DFT studies of camptothecins cytotoxicity II. Protonated lactone forms of camptothecin

Abstract

Cytotoxicity of camptothecin (CPT) in neutral lactone form (I) and its most stable forms protonated at pyridine nitrogen (II) and at pyridone oxygen (III), which is much less stable, is investigated at the B3LYP/6-311G* level of theory. The structures of their hypothetical Cu(II) complexes were optimized. The reduced experimental cytotoxicity of protonated CPT salts is rationalized in terms of metal-ion affinities, Cu charges, and electron-density Laplacians of Cu-ligand bond critical points. Electron density transfer to Cu occurs predominantly from O and N atoms. The carbonyl oxygen atom at the lactone ring is the most reactive site in all CPT forms. Protonation may weaken hydrogen bonding of CPT with topoisomerase I and DNA as well.