DFT studies of camptothecins cytotoxicity I. Active and inactive forms of camptothecin

Abstract

We optimized the structures of camptothecin (CPT) in neutral lactone (I), neutral carboxyl (II) and anionic carboxylate (III) forms and of their Cu(II) complexes at B3LYP/6-311G* level of theory. We evaluated metal ion affinities (MIA), Cu charges and electron density Laplacians of Cu-ligand bond critical points of possible CPT active sites. In most cases the electron density transfer from CPT carboxylate form III causes CO2 release and thus its destruction. MIA values indicate its significantly higher reactivity than of the remaining forms. CPT carboxylate inactivity might be explained by its decarboxylation during interaction with topoisomerase I - DNA complex. Higher toxicity is related to higher CPT → Cu electron density transfer which is highest at the pyridine B-ring nitrogen site in all the CPT forms and slightly increases in the sequence I < II < III.