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

The asymmetric unit of the title compound contains one 3′-azido-3′-deoxythymidine-5′aminocarbonylphosphonate (ACP–AZT) anion, half on 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.


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 HIVinfected patients, the first of which was 3 0 -azido-3 0 -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 (Stań czak 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 1 ; DeClercq, 2010), and one prodrug of AZT (5 0 -hydrogenphosphonate AZT, Nikavir 1 ) 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 0 -aminocarbonylphosphonate 3 0 -azido-3 0deoxythymidine (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, É m = 35.0 . These results correspond to a C3 0 -endo-C4 0 -exo ( 3 T 4 ) conformation of the sugar cycle. Atoms C3 0 and C4 0 deviate from the plane of atoms C1 0 /O4 0 / C2 0 by 0.458 and À0.101 Å , respectively. Unlike the AZT molecules and the molecule of thymidine, which exhibit a C3 0 -exo-class of pucker, the ACP-AZT molecule exhibits a C3 0 -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 ACP-AZT (O4 0 -C1 0 -N1-C2) = À147.75 (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
The C(O)NH 2 group of ACP-AZT is disordered, one part forming a C OÁ Á ÁH 4 N + hydrogen bond and the other a C- 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. Table 1 Hydrogen-bond geometry (Å , ).

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.
NH 2 Á Á ÁOH 2 hydrogen bond with the components of the NH 4 + / H 2 O position (Table 1 and Fig. 2). In the crystal, the various components are linked by N-HÁ Á ÁO, O-HÁ Á ÁO, N-HÁ Á ÁN, C-HÁ Á ÁO and C-HÁ Á ÁN 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.

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

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (