Crystal structure of 4,6-dimethyl-2-{[3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]sulfanyl}nicotinonitrile

In the title compound, the hydrophilic glucose residues lie in the regions z ≃ ab plane, from which the pyridyl rings project; pyridyl ring stacking parallel to the a axis links adjacent layers.

In the title compound, C 14 H 18 N 2 O 5 S, the C-S bond lengths are unequal, with S-C glucose = 1.8016 (15) Å and S-C pyridyl = 1.7723 (13) Å . The hydrophilic glucose residues lie in the regions z ' 0.25 and 0.75. Four classical hydrogen bonds link the molecules to form layers parallel to the ab plane, from which the pyridyl rings project; pyridyl ring stacking parallel to the a axis links adjacent layers.

Chemical context
The search for new anticancer chemotherapeutic agents continues to be an active area of research (Elgemeie, 2003;Elgemeie & Jones, 2004). In recent years nucleoside analogs have occupied a significant position in the search for effective chemotherapeutic agents, because many non-natural nucleoside derivatives have been shown to possess bioactivity (Elgemeie & Abou-Zeid, 2015). In the last few decades, pyridine derivatives have received considerable attention because of their wide-ranging applications as antimetabolic agents (Elgemeie et al., 2009). Recently, we reported that many pyridine thioglycosides showed strong cytotoxicity against several human cancer cell lines and block proliferation of various cancer cell lines (Elgemeie, Abou-Zeid et al., 2015). We also showed that thioglycosides involving pyridine and dihydropyridine groups exerted inhibitory effects on both DNA-and RNA-containing viruses and inhibitors of protein glycosylation, respectively (Elgemeie et al., 2010). In view of these observations and with the aim of identifying new anticancer agents with improved pharmacokinetic and safety profiles, we have synthesized some new non-classical nucleoside analogs incorporating pyridine thioglycosides.

Structural commentary
The X-ray structure determination indicated unambiguously the formation of the pyridine-2-thioglucoside (6) as the product in the solid state. The molecule is shown in Fig. 1 and geometrical parameters are given in Table 1. The C-S bond lengths are markedly unequal, with S-C glucose 1.8016 (15), S-C pyridyl 1.7723 (13) Å . The main torsional degrees of freedom are between the rings, as defined by the torsion angles N11-C12-S1-C1 = À2.08 (14) and C2-C1-S1-C12 = 152.98 (9) .

Database survey
Perhaps surprisingly, a database search revealed only one other example of a pyridine ring with a thioglucose substituent at the 2-position, namely pyridyl thioglucose monohydrate (Nordenson & Jeffrey, 1980;refcode PYSGPR). This compound also shows a marked inequality between the S-C bond lengths (cf. Table 1); S-C glucose is 1.793 (3), S-C pyridyl is 1.759 (3) Å .

Synthesis and crystallization
To a solution of the pyridine-2-(1H)-thione (1) (1.64 gm, 0.01 mol) in aqueous potassium hydroxide (6 ml, 0.56 g, 0.01 mol) was added a solution of 2,3,4,6-tetra-O-acetyl--dglucopyranosyl bromide (2) (4.52 g, 0.011 mol) in acetone (30 ml). The reaction mixture was stirred at room temperature until the reaction was judged complete by TLC (30 min to 2 h). The mixture was evaporated under reduced pressure at 313 K and the residue was washed with distilled water to remove the potassium bromide. The solid was collected by filtration and crystallized from ethanol to give compound (3) in 85% yield (m.p. 468 K). Dry gaseous ammonia was then passed through a solution of the protected thioglycoside (3) (0.5 g) in dry methanol (20 ml) at 273 K for 0.5 h, then the mixture was stirred at 273 K until completion of the reaction (TLC, 2-6 h). The mixture was evaporated at 313 K to give a solid residue, which was recrystallized from ethanol to give compound (6)

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The space group as initially found by the diffractometer program was P2 1 , with two independent but virtually identical molecules in the asymmetric unit. It became apparent that the two molecules formed layer structures independent of each other, and were related by a translation vector (0.5, 0.5, 0.5). The checkCIF program also indicated that the true space group should be centred, with a 100% fit and a small deviation. The same cell was retained for ease of checking, and the structure determination and refinement repeated in space group I2. The refinement was entirely satisfactory, and corresponds to the structure presented here. However, the reflections with (h + k + l) odd, which are required to be systematically absent in I2, seemed to   (Sheldrick, 2015) and XP (Siemens, 1994).
be quite definitely present. We are unable to explain this anomaly. The HKL file appended to the CIF contains these reflections. Crystal data, data collection and structure refinement details are summarized in Table 2. OH hydrogen atoms were refined freely but with an O-H distance restraint (SADI). Methyl groups were refined as idealized rigid groups allowed to rotate but not tip (AFIX 137), with C-H 0.98 Å and H-C-H 109.5 . Other hydrogen atoms were included using a riding model starting from calculated positions (C-H aromatic 0.95, C-H methylene 0.99, C-H methine 1.00 Å ).

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.