Theoretical study of the tautomerization of Carmustine in a biological media as an anti-cancer drug

Document Type : Research Paper


Department of Chemistry, Kerman Branch, Islamic Azad University, Kerman, Iran.


Tautomers can be defined as isomers of single molecules existing in solutions or cells. Tautomers have the ability to interchange due to numerous spontaneous arrangements of chemical bonds, unlike chirality, whose molecules represent mirror images of enantiomers of one another. Tautomerization of the carmustine mechanism as a potential anti-cancer medication was examined using the DFT method. Two conformational tautomers were identified in the structure of carmustine, and the structure of both tautomers was shown to consider the contribution of atom changes to carmustine conformation. It was possible to obtain the relative energies B3LYP/6-311G++ (d,p), Aug-cc-pVDZ, and 6-311++g(2d,2p) basis sets. Calculations of the highest occupied molecular orbital (HOMO), the lowest unoccupied orbital (LUMO), and bandgap energies of structures were performed while also obtaining the electronics parameters, electrophilicity, electronegativity, softness, and hardness in order to determine the compounds’ reactivity within the biological medium. Based on the results, the carmustine structure and both tautomer conformations showed stability, but T1 had greater stability than T2.

Graphical Abstract

Theoretical study of the tautomerization of Carmustine in a biological media as an anti-cancer drug


  • Considering gas catalysis tautomerism.
  • Applying Carmustine as anti-cancer drug.
  • Applied DFT method for considering drug behavior.
  • Use different basis sets for analysis.
  • Calculation of thermodynamic energy of tautomerism.


[1] S.K. Carter, F.M. Schabel Jr, L.E. Broder, T.P. Johnston, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and other nitrosoureas in cancer treatment: a review, Adv. Cancer Res. 16 (1973) 273-332.
[2]   A. Naghipur, M.G. Ikonomou, P. Kebarle, J.W. Lown, Mechanism of action of (2-haloethyl) nitrosoureas on DNA: discrimination between alternative pathways of DNA base modification by 1,3-bis(2-fluoroethyl)-1-nitrosourea by using specific deuterium labeling and identification of reaction products by HPLC/tandem mass spectrometry, J. Am. Chem. Soc. 112 (1990) 3178-3187.
[3] S. Puyo, D. Montaudon, P. Pourquier, From old alkylating agents to new minor groove binders, Crit. Rev. Oncol. Hemat. 89 (2014) 43-61.
[4] W.J. Bodell, Repair of DNA alkylation products formed in 9L cell lines treated with 1-(2-chloroethyl)-1-nitrosourea, Mutat. Res. -Fund. Mol. M. 522 (2003) 85-92.
[5] J.F. Schabel, Nitrosoureas: a review of experimental antitumor activity, Cancer Treat. Rep. 60 (1976) 665-698.
[6] M. Miyagami, T. Tsubokawa, M. Tazoe, Y. Kagawa, Intra-arterial ACNU chemotherapy employing 20% mannitol osmotic blood-brain barrier disruption for malignant brain tumors, Neurol. Med. Chir. 30 (1990) 582-590.
[7] J.S. Bindra, D. Lednicer, Chronicles of drug discovery, Vol. 1, John Wiley & Sons, Hoboken (1993).
[8] J.D. Boice Jr, M.H. Greene, J.Y. Killen Jr, S.S. Ellenberg, R.J. Keehn, E. McFadden, T. Chen, J.F. Fraumeni Jr, Leukemia and preleukemia after adjuvant treatment of gastrointestinal cancer with semustine (methyl-CCNU), N. Engl. J. Med. 309 (1983) 1079-1084.
[9] H.S. Zackheim, R.J. Feldmann, C. Lindsay, H.I. Maibach, Percutaneous absorption of 1,3-bis (2-chloroethyl)-I-nitrosourea (BCNU, carmustine) in mycosis fungoides, Brit. J. Dermatol. 97 (1977) 65-67.
[10] M.D. Walker, E. Alexander, W.E. Hunt, C.S. MacCarty, M.S. Mahaley, J. Mealey, et al., Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial, J. Neurosurg. 49 (1978) 333-343.
[11] M.D. Walker, S.B. Green, D.P. Byar, E. Alexander Jr, U. Batzdorf, W.H. Brooks, et al., Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery, Engl. J. Med. 303 (1980) 1323-1329.
[12] D.B. Ludlum, The chloroethy lnitrosoureas: sensitivity and resistance to cancer chemotherapy at the molecular level, Cancer Invest. 15 (1997) 588-598.
[13] L. Zhuang, J. Gao, Y. Zeng, F. Yu, B. Zhang, M. Li, et al., HPLC method validation for the quantification of lomustine to study pharmacokinetics of thermosensitive liposomeencapsulated lomustine containing iohexol for CT imaging in C6 glioma rats, J. Drug Metab. Ph. 36 (2011) 61-69.
[14] R.A. Kramer, M.R. Boyd, J.H. Dees, Comparative nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin: functional-structural correlations in the Fischer 344 rat, Appl. Pharm. 82 (1986) 540-550.
[15] F. Drablos, E. Feyzi, P.A. Aas, C.B. Vaagbo, B. Kavli, M.S. Bratlie, et al., Alkylation damage in DNA and RNA-repair mechanisms and medical significance, DNA Repair. 3 (2004) 1389-1407.
[16] T. Ducastelle, G. Raguenez-Viotte, H. Fouin-Fortunet, M. Matysiak, J. Hemet, J. Fillastre, The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats, Cancer Chemoth. Pharm. 22 (1988) 153-162.
[17] O. Kristal, K.M. Rassnick, J.M. Gliatto, N.C. Northrup, J.D. Chretin, K. Morrison-Collister, et al., Hepatotoxicity associated with CCNU (lomustine) chemotherapy in dogs, J. Vet. Intern. Med. 18 (2004) 75-80.
[18] G.P. Wheeler, S. Chumley, Alkylating activity of 1,3-bis (2- chloroethyl)-1-nitrosourea and related compounds, J. Med. Chem. 10 (1967) 259-261.
[19] S. Barranco, R. Humphrey, The effects of bleomycin on survival and cell progression in Chinese hamster cells in vitro, Cancer Res. 31 (1971) 1218-1223.
[20] B. Bhuyan, L. Scheidt, T. Fraser, Cell cycle phase specificity of antitumor agents, Cancer Res. 32 (1972) 398-407.
[21] R.A. Tobey, H.A. Crissman, Comparative effects of three nitrosourea derivatives on mammalian cell cycle progression, Cancer Res. 35 (1972) 460-470.
[22] G.A. Le Blanc, D.J. Waxman, Interaction of anticancer drugs with hepatic monooxygenase enzymes, Drug Metab. Rev. 20 (1989) 395-439.
[23] B.I. Fedeles, D. Li, V. Singh, Structural insights into tautomeric dynamics in nucleic acids and in antiviral nucleoside analogs, Front. Mol. Biosci. 8 (2022) 823253.
[24] S. Hadidi, F. Shiri, M. Norouzibazaz, A DFT study of the degradation mechanism of anticancer drug carmustine in an aqueous medium, Struct. Chem. 30 (2019) 1315-1321.
[25] M. Bayat, A.A. Taherpour, S.M. Elahi, T. Fellowes, Separation of anticancer medicines carmustine, lomustine, semustine and melphalan by PAMAM dendrimer: a theoretical study, J. Iran. Chem. Soc. 15 (2018) 1223-1234.
[26] S. Chen, Q. Qiu, D. Wang, D. She, B. Yin, M. Chai, et al., J. Wang, Long acting carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor resection, Front. Chem. Sci. Eng. 16 (2022) 536-545.
[27] M.H. Khorasanizadeh, R. Monsef, O. Amiri, M. Amiri, M. Salavati-Niasari, Sonochemical-assisted route for synthesis of spherical shaped holmium vanadate nanocatalyst for polluted waste water treatment, Ultrason. Sonochem. 58 (2019) 104686.
[28] M. Goudarzi, M. Salavati-Niasari, F. Yazdian, M. Amiri, Sonochemical assisted thermal decomposition method for green synthesis of CuCo2O4/CuO ceramic nanocomposite using Dactylopius Coccus for anti-tumor investigations, J. Alloy. Compd. 788 (2019) 944-953.
[29] M. Goudarzi, M. Salavati-Niasari, M. Amiri, Effective induction of death in breast cancer cells with magnetite NiCo2O4/NiO nanocomposite, Compos. Part B-Eng. 166 (2019) 457-463.
[30] M. Rezaeifar, H. Mahmoudvand, M. Amiri, Formulation and evaluation of diphenhydramine gel using different gelling agents, Der Pharma Chem. 8 (2016) 243-249.
[31] A. Lemoine, C. Lucas, R. Ings, Metabolism of the chloroethy lnitrosoureas. Xenobiotica, 21 (1991) 775-791.
[32] Y.P. Ramirez, J.L. Weatherbee, R.T. Wheelhouse, A.H. AH, Glioblastoma multiforme therapy and mechanisms of resistance, Pharmaceut. 6 (2013) 1475-1506.
[33] W.B. Pratt, W.D. Ensminger, R.W. Ruddon, The anticancer drugs, Oxford University Press, USA, (1994).
[34] Y. Najibzade, E. Sheikhhosseini, M.R. Akhgar, S.A. Ahmadi, The computational study of the tautomerization of Dacarbazine in a biological system: The DFT approach, J. Part. Sci. Technol. 6 (2020) 55-60.
[35] G.E.S.M.J. Frisch, G.W. Trucks, H.B. Schlegel, B.M.M.A. Robb, J.R. Cheeseman, G. Scalmani, V. et al., Gaussian 03, Revision A, 2, 2009.
Volume 7, Issue 1
May 2021
Pages 51-57
  • Receive Date: 11 February 2022
  • Revise Date: 08 April 2022
  • Accept Date: 10 April 2022
  • First Publish Date: 10 April 2022