Effects of solvent, pH and β-cyclodextrin on the fluorescent behaviour of lomustine

  • Hassina Fisli
  • Nadjia Bensouilah
  • Nabila Dhaoui
  • Mohamed Abdaoui
Original Article


Fluorescent behaviour of lomustine, a DNA cross-linking agent, was investigated in different solvents, pH and in the presence of β-cyclodextrin (β-CD). The solvents in which fluorescence spectra were observed play a major role in determining the spectral intensity of fluorophore, since it was found to exhibit new fluorescent properties essentially influenced by intermolecular interactions, particularly by intermolecular H-bonding formed with solvents. The pH-dependence profile was typically U-shape with a maximum at pH between 3.51 and 6.58. It was corroborated that the fluorescence emission band of lomustine is significantly intensified in the presence of β-CD. From the changes in the fluorescence spectra, it was concluded that β-CD forms a 1:1 inclusion complex with lomustine and its association constant was calculated.


Lomustine β-cyclodextrin Inclusion complex Fluorescence Solvent effect pH effect 



We are very grateful to the financial support within the general direction of scientific research and technology development of the Algerian ministry of higher education and scientific research.


  1. 1.
    Birks, J.B.: Photophysics of aromatic molecules. Wiley-Interscience, New York (1970)Google Scholar
  2. 2.
    Parker, C.A.: Photoluminescence of Solutions with Applications to Photochemistry and Analytical Chemistry. Elsevier, Amsterdam (1968)Google Scholar
  3. 3.
    Ireland, J.F., Wyatt, P.A.H.: Acid-base properties of electronically excited states of organic molecules. Adv. Phys. Org. Chem. 12, 131–221 (1976)CrossRefGoogle Scholar
  4. 4.
    Stalin, T., Rajendiran, N.: Intramolecular charge transfer associated with hydrogen bonding effects on 2-aminobenzoic acid. J. Photochem. Photobiol. A: Chem. 182(2), 137–150 (2006)CrossRefGoogle Scholar
  5. 5.
    Szejtli, J.: Cyclodextrins and their inclusion complexes. Kluwer, Academic Publishers, Dordrecht (1988)Google Scholar
  6. 6.
    Duchene, D.: Cyclodextrins and their industrial uses. Editions de Santé, Paris (1987)Google Scholar
  7. 7.
    Duchene, D.: New trends in cyclodextrins and derivatives. Editions de Santé, Paris (1991)Google Scholar
  8. 8.
    Kadri, M., Dhaoui, N., Abdaoui, M., Winum, J.Y., Montero, J.L.: Inclusion complexes of 2-chloroethylnitrososulfamides (CENS) with β-cyclodextrin. Eur. J. Med. Chem. 39(1), 79–84 (2004)CrossRefGoogle Scholar
  9. 9.
    Dhaoui, N., Fatfat, M., Abdaoui, M., Barragan-Montero, V.: Inclusion complexes of 2-chloroethylnitrososulfamides (CENS) in natural and modified β-cyclodextrins. Lett. Org. Chem. 6, 37–40 (2009)CrossRefGoogle Scholar
  10. 10.
    Tang, B., Ma, L., Ma, C.: Spectrofluorimetric study of the β-cyclodextrin-rubidate complex and determination of rubidate by β-CD-enhanced fluorimetry. Talanta 58, 841–848 (2002)CrossRefGoogle Scholar
  11. 11.
    Tang, B., Ma, L., Wang, H.Y., Zhang, G.Y.: Study on the supramolecular interaction of curcumin and α-cyclodextrin by spectrophotometry and its analytical application. J. Agric. Food Chem. 50(6), 1355–1361 (2002)CrossRefGoogle Scholar
  12. 12.
    Hinze, W.L., Dai, F., Frankewich, R.P., Thimmaiah, K.N., Szejtli, J.: Comprehensive molecular chemistry. In: Szejtli, J., Osa, T. (eds.) Cyclodextrins, vol. 3, pp. 587–602. Pergamon, Tarrytown, New York (1996)Google Scholar
  13. 13.
    Szejtli, J.: Cyclodextrin Technology. Kluwer Academic Publishers, Dordrecht (1988)Google Scholar
  14. 14.
    Szejtli, J., Osa, T.: Comprehensive Supramolecular Chemistry, Cyclodextrins, vol. 3. Elsevier, Oxford (1996)Google Scholar
  15. 15.
    Szejtli, J.: Molecular entrapment and release properties of drugs by Cyclodextrin. In: Smolen, V.F., Ball, L.A. (eds.) Controlled drug bioavailability, vol. 3, pp. 365–420. Wiley, New York (1989)Google Scholar
  16. 16.
    Djedaini, F., Perly, B.: Nuclear magnetic resonance investigation of the stoichiometries in β-cyclodextrin: steroid inclusion complexes. J. Pharm. Sci. 80(12), 1157–1161 (1991)CrossRefGoogle Scholar
  17. 17.
    Szejtli, J.: Medicinal applications of cyclodextrins. Med. Res. Rev. 14(3), 353–386 (1994)CrossRefGoogle Scholar
  18. 18.
    Szejtli, J.: Cyclodextrins and their inclusion complexes. Akademiai Kiado, Budapest (1982)Google Scholar
  19. 19.
    Singh, M., Sharma, R., Banerjee, U.C.: Biotechnological applications of cyclodextrins. Biotechnol. Adv. 20, 341–359 (2002)CrossRefGoogle Scholar
  20. 20.
    Hirayama, F., Uekama, K.: Cyclodextrin-based controlled drug release system. Adv. Drug Deliv. Rev. 36, 125–141 (1999)CrossRefGoogle Scholar
  21. 21.
    Kang, J., Kumar, V., Yang, D., Chowdhury, P.R., Hohl, R.J.: Cyclodextrin complexation: influence on the solubility, stability, and cytotoxicity of camptothecin, an antineoplastic agent. Eur. J. Pharm. Sci. 15, 163–170 (2002)CrossRefGoogle Scholar
  22. 22.
    Tsai, Y., Tsai, H.H., Wu, C.P., Tsai, F.J.: Preparation, characterization and activity of the inclusion complex of paeonol with β-cyclodextrin. Food Chem. 120(3), 837–841 (2010)CrossRefGoogle Scholar
  23. 23.
    Sætern, A.M., Nguyen, N.B., Bauer-Brandl, A., Brandl, M.: Effect of hydroxypropyl-β-cyclodextrin-complexation and pH on solubility of camptothecin. Int. J. Pharm. 284, 61–68 (2004)CrossRefGoogle Scholar
  24. 24.
    Králová, J., Kejík, Z., Bříza, T., Poučková, P., Král, A., Martásek, P., Král, V.: Porphyrin-cyclodextrin conjugates as a nanosystem for versatile drug delivery and multimodal cancer therapy. J. Med. Chem. 53(1), 128–138 (2010)CrossRefGoogle Scholar
  25. 25.
    Gallant, G., Salvador, R., Dulude, H.: Synthesis, chemical half-life and decomposition of new N3-(substituted) derivatives of CCNU. Bioorg. Med. Chem. Lett. 4(19), 2353–2358 (1994)CrossRefGoogle Scholar
  26. 26.
    Gnewuch, C.T., Sosnovsky, G.: A critical appraisal of the evolution of N-nitrosoureas as anticancer drugs. Chem. Rev. 97(3), 829–1013 (1997)CrossRefGoogle Scholar
  27. 27.
    Olivi, A., Grossman, S.A., Tatter, S., Barker, F., Judy, K., Olsen, J., Bruce, J., Hilt, D., Fisher, J., Piantadosi, S.: Dose escalation of carmustine in surgically implanted polymers in patients with recurrent malignant glioma: A new approaches to brain tumor therapy CNS consortium trial. J. Clin. Oncol. 21(9), 1845–1849 (2003)CrossRefGoogle Scholar
  28. 28.
    Bethune, C.R., Geyer, R.J., Spence, A.M., Ho, R.J.Y.: Lipid association improves the therapeutic index of lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea] to suppress 36B–10 tumor growth in rats. Cancer Res. 61(9), 3669–3674 (2001)Google Scholar
  29. 29.
    Hammond, L.A., Eckardt, J.R., Kuhn, J.G., Gerson, S.L., Johnson, T., Smith, L., Drengler, R.L., Campbell, E., Weiss, G.R., Von Hoff, D.D., Rowinsky, E.K.: A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms. Clin. Cancer Res. 10(5), 1645–1656 (2004)CrossRefGoogle Scholar
  30. 30.
    Marcantonio, D., Panasci, L.C., Hollingshead, M.G., Alley, M.C., Camalier, R.F., Sausville, E.A., Dykes, D.J., Carter, C.A., Malspeis, L.: 2-chloroethyl-3-sarcosinamide-1-nitrosourea, a novel chloroethylnitrosourea analogue with enhanced antitumor activity against human glioma xenografts. Cancer Res. 57(18), 3895–3898 (1997)Google Scholar
  31. 31.
    Liu, L., Yan, L., Donze, J.R., Gerson, S.L.: Blockage of a basic site repair enhances antitumor efficacy of 1,3-bis-(2-chloroethyl)-1-nitrosourea in colon tumor xenografts. Mol. Cancer Ther. 2(10), 1061–1066 (2003)Google Scholar
  32. 32.
    Looftsson, T., Fridriksdottir, H.: Degradation of lomustine (CCNU) in aqueous solution. Inter. J. Pharm. 62, 243–247 (1990)CrossRefGoogle Scholar
  33. 33.
    Job, P.: Formation and stability of inorganic complexes in solution. Ann. Chim. Appl. 9, 113–203 (1928)Google Scholar
  34. 34.
    Reichardt, C.: Solvents and solvent effects in organic chemistry. VCH, New York (1990)Google Scholar
  35. 35.
    Reichardt, C.: Solvatochromic dyes as solvent polarity indicators. Chem. Rev. 94(8), 2319–2358 (1994)CrossRefGoogle Scholar
  36. 36.
    Reichardt, C.: Solvents and solvent effects in organic chemistry, 3rd edn. Wiley-VCH, Weinheim (2003)Google Scholar
  37. 37.
    Synder, J.K., Stock, L.M.: Conformational preferences in alkylnitrosoureas. J. Org. Chem. 45(5), 886–891 (1980)CrossRefGoogle Scholar
  38. 38.
    Deylet, A.: Synthèse, structure et activité oncostatique de N-(chloro-2-ethyl)-N-nitrosocarbamates d’amino-acides et de composés apparentés. Dissertation, Université des Sciences et Techniques du Languedoc (1983)Google Scholar
  39. 39.
    Marcus, Y.: The properties of organic liquids that are relevant to their use as solvating solvents. Chem. Soc. Rev. 22, 409–416 (1993)CrossRefGoogle Scholar
  40. 40.
    Reichardt, C., Dimroth, K.: Lösungsmittel und empirische Parameter zur Charakterisierung ihrer Polarität. Fortschr. Chem. Forsch. 11, 1–73 (1968)CrossRefGoogle Scholar
  41. 41.
    Marcus, Y.: The properties of solvents. John Wiley, Chichester (1998)Google Scholar
  42. 42.
    Reichardt, C.: Empirical parameters of solvent polarity as linear free-energy relationships. Angew. Chem. Int. Ed. Engl. 18(2), 98–110 (1979)CrossRefGoogle Scholar
  43. 43.
    Kosower, E.M.: The effect of solvent on spectra I. A new empirical measure of solvent polarity: Z-values. J. Am. Chem. Soc. 80, 3253–3260 (1958)CrossRefGoogle Scholar
  44. 44.
    Dimroth, K., Reichardt, C., Siepman, T., Bollmann, F.: Pyridinium N-phenolbetaines and their use for the characterization of the polarity of solvents. Liebigs Ann. Chem. 661, 1–37 (1963)CrossRefGoogle Scholar
  45. 45.
    Lakowicz, J.R.: Principles of fluorescence spectroscopy. Plenum Press, New York (1983)CrossRefGoogle Scholar
  46. 46.
    Lippert, E.: Dipolmoment und Elektronenstruktur von angeregten Molekulen. Z. Naturforsch. A 10(7), 541–545 (1955)Google Scholar
  47. 47.
    Mataga, N., Kaifu, Y., Koizumi, M.: Solvent effects upon fluorescence spectra and the dipole-moments of excited molecules. Bull. Chem. Soc. Jpn. 29, 465 (1956)CrossRefGoogle Scholar
  48. 48.
    Seidegård, J., Grönquist, L., Tuvesson, H., Gunnarsson, P.O.: Increased degradation rate of nitrosoureas in media containing carbonate. In Vitro Cell. Dev. Biol.-Animal 45, 32–34 (2009)CrossRefGoogle Scholar
  49. 49.
    Connors, K.A.: Binding constants: the measurement of molecular complex stability. Wiley-Interscience, New York (1987)Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Hassina Fisli
    • 1
  • Nadjia Bensouilah
    • 1
  • Nabila Dhaoui
    • 1
  • Mohamed Abdaoui
    • 1
  1. 1.Laboratoire de Chimie AppliquéeGuelmaAlgeria

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