Crystal structure of ammonium 3'-azido-3'-de-oxy-thymidine-5'-amino-carbonyl-phospho-nate hemi-hydrate: an anti-HIV agent.

The asymmetric unit of the title compound, NH4 (+)·C11H14N6O7P(-)·0.5H2O, contains one 3'-azido-3'-de-oxy-thymidine-5'amino-carbonyl-phospho-nate (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 mol-ecule. 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.

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.

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, Ψm = 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 χACP–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.

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 (, )

DHA	DH	HA	D A	DHA
N1SH1SAO4i	0.85(2)	2.01(2)	2.8565(19)	173(2)
N1SH1SBO6	0.94(3)	1.86(3)	2.780(2)	168(2)
N3H3O5ii	0.90(3)	1.90(3)	2.781(2)	167(3)
O2SH2SAO5iii	0.87(2)	2.00(2)	2.868(11)	176(3)
N2SH2SAO5iii	0.93(2)	2.00(2)	2.857(11)	154(3)
N2SH2SCO6	0.94(3)	2.21(4)	3.013(12)	143(5)
N2SH2SCO7	0.94(3)	2.20(5)	2.901(16)	130(5)
O2SH2SBO2iv	0.93(2)	1.91(2)	2.822(11)	166(3)
N2SH2SBO2iv	0.95(2)	1.91(2)	2.818(12)	159(3)
N2SH2SDO7v	0.95(3)	1.99(3)	2.902(16)	162(5)
N7H7AN7vi	0.91(3)	1.93(5)	2.67(3)	136(5)
N7H7BN2S vii	0.92(3)	2.66(6)	3.265(17)	124(5)
N7AH7AAO2S v	0.90(3)	2.00(3)	2.887(18)	167(6)
N7AH7ABO2S	0.91(3)	2.03(3)	2.856(15)	150(4)
C1H1O6viii	0.90(3)	2.53(2)	3.100(2)	122.3(19)
C3H3N4iv	0.92(2)	2.65(2)	3.274(3)	125.1(19)
C4H4O4ix	1.00	2.51	3.257(2)	131
C6H6O5	0.95	2.47	3.402(2)	168

Symmetry codes: (i) ; (ii) ; (iii) ; (iv) ; (v) ; (vi) ; (vii) ; (viii) ; (ix) .

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.

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 ▶).

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.

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 +C11H14N6O7P0.5H2O
M r	400.30
Crystal system, space group	Tetragonal, P41212
Temperature (K)	100
a, c ()	18.5564(6), 10.1139(4)
V (3)	3482.6(3)
Z	8
Radiation type	Mo K
(mm1)	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 > 2(I)] reflections	47562, 5322, 4822
R int	0.047
(sin /)max (1)	0.714
Refinement
R[F 2 > 2(F 2)], wR(F 2), 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
max, min (e 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 ▶).

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536814022405/su2792sup1.cif

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

CCDC reference: 1028847

Additional supporting information: crystallographic information; 3D view; checkCIF report

NH4+·C11H14N6O7P−·0.5H2O	Dx = 1.527 Mg m−3
Mr = 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

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

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(Fo2) + (0.0415P)2 + 0.5648P] where P = (Fo2 + 2Fc2)/3
S = 1.09	(Δ/σ)max = 0.001
5322 reflections	Δρmax = 0.34 e Å−3
315 parameters	Δρmin = −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)

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.

	x	y	z	Uiso*/Ueq	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*

	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)

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)

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···O2iv	0.93 (2)	1.91 (2)	2.822 (11)	166 (3)
N2S—H2SB···O2iv	0.95 (2)	1.91 (2)	2.818 (12)	159 (3)
N2S—H2SD···O7v	0.95 (3)	1.99 (3)	2.902 (16)	162 (5)
N7—H7A···N7vi	0.91 (3)	1.93 (5)	2.67 (3)	136 (5)
N7—H7B···N2Svii	0.92 (3)	2.66 (6)	3.265 (17)	124 (5)
N7A—H7AA···O2Sv	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′···O6viii	0.90 (3)	2.53 (2)	3.100 (2)	122.3 (19)
C3′—H3′···N4iv	0.92 (2)	2.65 (2)	3.274 (3)	125.1 (19)
C4′—H4′···O4ix	1.00	2.51	3.257 (2)	131
C6—H6···O5′	0.95	2.47	3.402 (2)	168