Structural Chemistry

, Volume 24, Issue 1, pp 1–11 | Cite as

DFT study on Thiotepa and Tepa interactions with their DNA receptor

  • Hedieh Torabifard
  • Alireza FattahiEmail author
Original Research


Thiotepa (N,N′,N″-triethylenethiophosphoramide) and its major metabolite (Tepa) as trifunctional alkylating agents has recently been used in cancer therapy. In vivo and vitro studies show the possible pathways of alkylation of DNA by Thiotepa and Tepa. Two pathways are suggested, but the main pathway of mechanism remains unclear. In pathway 1, forming cross-links with DNA molecules can be carried out via two different mechanisms. In first mechanism, these agents undergo the ring opening reaction which is initiated by protonating aziridine, which then becomes the main target of nucleophilic attack by the N7-Guanine of DNA. The second probable mechanism is ring opening of aziridyl group by nucleophilic attack of N7-Guanine without initial protonation. 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 alkylating the Guanine via the first pathway to determine the most precise mechanism by applying density functional theory using B3LYP method. We carried out geometrical optimizations with the conductor-like polarizable continuum model to account for the solvent effect, and the results were compared with those in the gas phase. Hyperconjugation stabilization factors that affect on stability of generated transition state were investigated by natural bond order analysis. Furthermore, quantum theory of atoms in molecules analysis was performed to extract the bond critical points properties because the electron densities can be considered as a good description of the strength of different types of interactions.


Density functional theory (DFT) Thiotepa and Tepa Anticancer drugs Kinetic study Alkylating agents 



Support from Sharif University of Technology is gratefully acknowledged. We thank Z. Aliakbar Tehrani, M. Jebeli Javan and M. Shakourian-Fard, Ph.D. students of Physical Organic Chemistry Laboratory at Sharif University of Technology.

Supplementary material

11224_2012_20_MOESM1_ESM.doc (5.8 mb)
Supplementary material 1 (DOC 5938 kb)


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of ChemistrySharif University of TechnologyTehranIran

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