DFT studies of camptothecins cytotoxicity III: camptothecin, irinotecan and SN-38

Abstract

Geometries of camptothecin, irinotecan, SN-38, and of their hypothetical Cu(II) complexes were optimized at the B3LYP/6-311G* level of theory. Their electron structure, evaluated in terms of Mulliken population analysis and Quantum Theory of Atoms-in-Molecule, was subsequently related to in vitro cytotoxicity. Electron density transfer from the relevant active sites to Cu decreases in the sequence irinotecan > SN-38 > camptothecin. The absolute values of their metal-ligand interaction energies exhibit the same trend. Discrepancy with the least relative in vitro cytotoxicity of irinotecan can be explained by differences in its pharmacokinetics.

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

“…sites in model complexes with ligands I, II and III in agreement with our previous studies (Steklac and Breza, 2021, 2022a. Thus obtained geometry optimization of the 2 [L…Cu] q complexes leads to stable structures with QTAIM molecular graphs presented in (Steklac and Breza, 2022a) for L being the neutral lactone I ligand (q = +2), in Figs. 4-5 for L being the neutral carboxyl ligand II (q = +2), and in Figs.…”

“…In our studies Breza, 2021, 2022), we have explained why the carboxylate and protonated lactone forms of camptothecin are not suitable as anticancer drugs. In our previous comparative study (Steklac and Breza, 2022a), cytotoxicity of lactone forms was found to decrease in the sequence irinotecan > SN-38 > camptothecin. The discrepancy with the least relative in vitro irinotecan cytotoxicity is probably due to their different pharmacokinetics.…”

“…In the first step, structures of neutral lactone (I), neutral carboxyl (II), and three possible anionic car- of its neutral form I (carbon -black, hydrogen -white, nitrogen -blue, oxygen -red) studies (Steklac and Breza, 2022a).…”

“…Structure of the irinotecan lactone form has been determined by single crystal X-ray diffraction (Sawada et al, 1991), NMR measurements in DMSO solution (D'Amelio et al, 2012), and quantum-chemical model studies (Babu et al, 2012;Ivanova and Spiteller, 2012;Hussain et al, 2016). Relative cytotoxicity of various forms of campto thecin and lactone forms of irinotecan and SN-38 have been investigated in a series of studies (Steklac and Breza, 2018, 2021, 2022a) by means of quantum chemistry. This treatment was originally developed for antioxidants Ghio, 2009, 2009a;Mammino, 2013;Kabanda et al, 2014;Tsiepe et al, 2015;Serobatse et al, 2016Serobatse et al, , 2016aBreza, 2016, 2017;Jelemenska and Breza, 2021;Breza and Jelemenska, 2022) and is based on the complexation ability of their various active sites to Cu(II) with subsequent electron density transfer (ligand oxidation and metal reduction).…”

“…1. Atom and ring notation of the irinotecan (CPT-11) lactone (top) and the DFT structure (bottom)of its neutral form I (carbon -black, hydrogen -white, nitrogen -blue, oxygen -red) studies(Steklac and Breza, 2022a).…”