Comparative DFT study of inclusion complexes of thymidine-carborane conjugate with β-cyclodextrin and heptakis(2,6-O-dimethyl)-β-cyclodextrin in water

Abstract

Carboranes are unusual compounds with unique structural and chemical properties, which play an increasingly important role in the design of new potential pharmaceuticals. One of the noteworthy properties of closo-carboranes is their very high hydrophobicity, which can facilitate transport of carborane-containing compounds across biological membranes, but at the same time may limit their therapeutic availability. This problem can be solved by complexing the drug with cyclodextrins. In the present work, properties of thymidine-carborane conjugate (TC) and its ability to form in aqueous solution inclusion complexes with two cyclodextrins: β-CD and DM-β-CD, are investigated using the density functional (DFT) method B3LYP-GD2/6-31G (d, p) and the Polarizable Continuum Model (PCM) of water. The most stable structures of the molecules alone TC, DM-β-CD, as well as of the complexes TC: β-CD and TC: DM-β-CD in water, are presented. It is shown that in aqueous solution TC preferentially adopts a twisted shape, which differs significantly from its crystallographic structure. In the lowest energy complexes with both cyclodextrins, TC is docked in the host molecule via the wider entry point of CD, with the carborane cluster completely submersed in the cyclodextrin cavity. The corresponding complexation energies for TC: β-CD and TC: DM-β-CD are very similar, of about −49 kcal/mol, but the formation of TC: DM-β-CD is thermodynamically more favored. The solvation, interaction and deformation energies, as well as frontier orbitals in the complexes are analyzed in detail. An effect of the complex formation on the IR and NMR spectra of the individual molecules is also presented and discussed.