NDLI: Mechanisms and kinetics of thiotepa and tepa hydrolysis: DFT study

Content Provider	Springer Nature Link
Author	Torabifard, Hedieh Fattahi, Alireza
Copyright Year	2012
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.
Starting Page	3563
Ending Page	3576
Page Count	14
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	18
Issue Number	8
e-ISSN	09485023
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-02-14
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Anticancer drugs DFT Hydrolysis Kinetic study Thiotepa and Tepa Computer Application in Life Sciences Biomedicine general Life Sciences Molecular Medicine Computer Applications in Chemistry Health Informatics
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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