DFT studies of camptothecins cytotoxicity IV — active and inactive forms of irinotecan

Abstract Structures of irinotecan (CPT-11) in neutral lactone, neutral carboxyl, and anionic carboxylate forms in singlet ground states and of their complexes with Cu(II) in doublet ground states are optimized using B3LYP/6-311G* treatment. Metal ion affinities (MIA), Cu charges and Laplacians of Cu-ligand bond critical points of possible CPT active sites are evaluated. The formation of Cu(II) complexes with the anionic carboxylate ligand leads to the release of CO2 that can cause a decrease in the concentration of the active lactone form due to equilibria between all forms of the drug. MIA values and electron density transfer to Cu increase in the sequence lactone < neutral carboxyl < anionic carboxylate. Both neutral forms of irinotecan exhibit lower MIA values than those of camptothecin, unlike the anionic carboxylate form.