Mechanisms and kinetics of thiotepa and tepa hydrolysis: DFT study

Abstract

N,N',N″-triethylenethiophosphoramide (Thiotepa) and its oxo analogue (Tepa) as the major metabolite are trifunctional alkylating agents with a broad spectrum of antitumor activity. In vivo and vitro studies show alkylation of DNA by Thiotepa and Tepa can follow two pathways, but it remains unclear which pathway represents the precise mechanism of action. In pathway 1, these agents are capable of forming cross-links with DNA molecules via two different mechanisms. In the first mechanism, the ring opening reaction is initiated by protonating the aziridine, which then becomes the primary target of nucleophilic attack by the N7-Guanine. The second one is a direct nucleophilic ring opening of aziridyl group. Thiotepa and Tepa in pathway 2, act as a cell penetrating carrier for aziridine, which is released via hydrolysis. The released aziridine can form a cross-link with N7-Guanine. In this study, we calculated the activation free energy and kinetic rate constant for hydrolysis of these agents and explored interaction of aziridine with Guanine to predict the most probable mechanism by applying density functional theory (DFT) using B3LYP method. In addition, solvent effect was introduced using the conductor-like polarizable continuum model (CPCM) in water, THF and diethylether. Hyperconjugation stabilization factors that have an effect on stability of generated transition state were investigated by natural bond order (NBO) analysis. Furthermore, quantum theory of atoms in molecules (QTAIM) analysis was performed to extract the bond critical points (BCP) properties, because the electron densities can be considered as a good description of the strength of different types of interactions.

The Complexation of the Anticancer Drug ThioTEPA with Methylated DNA Base Guanine: Combined Ab Initio and QTAIM Investigation

“…ThioTEPA (the IUPAC name: 1,1′,1′′‐phosphorothioyltriaziridine) is the anti‐cancer drug invented over 60 years ago3 which still remains important for practical application in medicine4–8 and physiology 9. Although this pharmaceutical compound is widely used, not only the physical properties of its molecule have not been studied carefully until recently,10,11 but even the mechanism of its action remains vague enough 5,8,12–15. The researchers assume that the drug acts basically by cross‐linking the cancer cell DNA double helix via chemical bond between two strands, thus preventing the DNA replication process 5,14.…”

Molecular level insights into the direct health impacts of some organic aerosol components

“…Particularly, the CPT anticancer drug gives the best ligand efficiency, and the ThioTEPA alkylating agent shows a fairly noticeable LE value. These two reference compounds were neglected in the quantum mechanical calculations because their DNA cleavage mechanisms are reported elsewhere, 31,43 and just BaP, BPDE, DMBQ, IBPPA and PQ were concerned in further evaluation of OA-DNA interaction and oxidative stress. and atom pairs, and it utilizes wave functions to calculate orbital properties and follow the trends of charge transfer between them.…”

“…However, exhaustive reaction path scanning and TS predictions failed to propose any mechanism. Because many experimental studies have associated BPDE with genotoxicity, mutagenicity and carcinogenicity, [16][17][18]20 two common mechanisms were further studied for adduct formation between DNA and BPDE, DMBQ and PQ; type-2 nucleophilic substitution (SN2; formation of one bond between two reactants simultaneous with the cleavage of a bond in one of the reactants) similar to the alkylation mode of the thioTEPA anti-cancer agent, 31 and Michael addition (MA; nucleophilic addition of a nucleophile to a carbonyl compound) between the electron deficient carbon of quinones and the exocyclic NH2 moiety of nucleobases. 47 Here, just an A nucleobase was targeted to exclude steric restrictions and simplify the calculations.…”

“…28,29 DNA is chosen as the principal target of genotoxicity. For comparison purposes, the same analyses are done on cis-platin (CPT) and thioTEPA (N, N′, N′′-triethylenephosphoramide) (globally known anticancer drugs both forming adducts with DNA) 30,31 and ibuprofenate (IBPPA; isobutyl phenyl propionic acid or (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid) (a famous anti-inflammatory drug with no impact on DNA) 32 , as reference compounds. As cell membranes are made of lipid-type structures (i.e.…”

Revealing electronic features governing hydrolysis of cephalosporins in the active site of the L1 metallo-β-lactamase

“…Molecular modeling in combination with electron-density analysis is already used for organic reaction studies. Equilibrium geometry congurations and corresponding calculated electron densities of reagents, intermediates, transition states and products of chemical reactions are analyzed by various approaches as QTAIM (Quantum Theory of Atoms in Molecules) [29][30][31][32][33][34][35][36][37][38][39][40][41] or conceptual DFT (Density Functional Theory) 23,36,[42][43][44] as well as diverse bonding descriptors. [33][34][35][36][37]45,46 Current studies of enzymatic reactions [47][48][49] also demonstrate an enhanced interest in the application of such combined methods in biochemistry.…”