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The first X-ray crystal structure of a non-natural dinucleotide, 5′-O-phosphoryl-1′-deoxy-2′-isoadenylyl-(3′ → 5′)-cytidine 6.5-hydrate (pIsodApC), C19H26N8O13P2·6.5H2O, belonging to a family of dinucleotides that contain an isomeric nucleoside component, is described. A complex system of hydrogen bonds between water mol­ecules and various sites on the dinucleotide was found. All H atoms were located from electron-density difference maps, which allowed identification of protonation sites. Compounds of this family have been found to bind at the active site of HIV integrase and to be inhibitors of this key viral enzyme. These dinucleotides are completely resistant to cleavage by exonucleases; an abnormal dihedral angle twist in an inter­nucleotide phosphate bond revealed in the X-ray crystal structure may be contributing to this unusual stability towards nucleases.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270105019037/hj1051sup1.cif
Contains datablocks global, I

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270105019037/hj1051Isup2.hkl
Contains datablock I

CCDC reference: 254123

Comment top

The retroviral enzyme HIV-1 integrase incorporates HIV double-helical DNA into host chromosomal DNA (Dyda et al., 1994; Mazumder et al., 1996; Frankel & Young, 1998; Esposito & Craigie, 1999; Haren et al., 1999; Nair, 2002, 2003). This viral enzyme initially catalyzes the excision of two terminal nucleotides at the 3'-end of each strand of viral DNA (3'-processing), leaving recessed ends that terminate with xxCA—OH. In the next steps (strand transfer and integration), attack of the terminal 3'-OH of the tailored HIV DNA on a specific internucleotide phosphodiester bond results in cleavage of host DNA, which is followed by integration of the HIV DNA into host DNA (Dyda et al., 1994; Mazumder et al., 1996; Frankel & Young, 1998; Esposito & Craigie, 1999; Haren et al., 1999; Nair, 2002, 2003). The integration process is essential for the replication of HIV.

In designing inhibitors of this viral enzyme, it was suggested that residues immediately upstream of the dinucleotide cleavage site in the 3'-processing step may provide critical recognition/binding sites for HIV integrase. With this design concept in mind, natural dinucleotides were investigated by Pommier and co-workers, and non-natural dinucleotides were synthesized and investigated by Nair and co-workers, as potential anti-HIV integrase inhibitors (Mazumder et al., 1997; Taktakishvili, Neamati, Pommier & Nair, 2000; Taktakishvili, Neamati, Pommier, Pal & Nair, 2000; Taktakishvili et al., 2001). The non-natural dinucleotides contain one natural D-nucleoside component and one isomeric L-related nucleoside moiety (Nair & Jahnke, 1995), which are joined together by an internucleotide phosphodiester bond and are 5'-phosphorylated. While both the natural and non-natural dinucleotides with the AC base components were found to be strong inhibitors of HIV-1 integrase (IC50 low µM range for both the processing and strand-transfer steps), one remarkable aspect of the non-natural dinucleotides was that the internucleotide bond exhibited resistance to cleavage by mammalian 3'- and 5'-exonucleases (Taktakishvili, Neamati, Pommier & Nair, 2000; Taktakishvili, Neamati, Pommier, Pal & Nair, 2000; Taktakishvili et al., 2001; Nair & Pal, 2004). This was not the case for the natural dinucleotides, which were substrates for 5'-exonucleases (Nair & Pal, 2004). The observed hypochromicity from the quantitative UV spectra of non-natural dinucleotides suggested the presence of base stacking in preferred conformations, which implied the presence of conformationally unusual internucleotide phosphate bonds, because of the spatial arrangement of the two sugar rings required to accommodate base stacking (Taktakishvili, Neamati, Pommier & Nair, 2000; Taktakishvili, Neamati, Pommier, Pal & Nair, 2000; Taktakishvili et al., 2001). In order to obtain further structural information (conformation, internucleotide phosphate bond, base-stacking property) on this family of non-natural dinucleotides, we crystallized one of these compounds, the title compound, pIsodApC or (I), and examined its detailed X-ray crystallographic structure, which we report here.

The numbering scheme for (I) is shown in Fig. 1. Atoms included in the adenosine portion have an A as the last letter of their label and those atoms included in the cytosine portion have a C as the last letter of their label. This coding allows easy recognition of the nucleotide components. All atom labels follow the usual chemical numbering for ribose, adenosine and cytosine. The O atoms of the seven (formally 6.5) water molecules are labeled O1W–O7W. Atom O7W occupies a diagonal twofold axis of the space group, is likely to be disordered and has an occupancy factor of 0.5. The H atoms attached to atom O7W are also assigned an occupancy factor of 0.5.

H atoms were located from electron-density difference maps, providing information about protonation sites: adenosine atom N1A and cytosine atom N3C are protonated. Both phosphate groups are monoanions, giving a neutral structure overall. All bond lengths and angles involving non-H atoms are within expected limits. Overall, the structure is formally dimeric, with two dinucleotide molecules being connected by hydrogen bonds from the water molecule at the O7W site to the O6W water molecule, which is also hydrogen-bonded to the terminal phosphate group.

The seven water molecules form a very complex association with the dinucleotide structure. Table 1 lists all the water contacts of less than 3.25 Å between the dinucleotide and the water molecules and between water molecules. A summary of significant contacts of less than 3.0 Å (inter- and intra-molecular) is as follows. For O1W contacts, N3C—O1W 2.636 (5) Å and O1W—O3W 2.686 (6) Å. For O2W contacts, O2W—O21P 2.776 (4) Å, O2W—O11P 2.854 (4) Å and N6A—O2W 2.769 (4) Å. For additional O3W contacts, O3W—O3'C 2.821 (5) Å and O3W—O21P 2.978 (5) Å. For O4W contacts, O4W—O22P 2.672 (5) Å and O4W—O12P 2.782 (5) Å. For O5W contacts, O5W—O12P 2.756 (4) Å, O5W—N4C 2.948 (5) Å and O6W—O5W 2.897 (5) Å. For additional O6W contacts, O6W—O23P 2.833 (5) Å and O7W—O6W 2.924 (6) Å. Finally, O7W (disordered) sits on a diagonal twofold axis and bridges between two symmetry-related molecules through an O6W water molecule.

Fig. 2 shows a plot of a single molecule of (I) with the seven associated water molecules. From this diagram, the overlap of the cytosine and adenosine rings can be readily observed. Best-plane calculations of the adenosine and cytosine rings were performed and the angle between these planes was found to be 12.6°. The mean deviation of atoms in the adenosine plane is 0.006 Å, and 0.016 Å for the cytosine ring. The atom contacts from the adenosine plane to the cytosine best plane range from 3.223 (atom C8A) to 4.122 Å (atom C2A), while the atom contacts from the cytosine ring to the adenosine best plane range from 3.096 (atom N4C) to 4.015 Å (atom O2C).

The dihedral angles along the connecting phosphate backbone were compared with equivalent dihedral angles in structures of two previously reported normal dinucleotides, namely ApU (Seeman et al., 1976) and GpC (Rosenberg et al., 1976); both ApU and GpC are hydrated sodium salts. ApU had two independent molecules in the asymmetric unit and both units, labeled ApU1 and ApU2, were used in this comparison. The seven dihedral angles along the ribose–phosphate backbone around the C3'A—O3'A, O3'A—P1, P1—O5'C and O5'C—C4'C bonds were compared. All dihedral angles for these four structures, except for those around the C3'A—O3'A bond, were found to have approximately the same value (deviations range from 1–14° between (I) and the normal dinucleotides). However, around the C3'—O3' bond there is a 49° difference, on average, between the dihedral angles of (I) and ApU1, ApU2 and GpC. With the adenosine ring moved to C2', some change in the twisting of the flexible phosphate backbone is clearly necessary to accommodate the adenosine–cytosine overlap. This abnormal twist may contribute to the unusual stability of (I) towards nucleases. Fig. 3 compares Newman projections of the C3'—O3' bonds in ApU1, ApU2, GpC (Fig. 3ac) with (I) (Fig. 3 d).

Another notable difference between (I) and the ApU and GpC dinucleotides is the conformations of the ribose rings. On the pyrimidine base side (the 5'-side), ApU and GpC have envelope conformations, with atom C3' in the flap position; in (I), the conformation is twisted around C2'—C3'. On the purine base side (the 3'-side), ApU and GpC have twisted conformations around C2'—C3'; in (I), the conformation is twisted around C1'—O4'.

Experimental top

The dinucleotide 5'-monophosphate, (I), was synthesized through the coupling of 4-N-2',3'-O-tribenzoylcytidine and 6-N-benzoyl-5'-O-DMTr-isodeoxyadenosine (Wenzel & Nair, 1998), followed by 5'-phosphorylation (Chi et al., 2004). Its structure was characterized by multinuclear NMR, high-resolution MS and quantitative UV spectroscopy (see below). Crystals were obtained by very slow evaporation of an aqueous solution of (I) in a refrigerator. Experimental spectroscopic data for (I): 1H NMR (D2O, δ, p.p.m.): 8.28 (s, 1H), 8.23 (s, 1H), 7.50 (d, 1H, J = 8.0 Hz), 5.96 (d, 1H, J = 8.0 Hz), 5.49 (d, 1H, J = 4.5 Hz), 5.24 (m, 1H), 4.52 (m, 1H), 4.26 (dd, 1H, J = 11.0 and 6.0 Hz), 3.87–4.20 (m, 9H); 13CNMR (D2O, δ, p.p.m): 159.3, 150.7, 148.6, 148.5, 146.3, 142.5, 117.7, 95.4, 89.1, 84.8, 82.8, 80.4, 74.1, 71.1, 69.0, 64.2, 63.7, 61.7, one C atom not observable; 31P NMR (D2O, δ, p.p.m.): 0.86, −0.44. FAB–HRMS: [M+H]+ calculated for C19H27N8O13P2: 637.1173, found: 637.1170; UV (H2O): λmax 264 cm−1 (ε 19800)

Refinement top

All H atoms were initially located in a difference Fourier synthesis. H atoms bonded to C, O and N atoms were constrained to ride on their parent atoms, with Uiso(H) = 1.2Ueq(C,O,N). Water molecules were restrained geometrically to an O—H distance of 0.82 Å and to an H—H distance of 1.3 Å. The H atoms on atom O7W were fixed with occupancy factors of 0.5. A l l pertinent crystallographic data (experimental detail, xyz coordinates, displacement parameters, bond lengths and angles) have been deposited with the Cambridge Crystallographic Data Centre, deposition number CCDC 254123.

Computing details top

Data collection: PROTEUM (Bruker, 2003); loop mounted and flash frozen (Hope, 1988); cell refinement: PROTEUM; data reduction: PROTEUM and SADABS (Sheldrick, 1996); program(s) used to solve structure: SHELXTL (Sheldrick, 1997); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL and PLATON (Spek, 2003); software used to prepare material for publication: SHELXTL.

Figures top
[Figure 1] Fig. 1. A plot of dinucleotide (I), showing the atom-numbering scheme; atom labels ending in A are associated with the adenosine portion and those ending in C are associated with the cytosine portion. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2] Fig. 2. A comparison of the dihedral angles between (a) ApU1, (b) ApU2, (c) GpC and (d) (I), showing dihedral angle values in degrees.
4-amino-1-(6-O-{[2-(6-aminopurin-9-yl)-6-O-hydroxy(oxido)phosphoryl-1,2,5- trideoxy-3-furanosyl]oxidophosphoryl}-1,5-dideoxy-1-furanosyl)pyrimidin- 2(1H)-one 6.5 hydrate top
Crystal data top
C19H26N8O13P2·6.5H2ODx = 1.638 Mg m3
Mr = 753.52Cu Kα radiation, λ = 1.54178 Å
Tetragonal, P41212Cell parameters from 1009 reflections
a = 12.566 (5) Åθ = 2–50°
c = 38.708 (5) ŵ = 2.20 mm1
V = 6112 (4) Å3T = 100 K
Z = 8Needle, colorless
F(000) = 31600.35 × 0.15 × 0.15 mm
Data collection top
Bruker SMART 6000 CCD area-detector
diffractometer
5272 independent reflections
Radiation source: Rigaku FR-D rotating anode generator5266 reflections with I > 2σ(I)
Rigaku/MSC HiRes2 confocal optics monochromatorRint = 0.025
ω scansθmax = 67.0°, θmin = 3.7°
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)
h = 1114
Tmin = 0.513, Tmax = 0.734k = 1412
23451 measured reflectionsl = 4242
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.047H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.124 w = 1/[σ2(Fo2) + (0.0609P)2 + 10.5537P]
where P = (Fo2 + 2Fc2)/3
S = 1.10(Δ/σ)max = 0.002
5272 reflectionsΔρmax = 0.69 e Å3
474 parametersΔρmin = 0.49 e Å3
22 restraintsAbsolute structure: Flack (1983), with how many Friedel pairs
Primary atom site location: structure-invariant direct methodsAbsolute structure parameter: 0.04 (3)
Crystal data top
C19H26N8O13P2·6.5H2OZ = 8
Mr = 753.52Cu Kα radiation
Tetragonal, P41212µ = 2.20 mm1
a = 12.566 (5) ÅT = 100 K
c = 38.708 (5) Å0.35 × 0.15 × 0.15 mm
V = 6112 (4) Å3
Data collection top
Bruker SMART 6000 CCD area-detector
diffractometer
5272 independent reflections
Absorption correction: multi-scan
(SADABS; Sheldrick, 1996)
5266 reflections with I > 2σ(I)
Tmin = 0.513, Tmax = 0.734Rint = 0.025
23451 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.047H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.124 w = 1/[σ2(Fo2) + (0.0609P)2 + 10.5537P]
where P = (Fo2 + 2Fc2)/3
S = 1.10Δρmax = 0.69 e Å3
5272 reflectionsΔρmin = 0.49 e Å3
474 parametersAbsolute structure: Flack (1983), with how many Friedel pairs
22 restraintsAbsolute structure parameter: 0.04 (3)
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.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/UeqOcc. (<1)
P10.48271 (7)0.48721 (6)0.68406 (2)0.01756 (19)
P20.83819 (7)0.37702 (8)0.58340 (3)0.0272 (2)
O2'C0.41287 (19)0.0256 (2)0.70951 (6)0.0238 (5)
H2'O0.46890.00160.70320.080*
O3'C0.21760 (19)0.12178 (19)0.71591 (6)0.0225 (5)
H3'O0.23530.07940.73090.080*
O2C0.3899 (2)0.0555 (2)0.60528 (7)0.0292 (6)
O4'C0.29711 (19)0.19956 (19)0.64610 (6)0.0198 (5)
O5'C0.42734 (18)0.37265 (18)0.68109 (6)0.0202 (5)
O3'A0.46199 (19)0.54196 (18)0.64719 (6)0.0203 (5)
O5'A0.72489 (19)0.4268 (2)0.59338 (7)0.0239 (5)
O4'A0.6082 (2)0.6112 (2)0.57538 (7)0.0271 (6)
O11P0.42431 (19)0.55657 (19)0.70886 (6)0.0211 (5)
O12P0.59773 (19)0.46431 (19)0.68946 (6)0.0223 (5)
O21P0.8128 (2)0.2829 (2)0.56132 (7)0.0343 (7)
O22P0.8877 (2)0.3455 (3)0.61966 (8)0.0397 (7)
O23P0.9073 (3)0.4611 (3)0.56827 (11)0.0541 (9)
H23P0.90090.46100.54720.080*
N1A0.2373 (2)0.1937 (2)0.55125 (7)0.0210 (6)
H1NA0.20000.14870.54860.080*
N1C0.4458 (2)0.1040 (2)0.62829 (7)0.0191 (6)
N3A0.2732 (2)0.3564 (2)0.58083 (8)0.0200 (6)
N3C0.5264 (2)0.0315 (2)0.57907 (8)0.0233 (6)
H2NC0.53060.01830.56390.080*
N4C0.6683 (2)0.1135 (3)0.55172 (8)0.0276 (7)
H4AC0.67210.06130.53740.080*
H4BC0.71190.16600.55000.080*
N6A0.3494 (2)0.1157 (3)0.50967 (8)0.0246 (7)
H6NA0.30520.06400.50720.080*
H6NB0.40710.11690.49770.080*
N7A0.4928 (2)0.3093 (3)0.52318 (7)0.0228 (6)
N9A0.4429 (2)0.4318 (2)0.56227 (7)0.0209 (6)
C1'C0.3594 (3)0.1079 (3)0.65397 (9)0.0189 (7)
H1'C0.31550.04370.65210.080*
C2'C0.3972 (3)0.1224 (3)0.69174 (9)0.0187 (7)
H2'C0.46300.16420.69210.080*
C2A0.2141 (3)0.2738 (3)0.57430 (9)0.0201 (7)
H2A0.15030.26820.58640.080*
C2C0.4493 (3)0.0212 (3)0.60468 (9)0.0215 (7)
C3'C0.3061 (3)0.1879 (3)0.70735 (9)0.0189 (7)
H3'C0.32980.23040.72710.080*
C4'C0.2697 (3)0.2577 (3)0.67719 (8)0.0184 (7)
H4'C0.19190.26200.67820.080*
C4A0.3642 (3)0.3565 (3)0.56165 (8)0.0182 (7)
C4C0.5952 (3)0.1135 (3)0.57640 (9)0.0220 (7)
C5'C0.3119 (3)0.3709 (3)0.67603 (9)0.0202 (7)
H5AC0.29470.40250.65380.080*
H5BC0.27780.41290.69390.080*
C5A0.3951 (3)0.2813 (3)0.53764 (9)0.0198 (7)
C5C0.5872 (3)0.1983 (3)0.60042 (9)0.0223 (7)
H5C0.63160.25730.59900.080*
C3'A0.5181 (3)0.5054 (3)0.61694 (8)0.0192 (7)
H3'A0.53740.43010.61890.080*
C6A0.3289 (3)0.1928 (3)0.53158 (9)0.0212 (7)
C6C0.5126 (3)0.1901 (3)0.62562 (9)0.0208 (7)
H6C0.50630.24480.64170.080*
C4'A0.6172 (3)0.5755 (3)0.61027 (9)0.0207 (7)
H4'A0.61470.63740.62560.080*
C5'A0.7231 (3)0.5216 (3)0.61415 (10)0.0252 (8)
H5AA0.77950.56930.60690.080*
H5BA0.73490.50350.63820.080*
C8A0.5172 (3)0.3995 (3)0.53873 (9)0.0223 (7)
H8A0.58100.43940.53380.080*
C1'A0.4964 (3)0.6227 (3)0.56883 (10)0.0266 (8)
H1'A0.48220.62450.54420.080*
H1'B0.46930.68760.57920.080*
C2'A0.4461 (3)0.5252 (3)0.58535 (9)0.0190 (7)
H2'A0.37390.54240.59310.080*
O1W0.5664 (4)0.8772 (3)0.53483 (11)0.0613 (11)
H1WA0.508 (4)0.871 (5)0.5217 (16)0.080*
H1WB0.566 (5)0.8102 (17)0.5370 (17)0.080*
O2W0.2172 (2)0.9491 (2)0.49094 (7)0.0277 (6)
H2WA0.157 (3)0.972 (5)0.4863 (16)0.080*
H2WB0.231 (5)0.916 (5)0.4732 (10)0.080*
O3W0.4182 (3)0.7666 (3)0.50005 (10)0.0583 (10)
H3WA0.385 (5)0.716 (4)0.5102 (14)0.080*
H3WB0.380 (5)0.773 (5)0.4819 (10)0.080*
O4W0.7512 (3)0.8130 (3)0.57915 (9)0.0498 (9)
H4WA0.799 (4)0.852 (4)0.5744 (16)0.080*
H4WB0.709 (4)0.819 (5)0.5945 (13)0.080*
O5W0.7784 (2)0.9744 (3)0.50187 (8)0.0379 (7)
H5WA0.723 (3)0.972 (6)0.5118 (14)0.080*
H5WB0.823 (4)0.957 (5)0.5159 (13)0.080*
O6W0.8290 (3)0.6533 (3)0.53969 (9)0.0466 (8)
H6WA0.860 (5)0.688 (4)0.5243 (13)0.080*
H6WB0.852 (5)0.594 (3)0.5463 (16)0.080*
O7W0.6322 (4)0.6322 (4)0.50000.099 (3)
H7WA0.68940.63690.50910.080*0.50
H7WB0.62830.68850.48650.080*0.50
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
P10.0181 (4)0.0162 (4)0.0184 (4)0.0018 (3)0.0012 (3)0.0010 (3)
P20.0160 (4)0.0265 (5)0.0393 (6)0.0013 (4)0.0039 (4)0.0030 (4)
O2'C0.0192 (12)0.0254 (13)0.0268 (13)0.0058 (10)0.0055 (10)0.0098 (10)
O3'C0.0184 (12)0.0220 (12)0.0271 (13)0.0007 (10)0.0031 (10)0.0069 (10)
O2C0.0228 (13)0.0290 (14)0.0359 (15)0.0065 (11)0.0052 (11)0.0059 (11)
O4'C0.0208 (12)0.0184 (12)0.0203 (12)0.0026 (10)0.0016 (9)0.0001 (9)
O5'C0.0167 (11)0.0163 (12)0.0278 (13)0.0006 (9)0.0005 (10)0.0017 (10)
O3'A0.0228 (13)0.0166 (12)0.0215 (12)0.0021 (9)0.0010 (9)0.0000 (9)
O5'A0.0167 (12)0.0248 (13)0.0301 (14)0.0030 (10)0.0010 (10)0.0001 (10)
O4'A0.0205 (13)0.0280 (13)0.0329 (14)0.0014 (10)0.0004 (10)0.0098 (11)
O11P0.0225 (12)0.0208 (12)0.0200 (12)0.0039 (10)0.0021 (10)0.0004 (10)
O12P0.0199 (12)0.0234 (13)0.0236 (13)0.0019 (10)0.0025 (10)0.0001 (10)
O21P0.0210 (13)0.0453 (17)0.0366 (16)0.0013 (12)0.0063 (11)0.0098 (13)
O22P0.0293 (15)0.0461 (18)0.0438 (17)0.0099 (13)0.0125 (13)0.0092 (14)
O23P0.0313 (17)0.0443 (19)0.087 (3)0.0027 (14)0.0194 (17)0.0176 (18)
N1A0.0194 (14)0.0220 (15)0.0216 (15)0.0003 (12)0.0002 (11)0.0021 (12)
N1C0.0212 (14)0.0190 (14)0.0171 (14)0.0027 (12)0.0019 (11)0.0016 (11)
N3A0.0165 (14)0.0218 (15)0.0217 (15)0.0021 (12)0.0040 (11)0.0036 (12)
N3C0.0224 (15)0.0264 (16)0.0212 (15)0.0001 (13)0.0015 (12)0.0027 (12)
N4C0.0240 (16)0.0362 (18)0.0226 (16)0.0010 (14)0.0070 (12)0.0062 (14)
N6A0.0208 (15)0.0309 (17)0.0221 (16)0.0048 (13)0.0000 (12)0.0068 (13)
N7A0.0145 (14)0.0366 (17)0.0173 (14)0.0016 (12)0.0000 (11)0.0025 (12)
N9A0.0202 (14)0.0270 (16)0.0156 (14)0.0001 (12)0.0017 (11)0.0009 (12)
C1'C0.0138 (15)0.0195 (16)0.0234 (18)0.0004 (13)0.0028 (13)0.0040 (13)
C2'C0.0175 (16)0.0191 (16)0.0196 (18)0.0013 (13)0.0016 (13)0.0025 (13)
C2A0.0216 (17)0.0193 (17)0.0194 (17)0.0023 (14)0.0060 (13)0.0047 (13)
C2C0.0162 (16)0.0254 (18)0.0228 (17)0.0005 (14)0.0009 (13)0.0018 (14)
C3'C0.0169 (16)0.0210 (17)0.0188 (17)0.0014 (14)0.0027 (13)0.0012 (14)
C4'C0.0182 (16)0.0183 (17)0.0188 (17)0.0006 (13)0.0001 (13)0.0022 (13)
C4A0.0177 (16)0.0234 (17)0.0135 (16)0.0047 (13)0.0002 (12)0.0045 (13)
C4C0.0146 (16)0.0309 (19)0.0205 (18)0.0035 (14)0.0001 (13)0.0099 (15)
C5'C0.0163 (16)0.0173 (17)0.0269 (19)0.0004 (13)0.0042 (13)0.0020 (13)
C5A0.0177 (16)0.0250 (17)0.0167 (17)0.0042 (14)0.0012 (13)0.0040 (14)
C5C0.0214 (17)0.0213 (17)0.0241 (18)0.0019 (14)0.0020 (14)0.0032 (14)
C3'A0.0185 (16)0.0166 (16)0.0226 (17)0.0020 (13)0.0011 (13)0.0006 (12)
C6A0.0167 (16)0.0269 (18)0.0200 (18)0.0067 (14)0.0029 (13)0.0027 (14)
C6C0.0188 (17)0.0233 (17)0.0202 (16)0.0017 (14)0.0024 (13)0.0038 (13)
C4'A0.0191 (17)0.0193 (17)0.0238 (18)0.0033 (14)0.0011 (14)0.0024 (13)
C5'A0.0254 (18)0.0231 (18)0.0269 (19)0.0065 (15)0.0056 (15)0.0021 (15)
C8A0.0139 (15)0.0351 (19)0.0178 (17)0.0024 (15)0.0034 (13)0.0001 (14)
C1'A0.0203 (18)0.0289 (19)0.031 (2)0.0003 (15)0.0010 (15)0.0068 (16)
C2'A0.0188 (16)0.0196 (16)0.0187 (17)0.0035 (13)0.0012 (13)0.0013 (13)
O1W0.081 (3)0.0348 (18)0.068 (3)0.0053 (18)0.036 (2)0.0154 (18)
O2W0.0286 (14)0.0281 (14)0.0265 (14)0.0073 (11)0.0027 (11)0.0089 (11)
O3W0.063 (2)0.060 (2)0.052 (2)0.0147 (18)0.0090 (19)0.0216 (19)
O4W0.063 (2)0.0411 (19)0.045 (2)0.0199 (17)0.0126 (16)0.0045 (15)
O5W0.0404 (17)0.0433 (17)0.0301 (15)0.0010 (14)0.0093 (13)0.0043 (14)
O6W0.0409 (19)0.0468 (19)0.052 (2)0.0048 (15)0.0127 (15)0.0044 (16)
O7W0.124 (4)0.124 (4)0.048 (3)0.061 (5)0.024 (3)0.024 (3)
Geometric parameters (Å, º) top
P1—O12P1.489 (3)C1'C—C2'C1.548 (5)
P1—O11P1.490 (2)C1'C—H1'C0.9800
P1—O5'C1.603 (3)C2'C—C3'C1.533 (5)
P1—O3'A1.606 (2)C2'C—H2'C0.9797
P2—O23P1.488 (3)C2A—H2A0.9306
P2—O21P1.494 (3)C3'C—C4'C1.531 (5)
P2—O22P1.586 (3)C3'C—H3'C0.9793
P2—O5'A1.602 (3)C4'C—C5'C1.519 (5)
O2'C—C2'C1.410 (4)C4'C—H4'C0.9799
O2'C—H2'O0.8200C4A—C5A1.381 (5)
O3'C—C3'C1.427 (4)C4C—C5C1.418 (5)
O3'C—H3'O0.8196C5'C—H5AC0.9703
O2C—C2C1.220 (5)C5'C—H5BC0.9712
O4'C—C1'C1.426 (4)C5A—C6A1.408 (5)
O4'C—C4'C1.449 (4)C5C—C6C1.357 (5)
O5'C—C5'C1.464 (4)C5C—H5C0.9295
O3'A—C3'A1.442 (4)C3'A—C2'A1.542 (5)
O5'A—C5'A1.438 (4)C3'A—C4'A1.547 (5)
O4'A—C4'A1.428 (4)C3'A—H3'A0.9797
O4'A—C1'A1.434 (4)C6C—H6C0.9301
O23P—H23P0.8210C4'A—C5'A1.501 (5)
N1A—C2A1.376 (5)C4'A—H4'A0.9793
N1A—C6A1.380 (4)C5'A—H5AA0.9697
N1A—H1NA0.7417C5'A—H5BA0.9697
N1C—C6C1.373 (5)C8A—H8A0.9646
N1C—C2C1.385 (5)C1'A—C2'A1.520 (5)
N1C—C1'C1.473 (4)C1'A—H1'A0.9699
N3A—C2A1.301 (5)C1'A—H1'B0.9708
N3A—C4A1.363 (4)C2'A—H2'A0.9795
N3C—C4C1.349 (5)O1W—H1WA0.90 (2)
N3C—C2C1.391 (5)O1W—H1WB0.85 (2)
N3C—H2NC0.8611O2W—H2WA0.82 (2)
N4C—C4C1.326 (4)O2W—H2WB0.82 (2)
N4C—H4AC0.8602O3W—H3WA0.85 (2)
N4C—H4BC0.8601O3W—H3WB0.85 (2)
N6A—C6A1.313 (5)O4W—H4WA0.80 (2)
N6A—H6NA0.8598O4W—H4WB0.799 (19)
N6A—H6NB0.8596O5W—H5WA0.80 (2)
N7A—C8A1.320 (5)O5W—H5WB0.82 (2)
N7A—C5A1.395 (5)O6W—H6WA0.83 (2)
N9A—C8A1.366 (4)O6W—H6WB0.84 (2)
N9A—C4A1.369 (5)O7W—H7WA0.8029
N9A—C2'A1.476 (4)O7W—H7WB0.8809
O12P—P1—O11P120.05 (14)O4'C—C4'C—H4'C107.4
O12P—P1—O5'C104.95 (14)C5'C—C4'C—H4'C107.3
O11P—P1—O5'C110.96 (13)C3'C—C4'C—H4'C107.4
O12P—P1—O3'A111.43 (14)N3A—C4A—N9A126.7 (3)
O11P—P1—O3'A104.01 (13)N3A—C4A—C5A127.0 (3)
O5'C—P1—O3'A104.52 (13)N9A—C4A—C5A106.4 (3)
O23P—P2—O21P117.5 (2)N4C—C4C—N3C120.0 (3)
O23P—P2—O22P107.2 (2)N4C—C4C—C5C121.4 (4)
O21P—P2—O22P113.12 (17)N3C—C4C—C5C118.6 (3)
O23P—P2—O5'A109.66 (16)O5'C—C5'C—C4'C110.9 (3)
O21P—P2—O5'A104.91 (15)O5'C—C5'C—H5AC109.5
O22P—P2—O5'A103.46 (16)C4'C—C5'C—H5AC109.4
C2'C—O2'C—H2'O109.5O5'C—C5'C—H5BC109.5
C3'C—O3'C—H3'O109.4C4'C—C5'C—H5BC109.5
C1'C—O4'C—C4'C111.1 (2)H5AC—C5'C—H5BC108.1
C5'C—O5'C—P1117.0 (2)C4A—C5A—N7A110.2 (3)
C3'A—O3'A—P1120.4 (2)C4A—C5A—C6A119.1 (3)
C5'A—O5'A—P2118.2 (2)N7A—C5A—C6A130.7 (3)
C4'A—O4'A—C1'A106.1 (3)C6C—C5C—C4C117.6 (3)
P2—O23P—H23P109.5C6C—C5C—H5C121.2
C2A—N1A—C6A122.7 (3)C4C—C5C—H5C121.2
C2A—N1A—H1NA120.9O3'A—C3'A—C2'A107.8 (3)
C6A—N1A—H1NA116.3O3'A—C3'A—C4'A110.3 (3)
C6C—N1C—C2C121.5 (3)C2'A—C3'A—C4'A104.4 (3)
C6C—N1C—C1'C118.4 (3)O3'A—C3'A—H3'A111.4
C2C—N1C—C1'C119.5 (3)C2'A—C3'A—H3'A111.3
C2A—N3A—C4A112.0 (3)C4'A—C3'A—H3'A111.3
C4C—N3C—C2C124.9 (3)N6A—C6A—N1A121.8 (3)
C4C—N3C—H2NC117.6N6A—C6A—C5A125.0 (3)
C2C—N3C—H2NC117.6N1A—C6A—C5A113.2 (3)
C4C—N4C—H4AC120.2C5C—C6C—N1C122.5 (3)
C4C—N4C—H4BC119.8C5C—C6C—H6C118.9
H4AC—N4C—H4BC120.0N1C—C6C—H6C118.7
C6A—N6A—H6NA120.1O4'A—C4'A—C5'A107.9 (3)
C6A—N6A—H6NB120.0O4'A—C4'A—C3'A105.8 (3)
H6NA—N6A—H6NB120.0C5'A—C4'A—C3'A116.1 (3)
C8A—N7A—C5A103.8 (3)O4'A—C4'A—H4'A108.8
C8A—N9A—C4A106.1 (3)C5'A—C4'A—H4'A109.0
C8A—N9A—C2'A128.4 (3)C3'A—C4'A—H4'A109.0
C4A—N9A—C2'A125.5 (3)O5'A—C5'A—C4'A109.4 (3)
O4'C—C1'C—N1C106.7 (3)O5'A—C5'A—H5AA109.8
O4'C—C1'C—C2'C106.0 (3)C4'A—C5'A—H5AA109.9
N1C—C1'C—C2'C114.5 (3)O5'A—C5'A—H5BA109.9
O4'C—C1'C—H1'C109.9C4'A—C5'A—H5BA109.7
N1C—C1'C—H1'C109.8H5AA—C5'A—H5BA108.1
C2'C—C1'C—H1'C109.8N7A—C8A—N9A113.6 (3)
O2'C—C2'C—C3'C112.0 (3)N7A—C8A—H8A123.3
O2'C—C2'C—C1'C113.7 (3)N9A—C8A—H8A123.1
C3'C—C2'C—C1'C101.9 (3)O4'A—C1'A—C2'A104.6 (3)
O2'C—C2'C—H2'C109.7O4'A—C1'A—H1'A110.9
C3'C—C2'C—H2'C109.6C2'A—C1'A—H1'A110.8
C1'C—C2'C—H2'C109.7O4'A—C1'A—H1'B110.8
N3A—C2A—N1A126.0 (3)C2'A—C1'A—H1'B110.9
N3A—C2A—H2A117.1H1'A—C1'A—H1'B108.8
N1A—C2A—H2A116.9N9A—C2'A—C1'A113.5 (3)
O2C—C2C—N1C124.2 (3)N9A—C2'A—C3'A111.5 (3)
O2C—C2C—N3C120.8 (3)C1'A—C2'A—C3'A102.7 (3)
N1C—C2C—N3C115.0 (3)N9A—C2'A—H2'A109.6
O3'C—C3'C—C4'C106.1 (3)C1'A—C2'A—H2'A109.6
O3'C—C3'C—C2'C111.1 (3)C3'A—C2'A—H2'A109.7
C4'C—C3'C—C2'C103.3 (3)H1WA—O1W—H1WB88 (4)
O3'C—C3'C—H3'C111.9H2WA—O2W—H2WB100 (4)
C4'C—C3'C—H3'C112.0H3WA—O3W—H3WB100 (4)
C2'C—C3'C—H3'C111.9H4WA—O4W—H4WB128 (5)
O4'C—C4'C—C5'C111.4 (3)H5WA—O5W—H5WB106 (4)
O4'C—C4'C—C3'C105.9 (3)H6WA—O6W—H6WB121 (5)
C5'C—C4'C—C3'C117.1 (3)H7WA—O7W—H7WB104.5
O12P—P1—O5'C—C5'C179.3 (2)P1—O5'C—C5'C—C4'C174.5 (2)
O11P—P1—O5'C—C5'C48.2 (3)O4'C—C4'C—C5'C—O5'C73.5 (3)
O3'A—P1—O5'C—C5'C63.4 (2)C3'C—C4'C—C5'C—O5'C48.4 (4)
O12P—P1—O3'A—C3'A40.9 (3)N3A—C4A—C5A—N7A179.6 (3)
O11P—P1—O3'A—C3'A171.6 (2)N9A—C4A—C5A—N7A0.1 (4)
O5'C—P1—O3'A—C3'A71.9 (2)N3A—C4A—C5A—C6A0.7 (5)
O23P—P2—O5'A—C5'A51.3 (3)N9A—C4A—C5A—C6A179.6 (3)
O21P—P2—O5'A—C5'A178.4 (2)C8A—N7A—C5A—C4A0.1 (4)
O22P—P2—O5'A—C5'A62.8 (3)C8A—N7A—C5A—C6A179.8 (4)
C4'C—O4'C—C1'C—N1C136.5 (3)N4C—C4C—C5C—C6C177.7 (3)
C4'C—O4'C—C1'C—C2'C14.1 (3)N3C—C4C—C5C—C6C2.3 (5)
C6C—N1C—C1'C—O4'C57.4 (4)P1—O3'A—C3'A—C2'A150.5 (2)
C2C—N1C—C1'C—O4'C114.2 (3)P1—O3'A—C3'A—C4'A96.1 (3)
C6C—N1C—C1'C—C2'C59.5 (4)C2A—N1A—C6A—N6A179.9 (3)
C2C—N1C—C1'C—C2'C128.9 (3)C2A—N1A—C6A—C5A0.2 (5)
O4'C—C1'C—C2'C—O2'C150.6 (3)C4A—C5A—C6A—N6A179.5 (3)
N1C—C1'C—C2'C—O2'C92.1 (3)N7A—C5A—C6A—N6A0.2 (6)
O4'C—C1'C—C2'C—C3'C29.9 (3)C4A—C5A—C6A—N1A0.4 (5)
N1C—C1'C—C2'C—C3'C147.1 (3)N7A—C5A—C6A—N1A179.9 (3)
C4A—N3A—C2A—N1A0.4 (5)C4C—C5C—C6C—N1C0.3 (5)
C6A—N1A—C2A—N3A0.7 (5)C2C—N1C—C6C—C5C1.6 (5)
C6C—N1C—C2C—O2C177.8 (3)C1'C—N1C—C6C—C5C173.0 (3)
C1'C—N1C—C2C—O2C6.5 (5)C1'A—O4'A—C4'A—C5'A157.8 (3)
C6C—N1C—C2C—N3C1.4 (5)C1'A—O4'A—C4'A—C3'A32.9 (4)
C1'C—N1C—C2C—N3C172.7 (3)O3'A—C3'A—C4'A—O4'A126.3 (3)
C4C—N3C—C2C—O2C179.9 (3)C2'A—C3'A—C4'A—O4'A10.8 (3)
C4C—N3C—C2C—N1C0.7 (5)O3'A—C3'A—C4'A—C5'A114.1 (3)
O2'C—C2'C—C3'C—O3'C42.2 (4)C2'A—C3'A—C4'A—C5'A130.4 (3)
C1'C—C2'C—C3'C—O3'C79.7 (3)P2—O5'A—C5'A—C4'A160.4 (2)
O2'C—C2'C—C3'C—C4'C155.6 (3)O4'A—C4'A—C5'A—O5'A65.8 (3)
C1'C—C2'C—C3'C—C4'C33.7 (3)C3'A—C4'A—C5'A—O5'A52.8 (4)
C1'C—O4'C—C4'C—C5'C120.5 (3)C5A—N7A—C8A—N9A0.3 (4)
C1'C—O4'C—C4'C—C3'C7.8 (3)C4A—N9A—C8A—N7A0.4 (4)
O3'C—C3'C—C4'C—O4'C90.6 (3)C2'A—N9A—C8A—N7A177.0 (3)
C2'C—C3'C—C4'C—O4'C26.5 (3)C4'A—O4'A—C1'A—C2'A42.3 (4)
O3'C—C3'C—C4'C—C5'C144.7 (3)C8A—N9A—C2'A—C1'A37.1 (5)
C2'C—C3'C—C4'C—C5'C98.3 (3)C4A—N9A—C2'A—C1'A146.0 (3)
C2A—N3A—C4A—N9A179.8 (3)C8A—N9A—C2'A—C3'A78.3 (4)
C2A—N3A—C4A—C5A0.2 (5)C4A—N9A—C2'A—C3'A98.6 (4)
C8A—N9A—C4A—N3A179.4 (3)O4'A—C1'A—C2'A—N9A87.0 (3)
C2'A—N9A—C4A—N3A3.1 (5)O4'A—C1'A—C2'A—C3'A33.6 (3)
C8A—N9A—C4A—C5A0.3 (4)O3'A—C3'A—C2'A—N9A134.4 (3)
C2'A—N9A—C4A—C5A177.2 (3)C4'A—C3'A—C2'A—N9A108.3 (3)
C2C—N3C—C4C—N4C177.4 (3)O3'A—C3'A—C2'A—C1'A103.8 (3)
C2C—N3C—C4C—C5C2.6 (5)C4'A—C3'A—C2'A—C1'A13.5 (3)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3W—H3WA···O3Ci0.85 (2)1.99 (3)2.821 (4)167 (7)
O2C—H2O···O23Pii0.821.822.631 (4)167
O3C—H3O···N7Aiii0.822.042.767 (4)147
O23P—H23P···O3Wiv0.822.553.227 (6)141
N1A—H1NA···O11Pv0.741.972.692 (4)166
N3C—H2NC···O1Wvi0.861.792.636 (5)169
N4C—H4AC···O5Wvi0.862.212.948 (5)144
N4C—H4BC···O21P0.861.992.822 (5)163
N6A—H6NA···O2Wvi0.861.932.769 (4)167
N6A—H6NB···O2Cvii0.862.132.967 (4)163
O1W—H1WA···O3W0.90 (2)1.92 (5)2.686 (6)142 (6)
O2W—H2WA···O11Pviii0.82 (2)2.11 (4)2.854 (4)151 (7)
O2W—H2WB···O21Piv0.82 (2)1.97 (2)2.776 (4)166 (6)
O3W—H3WB···O21Piv0.85 (2)2.13 (2)2.978 (5)172 (6)
O4W—H4WA···O12Pix0.80 (2)1.99 (2)2.782 (4)172 (7)
O4W—H4WB···O22Pix0.80 (2)1.88 (2)2.672 (5)175 (7)
O5W—H5WA···N4Cx0.80 (2)2.45 (6)2.948 (5)122 (6)
O5W—H5WA···O1W0.80 (2)2.46 (4)3.195 (5)153 (7)
O5W—H5WB···O12Pix0.82 (2)1.99 (3)2.756 (4)156 (6)
O6W—H6WA···O5Wiv0.83 (2)2.10 (3)2.897 (4)161 (7)
O6W—H6WB···O23P0.84 (2)2.00 (2)2.833 (5)172 (7)
O7W—H7WA···O6W0.802.132.924 (6)172
O7W—H7WB···O6Wiv0.882.062.924 (6)166
Symmetry codes: (i) x+1/2, y+1/2, z+5/4; (ii) x+3/2, y1/2, z+5/4; (iii) y+1/2, x1/2, z+1/4; (iv) y, x, z+1; (v) x+1/2, y1/2, z+5/4; (vi) x, y1, z; (vii) y+1/2, x+1/2, z1/4; (viii) y1/2, x+3/2, z1/4; (ix) x+3/2, y+1/2, z+5/4; (x) x, y+1, z.

Experimental details

Crystal data
Chemical formulaC19H26N8O13P2·6.5H2O
Mr753.52
Crystal system, space groupTetragonal, P41212
Temperature (K)100
a, c (Å)12.566 (5), 38.708 (5)
V3)6112 (4)
Z8
Radiation typeCu Kα
µ (mm1)2.20
Crystal size (mm)0.35 × 0.15 × 0.15
Data collection
DiffractometerBruker SMART 6000 CCD area-detector
diffractometer
Absorption correctionMulti-scan
(SADABS; Sheldrick, 1996)
Tmin, Tmax0.513, 0.734
No. of measured, independent and
observed [I > 2σ(I)] reflections
23451, 5272, 5266
Rint0.025
(sin θ/λ)max1)0.597
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.047, 0.124, 1.10
No. of reflections5272
No. of parameters474
No. of restraints22
H-atom treatmentH atoms treated by a mixture of independent and constrained refinement
w = 1/[σ2(Fo2) + (0.0609P)2 + 10.5537P]
where P = (Fo2 + 2Fc2)/3
Δρmax, Δρmin (e Å3)0.69, 0.49
Absolute structureFlack (1983), with how many Friedel pairs
Absolute structure parameter0.04 (3)

Computer programs: PROTEUM (Bruker, 2003); loop mounted and flash frozen (Hope, 1988), PROTEUM and SADABS (Sheldrick, 1996), SHELXTL (Sheldrick, 1997), SHELXTL and PLATON (Spek, 2003).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O3W—H3WA···O3'Ci0.85 (2)1.99 (3)2.821 (4)167 (7)
O2'C—H2'O···O23Pii0.821.822.631 (4)167
O3'C—H3'O···N7Aiii0.822.042.767 (4)147
O23P—H23P···O3Wiv0.822.553.227 (6)141
N1A—H1NA···O11Pv0.741.972.692 (4)166
N3C—H2NC···O1Wvi0.861.792.636 (5)169
N4C—H4AC···O5Wvi0.862.212.948 (5)144
N4C—H4BC···O21P0.861.992.822 (5)163
N6A—H6NA···O2Wvi0.861.932.769 (4)167
N6A—H6NB···O2'Cvii0.862.132.967 (4)163
O1W—H1WA···O3W0.90 (2)1.92 (5)2.686 (6)142 (6)
O2W—H2WA···O11Pviii0.82 (2)2.11 (4)2.854 (4)151 (7)
O2W—H2WB···O21Piv0.82 (2)1.97 (2)2.776 (4)166 (6)
O3W—H3WB···O21Piv0.85 (2)2.13 (2)2.978 (5)172 (6)
O4W—H4WA···O12Pix0.80 (2)1.99 (2)2.782 (4)172 (7)
O4W—H4WB···O22Pix0.799 (19)1.88 (2)2.672 (5)175 (7)
O5W—H5WA···N4Cx0.80 (2)2.45 (6)2.948 (5)122 (6)
O5W—H5WA···O1W0.80 (2)2.46 (4)3.195 (5)153 (7)
O5W—H5WB···O12Pix0.82 (2)1.99 (3)2.756 (4)156 (6)
O6W—H6WA···O5Wiv0.83 (2)2.10 (3)2.897 (4)161 (7)
O6W—H6WB···O23P0.84 (2)2.00 (2)2.833 (5)172 (7)
O7W—H7WA···O6W0.802.132.924 (6)172
O7W—H7WB···O6Wiv0.882.062.924 (6)166
Symmetry codes: (i) x+1/2, y+1/2, z+5/4; (ii) x+3/2, y1/2, z+5/4; (iii) y+1/2, x1/2, z+1/4; (iv) y, x, z+1; (v) x+1/2, y1/2, z+5/4; (vi) x, y1, z; (vii) y+1/2, x+1/2, z1/4; (viii) y1/2, x+3/2, z1/4; (ix) x+3/2, y+1/2, z+5/4; (x) x, y+1, z.
 

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