B	111.1
O6—P1—O5	119.94 (9)	N4—C3'—C2'	109.21 (16)
O6—P1—O5'	106.13 (8)	N4—C3'—H3'	112.6 (15)
O6—P1—C6'	107.73 (9)	N4—C3'—C4'	112.67 (15)
H2SA—O2S—H2SB	109 (3)	C2'—C3'—H3'	109.6 (15)
C1'—O4'—C4'	110.47 (14)	C2'—C3'—C4'	102.23 (15)
C5'—O5'—P1	122.76 (12)	C4'—C3'—H3'	109.9 (15)
C2—N1—C1'	117.39 (15)	O4—C4—N3	120.38 (17)
C2—N1—C6	121.29 (16)	O4—C4—C5	124.32 (17)
C6—N1—C1'	121.17 (15)	N3—C4—C5	115.30 (16)
H1SA—N1S—H1SB	113 (2)	O4'—C4'—C3'	104.29 (14)
H2SA—N2S—H2SC	113 (4)	O4'—C4'—H4'	109.2
H2SA—N2S—H2SB	103 (3)	O4'—C4'—C5'	108.68 (16)
H2SA—N2S—H2SD	113 (4)	C3'—C4'—H4'	109.2
H2SC—N2S—H2SB	122 (4)	C5'—C4'—C3'	116.14 (16)
H2SC—N2S—H2SD	103 (5)	C5'—C4'—H4'	109.2
H2SB—N2S—H2SD	101 (4)	C4—C5—C7	118.58 (17)
C2—N3—H3	114.9 (18)	C6—C5—C4	118.44 (18)
C2—N3—C4	126.57 (16)	C6—C5—C7	122.99 (18)
C4—N3—H3	118.3 (18)	O5'—C5'—C4'	108.18 (15)
N5—N4—C3'	115.73 (17)	O5'—C5'—H5'A	110.1
N6—N5—N4	171.6 (2)	O5'—C5'—H5'B	110.1
H7A—N7—H7B	113 (5)	C4'—C5'—H5'A	110.1
C6'—N7—H7A	116 (4)	C4'—C5'—H5'B	110.1
C6'—N7—H7B	130 (4)	H5'A—C5'—H5'B	108.4
H7AA—N7A—H7AB	124 (5)	N1—C6—H6	118.5
C6'—N7A—H7AA	112 (4)	C5—C6—N1	123.00 (17)
C6'—N7A—H7AB	124 (3)	C5—C6—H6	118.5
O4'—C1'—N1	107.70 (14)	O7—C6'—P1	121.9 (6)
O4'—C1'—H1'	111.8 (15)	O7—C6'—N7	116.4 (11)
O4'—C1'—C2'	107.03 (15)	O7A—C6'—P1	117.2 (6)
N1—C1'—H1'	105.5 (16)	O7A—C6'—N7A	130.6 (9)
N1—C1'—C2'	113.71 (15)	N7—C6'—P1	121.6 (8)
C2'—C1'—H1'	111.1 (15)	N7A—C6'—P1	111.9 (7)
O2—C2—N1	123.25 (17)	C5—C7—H7C	109.5
O2—C2—N3	121.39 (17)	C5—C7—H7D	109.5
N3—C2—N1	115.35 (16)	C5—C7—H7E	109.5
C1'—C2'—H2'A	111.1	H7C—C7—H7D	109.5
C1'—C2'—H2'B	111.1	H7C—C7—H7E	109.5
H2'A—C2'—H2'B	109.0	H7D—C7—H7E	109.5

P1—O5'—C5'—C4'	−165.61 (14)	C1'—O4'—C4'—C3'	24.84 (18)
O4—C4—C5—C6	−177.9 (2)	C1'—O4'—C4'—C5'	149.32 (15)
O4—C4—C5—C7	2.6 (3)	C1'—N1—C2—O2	6.0 (3)
O4'—C1'—C2'—C3'	−18.00 (19)	C1'—N1—C2—N3	−173.72 (16)
O4'—C4'—C5'—O5'	−68.8 (2)	C1'—N1—C6—C5	174.96 (19)
O5—P1—O5'—C5'	25.85 (19)	C1'—C2'—C3'—N4	151.29 (15)
O5—P1—C6'—O7	139.4 (11)	C1'—C2'—C3'—C4'	31.75 (18)
O5—P1—C6'—O7A	−52.1 (6)	C2—N1—C1'—O4'	−147.75 (16)
O5—P1—C6'—N7	−38.8 (8)	C2—N1—C1'—C2'	93.8 (2)
O5—P1—C6'—N7A	132.9 (11)	C2—N1—C6—C5	−0.5 (3)
O5'—P1—C6'—O7	−103.3 (11)	C2—N3—C4—O4	179.38 (18)
O5'—P1—C6'—O7A	65.2 (6)	C2—N3—C4—C5	−0.6 (3)
O5'—P1—C6'—N7	78.4 (8)	C2'—C3'—C4'—O4'	−34.79 (18)
O5'—P1—C6'—N7A	−109.8 (11)	C2'—C3'—C4'—C5'	−154.33 (16)
O6—P1—O5'—C5'	157.72 (16)	C3'—C4'—C5'—O5'	48.3 (2)
O6—P1—C6'—O7	8.1 (11)	C4—N3—C2—O2	178.93 (18)
O6—P1—C6'—O7A	176.6 (6)	C4—N3—C2—N1	−1.3 (3)
O6—P1—C6'—N7	−170.1 (8)	C4—C5—C6—N1	−1.6 (3)
O6—P1—C6'—N7A	1.6 (11)	C4'—O4'—C1'—N1	−126.92 (15)
N1—C1'—C2'—C3'	100.81 (17)	C4'—O4'—C1'—C2'	−4.29 (19)
N3—C4—C5—C6	2.0 (3)	C6—N1—C1'—O4'	36.6 (2)
N3—C4—C5—C7	−177.5 (2)	C6—N1—C1'—C2'	−81.8 (2)
N4—C3'—C4'—O4'	−151.88 (15)	C6—N1—C2—O2	−178.36 (19)
N4—C3'—C4'—C5'	88.6 (2)	C6—N1—C2—N3	1.9 (3)
N5—N4—C3'—C2'	164.58 (18)	C6'—P1—O5'—C5'	−89.59 (17)
N5—N4—C3'—C4'	−82.6 (2)	C7—C5—C6—N1	177.9 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1S—H1SA···O4ⁱ	0.85 (2)	2.01 (2)	2.8565 (19)	173 (2)
N1S—H1SB···O6	0.94 (3)	1.86 (3)	2.780 (2)	168 (2)
N3—H3···O5ⁱⁱ	0.90 (3)	1.90 (3)	2.781 (2)	167 (3)
O2S—H2SA···O5ⁱⁱⁱ	0.87 (2)	2.00 (2)	2.868 (11)	176 (3)
N2S—H2SA···O5ⁱⁱⁱ	0.93 (2)	2.00 (2)	2.857 (11)	154 (3)
N2S—H2SC···O6	0.94 (3)	2.21 (4)	3.013 (12)	143 (5)
N2S—H2SC···O7	0.94 (3)	2.20 (5)	2.901 (16)	130 (5)
O2S—H2SB···O2^iv	0.93 (2)	1.91 (2)	2.822 (11)	166 (3)
N2S—H2SB···O2^iv	0.95 (2)	1.91 (2)	2.818 (12)	159 (3)
N2S—H2SD···O7^v	0.95 (3)	1.99 (3)	2.902 (16)	162 (5)
N7—H7A···N7^vi	0.91 (3)	1.93 (5)	2.67 (3)	136 (5)
N7—H7B···N2S^vii	0.92 (3)	2.66 (6)	3.265 (17)	124 (5)
N7A—H7AA···O2S^v	0.90 (3)	2.00 (3)	2.887 (18)	167 (6)
N7A—H7AB···O2S	0.91 (3)	2.03 (3)	2.856 (15)	150 (4)
C1′—H1′···O6^viii	0.90 (3)	2.53 (2)	3.100 (2)	122.3 (19)
C3′—H3′···N4^iv	0.92 (2)	2.65 (2)	3.274 (3)	125.1 (19)
C4′—H4′···O4^ix	1.00	2.51	3.257 (2)	131
C6—H6···O5′	0.95	2.47	3.402 (2)	168

Symmetry codes: (i) −x+3/2, y−1/2, −z+5/4; (ii) y+1/2, −x+3/2, z+3/4; (iii) −y+1, −x+1, −z+1/2; (iv) −y+3/2, x−1/2, z+1/4; (v) y, x, −z+1; (vi) y, x, −z; (vii) −x+1, −y+1, z−1/2; (viii) y+1/2, −x+3/2, z−1/4; (ix) x, y, z−1.

Experimental details

Crystal data
Chemical formula	NH₄⁺·C₁₁H₁₄N₆O₇P⁻·0.5H₂O
M_r	400.30
Crystal system, space group	Tetragonal, P4₁2₁2
Temperature (K)	100
a, c (Å)	18.5564 (6), 10.1139 (4)
V (Å³)	3482.6 (3)
Z	8
Radiation type	Mo Kα
µ (mm⁻¹)	0.21
Crystal size (mm)	0.21 × 0.20 × 0.20

Data collection
Diffractometer	Bruker APEXII CCD diffractometer
Absorption correction	Multi-scan (SADABS; Bruker, 2009)
T_min, T_max	0.670, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections	47562, 5322, 4822
R_int	0.047
(sin θ/λ)_max (Å⁻¹)	0.714

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.032, 0.079, 1.09
No. of reflections	5322
No. of parameters	315
No. of restraints	32
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.29
Absolute structure	Flack x determined using 1919 quotients [(I⁺)-(I^-)]/[(I⁺)+(I^-)] (Parsons et al., 2013)
Absolute structure parameter	0.00 (3)

Computer programs: APEX2 (Bruker, 2009), SAINT (Bruker, 2009), SAINT (Bruker, 2009), SHELXS2014 (Sheldrick, 2008), SHELXL2014 (Sheldrick, 2008), OLEX2 (Dolomanov et al., 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1S—H1SA···O4ⁱ	0.85 (2)	2.01 (2)	2.8565 (19)	173 (2)
N1S—H1SB···O6	0.94 (3)	1.86 (3)	2.780 (2)	168 (2)
N3—H3···O5ⁱⁱ	0.90 (3)	1.90 (3)	2.781 (2)	167 (3)
O2S—H2SA···O5ⁱⁱⁱ	0.874 (19)	1.996 (19)	2.868 (11)	176 (3)
N2S—H2SA···O5ⁱⁱⁱ	0.93 (2)	1.996 (19)	2.857 (11)	154 (3)
N2S—H2SC···O6	0.94 (3)	2.21 (4)	3.013 (12)	143 (5)
N2S—H2SC···O7	0.94 (3)	2.20 (5)	2.901 (16)	130 (5)
O2S—H2SB···O2^iv	0.93 (2)	1.907 (18)	2.822 (11)	166 (3)
N2S—H2SB···O2^iv	0.95 (2)	1.907 (18)	2.818 (12)	159 (3)
N2S—H2SD···O7^v	0.95 (3)	1.99 (3)	2.902 (16)	162 (5)
N7—H7A···N7^vi	0.91 (3)	1.93 (5)	2.67 (3)	136 (5)
N7—H7B···N2S^vii	0.92 (3)	2.66 (6)	3.265 (17)	124 (5)
N7A—H7AA···O2S^v	0.90 (3)	2.00 (3)	2.887 (18)	167 (6)
N7A—H7AB···O2S	0.91 (3)	2.03 (3)	2.856 (15)	150 (4)
C1'—H1'···O6^viii	0.90 (3)	2.53 (2)	3.100 (2)	122.3 (19)
C3'—H3'···N4^iv	0.92 (2)	2.65 (2)	3.274 (3)	125.1 (19)
C4'—H4'···O4^ix	1.00	2.51	3.257 (2)	131
C6—H6···O5'	0.95	2.47	3.402 (2)	168

Acknowledgements

This work was supported by the Russian Foundation for Basic Research (Project 12–04-00581), and the project of Presidium RAN `Molecular and Cellular Biology'.

References

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Volume 70| Part 11| November 2014| Pages 396-399

doi:10.1107/S1600536814022405

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

Crystal structure of ammonium 3′-azido-3′-de­­oxy­thymidine-5′-amino­carbonyl­phospho­nate hemi­hydrate: an anti-HIV agent

1. Chemical context

2. Structural commentary

3. Supra­molecular features

4. Database survey

5. Synthesis and crystallization

6. Refinement

Supporting information

Acknowledgements

References

research communications

Crystal structure of ammonium 3′-azido-3′-deoxythymidine-5′-aminocarbonylphosphonate hemihydrate: an anti-HIV agent

3. Supramolecular features