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.
). 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.
; MEFZOM: Evans et al.
) (alphabetic codes used herein are those used in the Cambridge Structural Database, 2009
). A related compound, with oxygen replacing NH in the saturated five-membered ring, is VOVJIZ (Otter et al.
), while compound VILHON (Ikegami et al.
) has been re-assigned as a related 6′-amino compound by Otter et al.
). 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.
). 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.
The asymmetric unit contents of the title compound, (I)
, are shown in Fig. 1; the polymer linking bonds (Na1*—O16, Na1—O16*) are shown at the top and bottom of the figure (see also Fig. 2 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), and ring comparisons (Spek, 2009
) 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
) 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.
) which also twists along C2′—C3′ [Q
(2) = 0.426 Å and ϕ(2) = 266.4 (3)°].
Figure 1 Diagram of the asymmetric unit and two extra atoms of (I), shown with 50% displacement ellipsoids (Farrugia, 1997 ). Atoms Na1* (at x − 1, y − 1, z) and O16* (at ) are included and linked by three-line (more ...)
Figure 2 Packing diagram of the cell of (I) (Bruno et al., 2002 ), viewed approximately down the c axis. Representative atom labels are given (see Comment and Table 2) and H atoms have been omitted for clarity. Hydrogen bonds are shown (more ...)
Selected geometric parameters (Å, °)
For completeness, we note that other pyrimidin-4-one structures have been reported: FOYWIZ (Girgis et al.
) and QINBOE (Jukic et al.
); 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). 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, and scheme). Overall, the structure can be described as a polymeric chain parallel to the (1
1) plane crosslinked by hydrogen bonds to the water molecules that lie between the chains (Fig. 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). 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) 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.
Comparison of immucillin ring conformations (angles in °)