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

Journal of Molecular Modeling
Hedieh Torabifard, Alireza Fattahi

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 ...Continue Reading

References

Aug 15, 1988·Cancer Letters·B MillerP L Gutierrez
Oct 10, 1970·Lancet·E J Campbell
Jan 1, 1974·Biochemical Pharmacology·J MaxwellC G Butler
Mar 1, 1984·Chemico-biological Interactions·K Hemminki
Mar 1, 1995·Cancer Treatment Reviews·E van der WallS Rodenhuis
Dec 16, 1997·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·K M MurrayS Pankey
Jun 27, 2000·International Journal of Pharmaceutics·M J van MaanenJ H Beijnen
Nov 1, 2000·Frontiers in Bioscience : a Journal and Virtual Library·R H HargreavesJ Butler
Apr 1, 2003·Journal of Computational Chemistry·Maurizio CossiVincenzo Barone
Sep 16, 1961·Lancet·H C JONES, J SWINNEY
May 20, 2005·Toxicological Sciences : an Official Journal of the Society of Toxicology·Richard M Lopachin, Anthony P Decaprio
Apr 28, 2006·The Journal of Physical Chemistry. a·Agata Kranjc, Janez Mavri
Jul 21, 2006·The Journal of Physical Chemistry. B·Fahmi HimoPär Nordlund
Oct 2, 2007·Bioorganic Chemistry·Robin Sevastik, Fahmi Himo
Feb 12, 2008·Journal of Controlled Release : Official Journal of the Controlled Release Society·Srinivas GantaMansoor Amiji
Aug 30, 2008·Journal of Agricultural and Food Chemistry·Katja GalesaJanez Mavri
Dec 17, 2008·Journal of Molecular Modeling·Jane S MurrayPeter Politzer

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Citations

Oct 12, 2013·Survey of Ophthalmology·Bruno F FernandesMiguel N Burnier

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