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DFT study on Thiotepa and Tepa interactions with their DNA receptor

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Abstract

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.

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References

  1. Katzung BG (1998) Basic and clinical pharmacology, 7th edn. Prentice Hall, Englewood Cliffs, NJ

    Google Scholar 

  2. Benigni R, Bossa C (2010) Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology. Chem Rev 111:2507–2536

    Article  Google Scholar 

  3. Pullman B (1980) Carcinogenesis: fundamental mechanisms and environmental effects. D Reidel, Dordrecht, pp 51–55

    Book  Google Scholar 

  4. Sykes M, Karnofsky D, Phillips F, Burchenal JH (1953) Clinical studies of triethylene-phosphoramide and diethylene-phosphoramide compounds with nitrogen mustard-like activity. Cancer 6:142–148

    Article  CAS  Google Scholar 

  5. Van der Wall E, Beijnen JH, Rodenhuis S (1995) High-dose chemotherapy regimens for solid tumors. Cancer Treat Rev 21:105–132

    Article  Google Scholar 

  6. Mellet LB, Woods LA (1960) The comparative physiological disposition of thiotepa and tepa in the dog. Cancer Res 20:524–532

    Google Scholar 

  7. Van Maanen MJ, Smeets CJM, Beijnen JH (2000) Chemistry, pharmacology and pharmacokinetics of N,N’,N”-triethylenethiophosphoramide (ThioTEPA). Cancer Treat Rev 26:257–268

    Article  CAS  Google Scholar 

  8. Van Maanen MJ, Tijhof IM, Damen JMA et al (1999) A search for new metabolites of N,N′,N″-triethylenethiophosphoramide. Cancer Res 59:4720–4724

    Google Scholar 

  9. Van Maanen MJ, Doesburg Smits K, Damen JMA et al (2000) Stability of Thiotepa and its metabolites, TEPA, monochloroTEPA and thioTEPA-mercapturate, in plasma and urine. Int J Pharm 200:187–194

    Article  Google Scholar 

  10. Musser SM, Pan SS, Egorin MJ et al (1992) Alkylation of DNA with aziridine produced during the hydrolysis of N,N’,N’’-triethylenethiophosphoramide. Chem Res Toxicol 5:95–99

    Article  CAS  Google Scholar 

  11. Hemminki K (1984) Reactions of ethyleneimine with guanosine and deoxyguanosine. Chem Biol Interact 48:249–260

    Article  CAS  Google Scholar 

  12. Hunt CA, MacGregor RD, Siegal RA (1986) Engineering targeted in vivo drug delivery I. The physiological & physicochemical principles governing opportunities & limitations. Pharm Res 3:333–344

    Article  CAS  Google Scholar 

  13. Segerback D, Calleman CJ, Schroeder JL, Costa LG, Faustman EM (1995) Formation of N-7-(2-carbamoyl-2-hydroxyethyl) guanine in DNA of the mouse and the rat following intraperitoneal administration of [14C] acrylamide. Carcinogenesis 16:1161–1165

    Article  CAS  Google Scholar 

  14. Gamboa da Costa G, Churchwell MI, Hamilton LP, Von Tungeln LS, Beland FA, Marques MM (2003) DNA adduct formation from acrylamide via conversion to glycidamide in adult and neonatal mice. Chem Res Toxicol 16:1328–1337

    Article  CAS  Google Scholar 

  15. Johnson WW, Guengerich FP (1997) Reaction of aflatoxin B1 exo-8,9-epoxide with DNA: kinetic analysis of covalent binding and DNA-induced hydrolysis. Proc Natl Acad Sci USA 94:6121–6125

    Article  CAS  Google Scholar 

  16. Twaddle NC, McDaniel LP, Gamboa da Costa G, Churchwell MI, Beland FA, Doerge DR (2004) Determination of acrylamide and glycidamide serum toxicokinetics in B6C3F1 mice using LC-ES/MS/MS. Cancer Lett 207:9–17

    Article  CAS  Google Scholar 

  17. Warshel A (1991) Computer modeling of chemical reactions in enzymes and solutions. Wiley, New York

    Google Scholar 

  18. Miertus S, Scrocco E, Tomasi J (1981) Electrostatic interaction of a solute with a continuum. A direct utilization of ab initio molecular potentials for the prevision of solvent effects. Chem Phys 55:117–129

    Article  CAS  Google Scholar 

  19. Spartan’06V102’ Wavefunction Inc., Irvine

  20. Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652

    Article  CAS  Google Scholar 

  21. Lee C, Yang W, Parr RG (1988) Development of the Colle-Salvetti correlation-energy formula into a functional of the electron density. Phys Rev B 37:785–789

    Article  CAS  Google Scholar 

  22. Cossi M, Barone V, Mennucci B, Tomasi J (1998) Ab initio study of ionic solutions by a polarizable continuum dielectric model. Chem Phys Lett 286:253–260

    Article  CAS  Google Scholar 

  23. Cossi M, Rega N, Scalmani G, Barone V (2003) Energies, structures, and electronic properties of molecules in solution with the C-PCM solvation model. J Comput Chem 24:669–681

    Article  CAS  Google Scholar 

  24. Sevastik R, Himo F (2007) Quantum chemical modeling of enzymatic reactions: the case of 4-oxalocrotonate tautomerase. J Bioorg Chem 35:444–457

    Article  CAS  Google Scholar 

  25. Georgieva P, Himo F (2008) Density functional theory study of the reaction mechanism of the DNA repairing enzyme alkylguanine alkyltransferase. Chem Phys Lett 463:214–218

    Article  CAS  Google Scholar 

  26. Chen S, Fang w, Himo F (2008) Technical aspects of quantum chemical modeling of enzymatic reactions: the case of phosphotriesterase. Theor Chem Account 120:515–522

    Article  CAS  Google Scholar 

  27. Himo F, Guo J, Rinaldo-Matthis A, Nordlund P (2005) Reaction mechanism of deoxyribonucleotidase: a theoretical study. J Phys Chem B 109:20004–20008

    Article  CAS  Google Scholar 

  28. Pliego JR (2004) Basic hydrolysis of formamide in aqueous solution: a reliable theoretical calculation of the activation free energy using the cluster-continuum model. Chem Phys 306(1–3):273–280

    Article  CAS  Google Scholar 

  29. Stare J, Henson NJ, Eckert J (2009) Mechanistic aspects of propene epoxidation by hydrogen peroxide. Catalytic role of water molecules, external electric field, and zeolite framework of TS-1. J Chem Inf Model 49(4):833–846

    Article  CAS  Google Scholar 

  30. Nguyen MT, Raspoet G, Vanquickenborne LG (1999) Necessity to consider a three-water chain in modelling the hydration of ketene imines and carbodiimides. J Chem Soc 4:813–820

    Google Scholar 

  31. Reed AE, Weinhold F (1985) Natural localized molecular orbitals. J Chem Phys 83:1736–1740

    Article  CAS  Google Scholar 

  32. Reed AE, Weinstock RB, Weinhold F (1985) Natural population analysis. J Chem Phys 83:735–746

    Article  CAS  Google Scholar 

  33. Reed AE, Weinhold F (1983) Natural bond orbital analysis of near‐Hartree–Fock water dimer. J Chem Phys 78:4066–4073

    Article  CAS  Google Scholar 

  34. Foster JP, Weinhold F (1980) Natural hybrid orbitals. J Am Chem Soc 102:7211–7218

    Article  CAS  Google Scholar 

  35. Chocholousova J, Vladimir Spirko V, Hobza P (2004) First local minimum of the formic acid dimer exhibits simultaneously red-shifted O–H···O and improper blue-shifted C–H···O hydrogen bonds. Phys Chem Chem Phys 6:37–41

    Article  CAS  Google Scholar 

  36. Reed AE, Curtiss LA, Weinhold F (1988) Intermolecular interactions from a natural bond orbital, donor–acceptor viewpoint. Chem Rev 88:899–926

    Article  CAS  Google Scholar 

  37. Bader RFW (2002) AIM2000 program package, Ver. 2.0. McMaster University, Hamilton

  38. Bader RFW (1998) Bond path: a universal indicator of bonded interactions. J Phys Chem A 102:7314–7323

    Article  CAS  Google Scholar 

  39. Bader RFW (1990) Atoms in molecules. A quantum theory. Clarendon, Oxford

    Google Scholar 

  40. Pakiari AH, Eskandari K (2006) The chemical nature of very strong hydrogen bonds in some categories of compounds. J Mol Struct 759:51–60

    Article  CAS  Google Scholar 

  41. Abboud JLM, Mó O, De Paz JLG et al (1993) Thiocarbonyl versus carbonyl compounds: a comparison of intrinsic reactivities. J Am Chem Soc 115:12468–12476

    Article  CAS  Google Scholar 

  42. Hocquet A (2001) Intramolecular hydrogen bonding in 2′-deoxyribonucleosides: an AIM topological study of the electronic density. Phys Chem/Chem Phys 3:3192–3199

    Article  CAS  Google Scholar 

  43. Rozas I, Alkorta I, Elguero J (2000) Behavior of ylides containing N, O, and C atoms as hydrogen bond acceptors. J Am Chem Soc 122:11154–11161

    Article  CAS  Google Scholar 

  44. Kheffache D, Oumerali O (2010) Some physicochemical properties of the antitumor drug Thiotepa and its metabolite Tepa as obtained by density functional theory (DFT) calculations. J Mol Model 16:1383–1390

    Article  CAS  Google Scholar 

  45. Barone V, Cossi M (1998) Quantum Calculation of Molecular Energies and Energy Gradients in Solution by a Conductor Solvent Model. Phys Chem A 102(11):1995–2001

    Article  CAS  Google Scholar 

  46. Cammi R, Mennucci B, Tomasi J (1999) Second-Order Møller-Plesset Analytical Derivatives for the Polarizable Continuum Model Using the Relaxed Density Approach. Phys Chem A 103(45):9100–9108

    Article  CAS  Google Scholar 

  47. Klamt A, Schüürmann G (1993) COSMO: a new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient. Chem Soc, Perkin Trans 2:799–805

    Article  Google Scholar 

  48. Tomasi J, Mennucci B, Cammi R (2005) Quantum Mechanical Continuum Solvation Model. Chem Rev 105(8):2999–3094

    Article  CAS  Google Scholar 

Download references

Acknowledgment

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.

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Authors and Affiliations

  1. Department of Chemistry, Sharif University of Technology, P.O. Box 11365-9516, Tehran, Iran

    Hedieh Torabifard & Alireza Fattahi

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  1. Hedieh Torabifard
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  2. Alireza Fattahi
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Correspondence to Alireza Fattahi.

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Torabifard, H., Fattahi, A. DFT study on Thiotepa and Tepa interactions with their DNA receptor. Struct Chem 24, 1–11 (2013). https://doi.org/10.1007/s11224-012-0020-4

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