Dft Studies of Camptothecines Cytotoxicity I. Active and Inactive Forms of Camptothecin

Abstract

The structures of camptothecin (CPT) in neutral lactone (I), neutral carboxyl (II) and anionic carboxylate (III) forms in singlet ground states and of their complexes with Cu(II) in doublet ground states were optimized at B3LYP/6-311G* level of theory. Metal ion affinities (MIA), Cu charges and Laplacians of Cu-ligand bond critical points of possible CPT active sites were evaluated. In most cases the electron density transfer from CPT carboxylate form III causes CO2 release and thus its termination. MIA values indicate that this form exhibits significantly higher reactivity than the remaining forms. Its inactivity might be explained by similar decarboxylation during interaction with topoisomerase I - DNA complex due to analogous electron density transfer. Higher toxicity is connected with higher CPT → Cu electron density transfer which is highest at the pyridine B-ring nitrogen site in all CPT forms and slightly increases in the sequence I < II < III. Non-vanishing Cu spin density is observed at the sites with minimal electron density transfer only.