Experimental and Computational Studies on Structure and Energetic Properties of Halogen Derivatives of 2-Deoxy-D-Glucose

Abstract

The results of structural studies on a series of halogen-substituted derivatives of 2-deoxy-D-glucose (2-DG) are reported. 2-DG is an inhibitor of glycolysis, a metabolic pathway crucial for cancer cell proliferation and viral replication in host cells, and interferes with D-glucose and D-mannose metabolism. Thus, 2-DG and its derivatives are considered as potential anticancer and antiviral drugs. X-ray crystallography shows that a halogen atom present at the C2 position in the pyranose ring does not significantly affect its conformation. However, it has a noticeable effect on the crystal structure. Fluorine derivatives exist as a dense 3D framework isostructural with the parent compound, while Cl- and I-derivatives form layered structures. Analysis of the Hirshfeld surface shows formation of hydrogen bonds involving the halogen, yet no indication for the existence of halogen bonds. Density functional theory (DFT) periodic calculations of cohesive and interaction energies (at the B3LYP level of theory) have supported these findings. NMR studies in the solution show that most of the compounds do not display significant differences in their anomeric equilibria, and that pyranose ring puckering is similar to the crystalline state. For 2-deoxy-2-fluoro-D-glucose (2-FG), electrostatic interaction energies between the ligand and protein for several existing structures of pyranose 2-oxidase were also computed. These interactions mostly involve acidic residues of the protein; single amino-acid substitutions have only a minor impact on binding. These studies provide a better understanding of the structural chemistry of halogen-substituted carbohydrates as well as their intermolecular interactions with proteins determining their distinct biological activity.

X-ray wavefunction refinement and comprehensive structural studies on bromo-substituted analogues of 2-deoxy-d-glucose in solid state and solution

“…These findings are in agreement with the previously published study on similar halogen-substituted analogues of 2-DG. 25 The other CP parameters are summarised in Table S11. †…”

“…In both crystals, the pattern of H-bonds and their connectivity is virtually the same, indicating that the replacement of Cl to Br atom preserves the structure of the H-bond network within the crystal even if the substituent has a higher van der Waals radius. 25 Due to the presence of two different molecules in the asymmetric unit, the crystal lattice of 2-BM is more complicated. Both molecules form a dense 3-dimensional network of inter-and intramolecular H-bonds.…”

“…25 Nonetheless both compounds form layered assembly connected via either water (in case of 2-CM) or a-2-BM molecules acting as a kind of "molecular glue". 25 We also analysed the structure of sucrose substituted at the C4 position by the bromine (4-BS) and compared it to the crystal (Fig. 5).…”

“…Nevertheless, in the case of halogenated mannose derivatives, such a tendency was not observed even for highly electronegative uorine. 25 The volume of substituent has major importance, which explains the diminishing contribution of a-anomer in the following order F > Cl z Br > I. For the 2-BM, the population of a-anomeric form is 47%.…”

“… 24 As we mentioned in our previous study, the number of available crystallographic structures of halogenated carbohydrates is very limited. 25 This is especially evident in the case of brominated carbohydrates since there are only several structures deposited in the CCDC database, and almost all of them are synthetic intermediates with no resemblance to naturally occurring saccharides in terms of their structure and ability to form H-bonds. This is most likely due to challenges in preparation of high-quality crystals critical for X-ray studies.…”