MOLECULAR COMPUTATIONAL CHEMISTRY – Research –
Cyclodextrins as effective carriers of pharmaceuticals

The ability of positively charged cyclodextrins (PCCD) to cross cell membranes enables their utilization as effective carriers of sensitive drugs into cells to combat a variety of diseases. Of particular interest is gemcitabine (2,2′-difluorodeoxycytidine, dFdC), being well known for its instability and inability to permeate cell membranes. In parallel with experimental investigations, the quantum-mechanical study of gemcitabine monophosphate (dFdCMP) and its inclusion complexes with aminoalkyl-β-CD was performed at the semi-empirical PM7 level of theory in conjunction with the treatment of solvent effects by the conductor-like screening model (COSMO). The theoretical work revealed structural details regarding the preferred complexation modes which corroborated the 2D-NMR spectra, in addition to thermochemical properties which revealed the relative stability of various conformers of the drug itself and its complexes in aqueous solutions. Overall, the study offered the proof-of-principle that phosphorylated nucleoside drugs could be efficiently transported by PCCDs into cells. In Figure 1, a schematic drawing of two ionic states of dFdCMP itself and their thermochemically most stable complexes with aminoalkyl-β-CD are shown.

Figure 1. The lowest-energy conformers of dFdCMP−2 (A) and dFdCMP−1 (B) and the most stable complexes of per-[6-(2-aminoalkylamino)-6-deoxy]-β-CD cation (7-fold protonated) via inclusion of dFdCMP−1 (C) and external association of dFdCMP−2 (D) at the PM7-COSMO level of theory.