Search tips
Search criteria 


Logo of actacInternational Union of Crystallographysearchsubscribearticle submissionjournal home pagethis article
Acta Crystallogr C. Mar 15, 2010; 66(Pt 3): m65–m68.
Published online Feb 3, 2010. doi:  10.1107/S0108270110002738
PMCID: PMC2855577
A synchrotron radiation study of the one-dimensional complex of sodium with (1S)-N-carboxyl­ato-1-(9-deaza­adenin-9-yl)-1,4-dide­oxy-1,4-imino-d-ribitol, a member of the ’immucillin’ family
Graeme J. Gainsford,a* Richard H. Furneaux,a Peter C. Tyler,a Anthony Sauve,b and Vern L. Shrammb
aIndustrial Research Limited, PO Box 31-310, Lower Hutt, New Zealand
bAlbert Einstein College of Medicine of Yeshiva University, 1300 Morris Park Avenue, Bronx, New York 10461, USA
Correspondence e-mail: g.gainsford/at/
Received January 13, 2010; Accepted January 21, 2010.
The sodium salt of [immucillin-A–CO2H] (Imm-A), namely catena-poly[[[triaqua­disodium(I)](μ-aqua)[μ-(1S)-N-car­box­yl­ato-1-(9-deaza­adenin-9-yl)-1,4-dide­oxy-1,4-imino-d-ribi­tol][triaqua­disodium(I)][μ-(1S)-N-carboxyl­ato-1-(9-deaza­aden­in-9-yl)-1,4-dide­oxy-1,4-imino-d-ribitol]] tetra­hydrate], {[Na2(C12H13N4O6)2(H2O)7]·4H2O}n, (I), forms a polymeric chain via Na+—O inter­actions involving the carboxyl­ate and keto O atoms of two independent Imm-A mol­ecules. Extensive N,O—H(...)O hydrogen bonding utilizing all water H atoms, including four waters of crystallization, provides crystal packing. The structural definition of this novel compound was made possible through the use of synchrotron radiation utilizing a minute fragment (volume ~2.4 × 10−5 mm−3) on a beamline optimized for protein data collection. A summary of intra-ring conformations for immucillin structures indicates considerable flexibility while retaining similar intra-ring orientations.
The title compound, (I), was prepared as part of continuing studies of the so-called ‘immucillin’ family of compounds which are potent aza-C-nucleoside inhibitors of purine nucleoside phospho­rylase (Evans et al., 2003 [triangle]). The immucillin compounds do not usually form adequate-quality crystals, and only adducts protonated on the aza-ribitol sugar (N1) positions have been reported (MILMAV: Federov et al., 2001 [triangle]; MEFZOM: Evans et al., 2000 [triangle]) (alphabetic codes used herein are those used in the Cambridge Structural Database, 2009 [triangle]). A related compound, with oxygen replacing NH in the saturated five-membered ring, is VOVJIZ (Otter et al., 1992 [triangle]), while compound VILHON (Ikegami et al., 1990 [triangle]) has been re-assigned as a related 6′-amino compound by Otter et al. (1992 [triangle]). Some of these compounds have been successfully defined ‘in action’ as inhibitors in sites within the enzymes (e.g. MT-Imm-A; Singh et al., 2004 [triangle]). The size of the crystal fragment used here meant that both the superb power and resolution of synchrotron radiation were essential even when used in the less than optimum settings at the end of a protein data collection. We are thus able to present the first anionic derivative of this family.
An external file that holds a picture, illustration, etc.
Object name is c-66-00m65-scheme1.jpg Object name is c-66-00m65-scheme1.jpg
The asymmetric unit contents of the title compound, (I), are shown in Fig. 1 [triangle]; the polymer linking bonds (Na1*—O16, Na1—O16*) are shown at the top and bottom of the figure (see also Fig. 2 [triangle] and the scheme above). The two independent Imm-A–CO2 mol­ecules, which are label-related by adding 10 to the number of the first (i.e. N1 and N11), are almost superimposable. The absolute configurations at C1′ (S), C2′ (S), C3′ (R) and C4′ (R) indicated by a Flack parameter of 0.0 (3) agree with the stereochemistry known from the synthesis. There is a slight difference in tilt angle, ~10°, between the two rings (see the dihedral angles around C1′—C9 and C11′—C19 in Table 1 [triangle]), and ring comparisons (Spek, 2009 [triangle]) give r.m.s. bond and angle fits of 0.016 Å and 1.25°, respectively. The 1,9-deaza­adenin-9-yl nine-membered rings (e.g. N1/C2/N3/C4/C9/C8/N7/C5/C6) are made up of two rigidly planar five- and six-membered rings, with the planes at an average angle of 1.8 (3)° with respect to each other. The five-membered (imino-ribitol) rings (e.g. N1′/C1′–C4′) are puckered on C2′ and C3′ [Cremer & Pople (1975 [triangle]) parameters Q(2) = 0.342 (6) Å and ϕ(2) = 272.3 (9)°] in mol­ecule 1 and twisted on C12′—C13′ [Q(2) = 0.307 (6) Å and ϕ(2) = 268.2 (10)°] in the other. Such variations are normal, as shown by the pyrrolidine-1-carboxyl­ate adduct FISNUR (Zukerman-Schpector et al., 2005 [triangle]) which also twists along C2′—C3′ [Q(2) = 0.426 Å and ϕ(2) = 266.4 (3)°].
Figure 1
Figure 1
Diagram of the asymmetric unit and two extra atoms of (I), shown with 50% displacement ellipsoids (Farrugia, 1997 [triangle]). Atoms Na1* (at x − 1, y − 1, z) and O16* (at An external file that holds a picture, illustration, etc.
Object name is c-66-00m65-efi3.jpg) are included and linked by three-line (more ...)
Figure 2
Figure 2
Packing diagram of the cell of (I) (Bruno et al., 2002 [triangle]), viewed approximately down the c axis. Representative atom labels are given (see Comment and Table 2 [triangle]) and H atoms have been omitted for clarity. Hydrogen bonds are shown (more ...)
Table 1
Table 1
Selected geometric parameters (Å, °)
For completeness, we note that other pyrimidin-4-one structures have been reported: FOYWIZ (Girgis et al., 1987 [triangle]) and QINBOE (Jukic et al., 2000 [triangle]); the former has (fortuitously) similar relative orientations of the two rings to mol­ecule 1 here.
One of the Imm-A–CO2 mol­ecules provides a bridging oxygen (O6) to the two independent cations, while the other bonds to only Na2 through carboxyl­ate atom O7b′ (Fig. 1 [triangle]). The Na cations are further bridged by one water mol­ecule (O2W) and both have the usual approximate octa­hedral binding stereochemistry, with variation in Na—O distances depending on the trans donor atoms. Finally, the packing cohesion is provided by extensive hydrogen bonds involving all the waters of crystallization, the aqua mol­ecules and the Imm-A–CO2 N-bound H atoms as donors (Table 2 [triangle], and scheme). Overall, the structure can be described as a polymeric chain parallel to the (1An external file that holds a picture, illustration, etc.
Object name is c-66-00m65-efi1.jpg1) plane crosslinked by hydrogen bonds to the water mol­ecules that lie between the chains (Fig. 2 [triangle]).
Table 2
Table 2
Hydrogen-bond geometry (Å, °)
It is of inter­est to compare the relative conformations of the two independent Imm-A–CO2 mol­ecules here with the previously reported (free) Imm-H cationic mol­ecules and Imm-H as found bound in a human purine nucleoside phospho­rylase mutant (Table 3 [triangle]). There is quite a wide variation of relative conformations of the ten-membered 9-deaza­adenin-9-yl and the 4-aza-ribitol rings with respect to the linking bond (e.g. C1—C9′), with the two independent mol­ecules here being closely related both in intra-ring orientations and in the 4-aza-ribitol ring descriptions. This is rather remarkable given the variation that might be expected in the strongly hydrogen-bonded network and with each mol­ecule involved in different inter­actions with the cations. Agreement between the two free Imm-H studies (entries 4 and 6 in Table 3 [triangle]) is also notable. It is also apparent that the protein-bound mol­ecule (entry 5) has been twisted about the link bond in response to close inter­actions, but still retains a similar intra­planar angle (between the two rings) to that in the free ligand structures. The linking factor in these determinations is that the variable conformations retain a similar intra­planar angle with only minor variations in the attachment angles [e.g. C1′—C9—C8 = 126.3 (5)° and C11′—C19—C18 = 129.1 (5)° here, compared with 130.2° in the bound mol­ecule (Murkin et al., 2007 [triangle])].
Table 3
Table 3
Comparison of immucillin ring conformations (angles in °)
The title compound (immucillin-A–CO2H) was made by incubation of the Imm-A–HCl salt (50 mg, 0.165 mmol) (Evans et al., 2003 [triangle]) dissolved in water (2 ml). The compound was deprotonated with sodium hydroxide (0.165 mmol, 6.6 mg) dissolved in water (100 µl), which caused precipitation, but the addition of more sodium hydroxide (0.165 mmol, 6.6 mg) dissolved in water (100 µl) caused the compound to redissolve. The aqueous mixture was left open to the atmosphere to allow evaporation of the solvent (and absorption of CO2) and for crystallization. The described material crystallized after a week.
Crystal data
  • [Na2(C12H13N4O6)2(H2O)7]·4H2O
  • M r = 862.68
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is c-66-00m65-efi2.jpg
  • a = 7.6620 (15) Å
  • b = 10.488 (2) Å
  • c = 11.606 (2) Å
  • α = 98.24 (3)°
  • β = 91.07 (3)°
  • γ = 98.49 (3)°
  • V = 912.1 (3) Å3
  • Z = 1
  • Synchrotron radiation
  • λ = 0.98000 Å
  • μ = 0.16 mm−1
  • T = 100 K
  • 0.08 × 0.06 × 0.01 mm
Data collection
  • MAR CCD detector diffractometer
  • 2357 measured reflections
  • 2357 independent reflections
  • 2330 reflections with I > 2σ(I)
  • R int = 0.034
  • θmax = 25.5°
  • R[F 2 > 2σ(F 2)] = 0.035
  • wR(F 2) = 0.092
  • S = 1.07
  • 2357 reflections
  • 360 parameters
  • 27 restraints
  • H atoms treated by a mixture of independent and constrained refinement
  • Δρmax = 0.22 e Å−3
  • Δρmin = −0.21 e Å−3
  • Absolute structure: Flack (1983 [triangle]), with 1161 Friedel pairs
  • Flack parameter: 0.0 (3)
One low-angle reflection (An external file that holds a picture, illustration, etc.
Object name is c-66-00m65-efi1.jpg10) and eight high-angle reflections (Δ(F 2)/e.s.d. > 3.8) were omitted. A total of 44 non-H atoms were refined with isotropic displacement parameters (some being unstable to anisotropic refinement) thereby improving the data/parameter value. The number of Friedel pairs was 1161. All H atoms were constrained, with U iso values of 1.2 times the U eq of the parent atom for C, N and hydr­oxy O atoms, and with U iso values of 1.2 times the U eq of the parent atom for water O atoms. Most water H atoms were located on difference Fourier maps; other water H atoms were positioned from stereochemical considerations and confirmed by improved agreement factors and Fourier maps. The O10W water H atoms could not be resolved from difference Fourier maps and their placement lead to unacceptably close contacts with other water H atoms (<1.5 Å); they were thus excluded from the final refinement. In the final refinements, all water O—H distances were constrained to 0.82 (3) Å, with a minimum H(...)H distance of 1.35 (3) Å. In the final model, there are some close water H(...)H distances reflecting the model and data limitations. All other H atoms were geometrically constrained (riding model) to C—H, N—H and O—H bond lengths of 0.99, 0.88 and 0.84 Å, respectively.
Data collection: DENZO (Otwinowski & Minor, 1997 [triangle]); cell refinement: DENZO; data reduction: DENZO and SCALEPACK (Otwinowski & Minor, 1997 [triangle]); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP in WinGX (Farrugia, 1997 [triangle]) and PLATON (Spek, 2009 [triangle]); software used to prepare material for publication: SHELXL97, PLATON and Mercury (Bruno et al., 2002 [triangle]).
Supplementary Material
Crystal structure: contains datablocks global, I. DOI: 10.1107/S0108270110002738/sk3359sup1.cif
Structure factors: contains datablocks I. DOI: 10.1107/S0108270110002738/sk3359Isup2.hkl
We thank Drs J. Hanson and K. R. Rajashankar of the Brookhaven National Laboratory, Long Island, New York, for their assistance, and the National Synchrotron Light Source for financial support.
Supplementary data for this paper are available from the IUCr electronic archives (Reference: SK3359). Services for accessing these data are described at the back of the journal.
  • Bruno, I. J., Cole, J. C., Edgington, P. R., Kessler, M., Macrae, C. F., McCabe, P., Pearson, J. & Taylor, R. (2002). Acta Cryst. B58, 389–397. [PubMed]
  • Cambridge Structural Database (2009). Version 5.31 with November 2009 updates. Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, England.
  • Cremer, D. & Pople, J. A. (1975). J. Am. Chem. Soc.97, 1354–1358.
  • Evans, G. B., Furneaux, R. H., Gainsford, G. J., Hanson, J. C. G. J., Kicska, G. A., Sauve, A. A., Schramm, V. L. & Tyler, P. C. (2003). J. Med. Chem.46, 155–160. [PubMed]
  • Evans, G. B., Furneaux, R. H., Gainsford, G. J., Hanson, J. C., Sauve, A. A., Schramm, V. L. & Tyler, P. C. (2010). Unpublished results.
  • Evans, G. B., Furneaux, R. H., Gainsford, G. J., Schramm, V. L. & Tyler, P. C. (2000). Tetrahedron, 56, 3053–3062.
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Federov, A., Shi, W., Kickska, G., Federov, E., Tyler, P. C., Furneaux, R. H., Hanson, J. C., Gainsford, G. J., Larese, J. Z., Schramm, V. L. & Almo, S. C. (2001). Biochemistry, 40, 853–860. [PubMed]
  • Flack, H. D. (1983). Acta Cryst. A39, 876–881.
  • Girgis, N. S., Cottam, H. B., Larson, S. B. & Robins, R. K. (1987). J. Heterocycl. Chem.24, 821–827.
  • Ikegami, S., Hayase, T., Yugami, T., Okhishi, H. & Matsuzaki, T. (1990). J. Am. Chem. Soc.112, 9668–9669.
  • Jukic, L., Svete, J., Golobic, A. & Stanovnik, B. (2000). Heterocycles, 53, 805–820.
  • Murkin, A. S., Birck, M. R., Rinaldo-Matthis, A., Shi, W., Taylor, E. A., Almo, S. C. & Schramm, V. L. (2007). Biochemistry, 46, 5038–5049. [PMC free article] [PubMed]
  • Otter, B. A., Patil, S. A., Klein, R. S. & Ealick, S. E. (1992). J. Am. Chem. Soc.114, 668–671.
  • Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Singh, V., Shi, W., Evans, G. B., Tyler, P. C., Furneaux, R. H., Almo, S. C. & Schramm, V. L. (2004). Biochemistry, 43, 9–18. [PubMed]
  • Spek, A. L. (2009). Acta Cryst. D65, 148–155. [PMC free article] [PubMed]
  • Zukerman-Schpector, J., Caracelli, I., Teijido, M. V., Garcia, A. L. L., Costenaro, C. R. D. & Correia, C. R. D. (2005). Z. Kristallogr.220, 45–49.
Articles from Acta Crystallographica Section C: Crystal Structure Communications are provided here courtesy of
International Union of Crystallography