Calix[n]arene-based drug carriers: A DFT study of their electronic interactions with a chemotherapeutic agent used against leukemia

The suitability of eight differently substituted calix[n]arenes (with R = -OEt; SO3H and n = 4, 5, 6, 8) as drug delivery agents for 3-phenyl-1H-[1]benzofuro[3,2-c]pyrazole (henceforth referred to as GTP), a promising new tyrosine kinase inhibitor drug, has been analyzed by means of DFT theoretical calculations at the B97D/6-31G(d,p) level of theory. Geometries and interaction energies for all inclusion complexes were calculated with NBO, as well as NBO deletion calculations in order to evaluate the energetics of the interactions between GTP and the inner walls of the calix[n]arene cavities. Second order perturbation theory analysis of the charge transfer based on the NBO population analysis was also performed to assess the energetics of the intramolecular bonding in the host guest complexes. Bond indexes suggest the formation of hydrogen-bonds as part of the stabilizing forces of the complex. Two possible insertion modes were explored for the insertion of GTP in the macrocyclic cavity yielding a total of 16 inclusion complexes studied. Interaction energies were higher for R = SO3H. Hosts (8) and (6) (n = 8 and 6, respectively) are the most promising candidates for becoming GTP delivery agents within the chemical space under exploration herein.