A DFT study of a novel oxime anticancer trans platinum complex: Monofunctional and bifunctional binding to purine bases

Abstract

ABSTRACT:The first and second substitution reactions binding of the anticancer drug trans-[Pt((CH 3 ) 2 C¼ ¼NOH)((CH 3 ) 2 CHNH 2 )Cl 2 ] to purine bases were studied computationally using a combination of density functional theory and isoelectric focusing polarized continuum model approach. Our calculations demonstrate that the trans monoaqua and diaqua reactant complexes (RCs) can generate either trans-or cismonoadducts via identical or very similar trans trigonal-bipyramidal transition-state structures. Furthermore, these monoadducts can subsequently close by coordination to the adjacent purine bases to form 1,2-intrastrand Pt-DNA adducts and eventually distort DNA in the same way as cisplatin. Thus, it is likely that the transplatin analogues have the same mechanism of anticancer activity as cisplatin. For the first substitutions, the activation free energies of monoaqua complexes are always lower than that of diaqua complexes. The lowest activation energy for monoaqua substitutions is 16.2 kcal/mol for guanine and 16.5 kcal/mol for adenine, whereas the lowest activation energy for diaqua substitutions is 17.1 kcal/mol for guanine and 25.9 kcal/ mol for adenine. For the second substitutions, the lowest activation energy from transmonoadduct to trans-diadduct is 19.1 kcal/mol for GG adduct and 20.7 kcal/mol for GA adduct, whereas the lowest activation energy from cis-monoadduct to cis-diadduct is 18.9 kcal/mol for GG adduct and 18.5 kcal/mol for GA adduct. In addition, the first and second substitutions prefer guanine over adenine, which is explained by the remarkable larger complexation energy for the initial RC in combination with lower activation energy for the guanine substitution. Overall, the hydrogen-bonds play an important role in stabilizing these species of the first and second substitutions.

Theoretical study on the mechanism of reaction of novel iminoether-containing Pt(II) anticancer drugs with biological targets

“…All reaction processes can generate similar trigonal-bipyramidal transition-state geometries and planar four-coordinated product complexes. That is consistent with the computational study on the cisplatin substitution and other platinum drugs [16,[63][64][65][66][67].…”

“…This calculation is in agreement with the reported results of cisplatin and other platinum-based complexes [16,[63][64][65][66][67]; secondly, the activity of S-donor AAR is much higher than the N-donor AAR in bifunctional binding reaction indicates that the S-containing protein is more likely to be biological target. These computing results have further confirmed that our previous calculations of trans-[PtCl 2 (NH 3 )(thiazole)] and trans-[PtCl 2 (thiazole) 2 ] binding to A/G and AAR are reliable [63].…”

Using Theory To Reinterpret the Kinetics of Monofunctional Platinum Anticancer Drugs: Stacking Matters

“…To help to resolve this key question, we assessed the reactivity of phenPt using density functional theory (DFT) calculations, a computational approach widely exploited in studying the reactivity of bifunctional metallo-drugs, [8][9][10][11][12] but rarely used for monofunctional drugs such as phenPt. 13 Our conclusions are based on B3LYP-D3 calculations implemented in Gaussian 16. 14,15 All the quantum mechanical details are given in the Supporting Information (SI).…”

Structural, vibrational, NMR, quantum chemical, DNA binding and protein docking studies of two flexible imine oximes

“…IR spectra of molecules were recorded as KBr pellets on a Thermo Nicolet 6700 FT-IR spectrophotometer in the frequency range of 4000-400 cm −1 . 1 H NMR 1480 Yunus Kaya (400 MHz) and 13 C NMR (100 MHz) spectra were recorded on a Varian Mercury plus spectrometer in DMSO-d 6 and TMS was used as an internal standard.…”

“…In addition, the multiple peaks between 8.56 and 7.11 ppm represent the aromatic protons of pyridine group and they were calculated as 8.93 and 7.47 ppm for both imine oximes. 13 C NMR spectra for HL 1 and HL 2 show 10 and 11 different carbon atoms. The signal at 169.2 ppm belongs to the C2 carbon atom and was calculated at 173.9 ppm in HL 1 , while this chemical shift was observed 170.6 ppm (calcd.…”