Host–guest interactions between niobocene dichloride and α-, β-, and γ-cyclodextrins: preparation and characterization

  • Alexis Morales
  • Jochem Struppe
  • Enrique MeléndezEmail author
Original Article


The possible inclusion complexes of Cp2NbCl2 into α-, β-, and γ-CD hosts have been investigated. The existence of a true inclusion complex in the solid state was confirmed by a combination of thermogravimetric analysis, FTIR, PXRD, and 13C CP-MAS NMR spectroscopies. The solid-state results demonstrated that α-cyclodextrin does not form inclusion complexes with Cp2NbCl2 whereas β- and γ-cyclodextrins do form such complexes. PXRD, NMR, and thermal analysis showed that the organometallic molecules of Cp2NbCl2OH are included in the cavities of β- and γ-cyclodextrins, possibly adopting a symmetrical conformation in the complex, with each glucose unit in a similar environment. In solution, 1H NMR experiments suggest that niobocene has a shallow penetration on the β-CD leading to upfield shift on H-3 signal with a minor perturbation on the H-5 proton while for γ-CD, both H-3 and H-5 are shifted upfield substantially. This suggests that niobocene penetrates deeper into the γ-CD cavity than in the β-CD cavity, as a result of the cavity size.


Cyclodextrin Niobocene Inclusion complex PXRD 13C CP-MAS 



The authors are thankful to the National Institute of Health for financing this project and NSF-MRI for providing funds for the 500 MHz NMR instrument. AM is grateful to the Sloan Foundation—National Action Council for Minorities in Engineering for the pre-doctoral fellowship.

Supplementary material

10847_2007_9374_MOESM1_ESM.doc (871 kb)
(DOC 871 kb)


  1. 1.
    Köpf-Maier, P.: Complexes of metals other than platinum as antitumor agents. Eur. J. Clin. Pharmacol. 47, 1–16 (1994)CrossRefGoogle Scholar
  2. 2.
    Köpf-Maier, P., Köpf, H.: Transition and main group metal cyclopentadienyl complexes: preclinical studies on a series of antitumor agents of different structural type. Struct. Bonding 70, 103–185 (1988)Google Scholar
  3. 3.
    Köpf-Maier, P., Köpf, H.: Non-platinum-group metal antitumor agents. Chem. Rev. 87, 1137–1152 (1987)CrossRefGoogle Scholar
  4. 4.
    Köpf-Maier, P., Köpf, H.: in: Fricker, S.P. (Ed.), Metal Compounds in Cancer Therapy, Organometallic Titanium, Vanadium, Niobium, Molybdenum and Rhenium Complexes—Early Transition Metal Antitumor Drugs, pp. 109–146. Chapman and Hall, London (1994)Google Scholar
  5. 5.
    Harding, M.M., Mokdsi, G.: Non-platinum-group metal antitumor agents. Curr. Med. Chem. 7, 1289–1303 (2000)Google Scholar
  6. 6.
    Meléndez, E.: Titanium complexes in cancer therapy. Crit. Rev. Oncol. Hematol. 42, 309–315 (2002)CrossRefGoogle Scholar
  7. 7.
    Köpf, H., Köpf-Maier, P.: Titanocene dichloride—The first metallocene with cancerostatic activity. Angew. Chem., Int. Ed. Engl. 18, 477 (1979)CrossRefGoogle Scholar
  8. 8.
    Köpf-Maier, P., Köpf, H.: Vanadocen-dichlorid-ein weiteres antitumor-agens aus der metallocenreihe. Z. Naturforscher 34b, 805–807 (1979)Google Scholar
  9. 9.
    Köpf-Maier, P., Leitener, M., Voitländer, R., Köpf, H.: Molybdenocen-dichlorid als antitumor-agens. Z. Naturforscher. 34C, 1174–1176 (1979)Google Scholar
  10. 10.
    Köpf-Maier, P., Köpf, H.: Tumor inhibition by titanocene dichloride: first clues to the mechanism of action. Naturwissenschaften 67, 415–416 (1980)CrossRefGoogle Scholar
  11. 11.
    Köpf-Maier, P., Hesse, B., Voigtlander, R., Köpf, H.: Tumor inhibition by metallocenes: antitumor activity of titanocene dihalides (X = F, Cl, Br, I, NCS) and their application. J. Cancer. Res. Clin. Oncol. 97, 31–39 (1980)CrossRefGoogle Scholar
  12. 12.
    Köpf-Maier, P., Leitener, P.M., Köpf, H.: Tumor inhibition of metallocenes: antitumor activity of niobocene and tungstocene dichlorides. J. Inorg. Nucl. Chem. 42, 1789–1791 (1980)CrossRefGoogle Scholar
  13. 13.
    Kurbacher, C.M., Bruckner, H.W., Andreotti, P.E., Kurbacher, J.A., Saβ, G., Krebs, D.: In vitro activity of titanocenedichloride versus cisplatin in four ovarian carcinoma cell lines evaluated by a microtiter plate ATP bioluminescence assay. Anti-Cancer Drugs 6, 697–704 (1995)CrossRefGoogle Scholar
  14. 14.
    Kurbacher, C.M., Mallmann, P., Kurbacher, J.A., Saβ, G., Andreotti, P.E., Rahmun, A., Hübner, H., Krebs, D.: In vitro activity of titanocene dichloride versus cisplatin and doxorubicin in primary and recurrent epithelial ovarian cancer. Anti-Cancer. Res. 14, 1961–1966 (1994)Google Scholar
  15. 15.
    Villena-Heisen, C., Friedich, M., Ertan, A.K., Farnhammer, C., Schmidt, W.: Human ovarian cancer xenografts in nude mice: chemotherapy trials with pacitaxel, cisplatin, vinorelbine and titanocene dichloride. Anti-Cancer Drugs 9, 557–563 (1998)CrossRefGoogle Scholar
  16. 16.
    Christodoulou, C.V., Ferry, D.R., Fyfe, D.W., Young, A., Doran, J., Sheehan, T.M.T., Eliopoulos, A., Hale, K., Baumgart, J., Sass, G., Kerr, D.J.: Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer. J. Clin. Oncol. 16(8), 2761–2769 (1998)Google Scholar
  17. 17.
    Köpf-Maier, P., Köpf, H.: Organometallic titanium, vanadium, niobium, molybdenum and rhenium – early transition metal drugs. In: Fricker, S.P. (ed.) Metal Compounds in Cancer Therapy, pp. 109–146. Chapman & Hall, London (1994)Google Scholar
  18. 18.
    Kuo, L.Y., Kanatzidis, M.G., Sabat, M., Tipton, A.L., Marks, T.J.: Metallocene antitumor agents. Solution and solid-state molybdenocene coordination of DNA constituents. J. Am. Chem. Soc. 113, 9027–9045 (1991)CrossRefGoogle Scholar
  19. 19.
    Toney, J.H., Marks, T.J.: Hydrolysis chemistry of the metallocene dichlorides, M(Cp2)Cl2, M = Ti, V, Zr: aqueous kinetics, equilibria and mechanistic implications for a new class of antitumor agents. J. Am. Chem. Soc. 107, 947–953 (1985)CrossRefGoogle Scholar
  20. 20.
    Martin Del Valle, E.M.: Cyclodextrins and their uses: a review. Process. Biochem. 39, 1033–1046 (2004)CrossRefGoogle Scholar
  21. 21.
    (a) Harada, N., Takahashi, T.: J. Inclusion Phenom. 2, 791–98 (1984); (b) Ferreira, P., Gonclaves, I.S., Pillinger, M., Rocha, J., Santos, P., Teixeira-Dias, J.J.C.: Organometallics 19, 1455–57 (2000)Google Scholar
  22. 22.
    (a) Braga, S.S., Gonclaves, I.S., Lopes, A.D., Pillinger, M., Rocha, J., Romão, C.C., Teixeira-Dias, J.J.C.: J. Chem. Soc. Dalton Trans. 2964–2968 (2000); (b) Lima, S., Gonclaves, I.S., Ribeiro-Claro, P., Pillinger, M., Lopes, A.D., Ferreira, P., Teixeira-Dias, J.J.C.: Organometallics 20, 2191–2197 (2001)Google Scholar
  23. 23.
    Turel, I., Demsar, A., Kosmrlj, T.: The interactions of titanocene dichlorides and α-, β- and γ-cyclodextrin host molecules. J. Inclusion Phenom. Macrocyclic Chem. 35, 595–604 (1999)CrossRefGoogle Scholar
  24. 24.
    Vinklarek, J., Honzicek, J., Holubova, J.: Inclusion compounds of cytostatic active (C5H5)2VCl2 and (CH3–C5H5)2VCl2 with α-, β- and γ-cyclodextrins: synthesis, EPR study and microbiological behavior toward Escherichia coli. Central Eur. J. Chem. 1, 72–81 (2005)CrossRefGoogle Scholar
  25. 25.
    Braga, S.S., Gonclaves, I.S., Pillinger, M., Ribeiro-Claro, P., Teixeira-Dias, J.J.C.: Experimental and theoretical study of the interaction of molybdenocene dichloride (Cp2MoCl2) with β-cyclodextrin. J. Organomet. Chem. 632, 11–16 (2001)CrossRefGoogle Scholar
  26. 26.
    Modski, G., Harding, M.M.: 1H NMR study of the interaction of antitumour metallocenes with glutathione. J. Inorg. Biochem. 86, 611–616 (2001)CrossRefGoogle Scholar
  27. 27.
    Gidley, M.J., Bociek, S.M.: C-13 CP/MAS studies of amylase inclusion complexes, cyclodextrins and the amorphous phase of starch granules: relationship between glycosidic linkage conformation and the solid-state carbon-13 chemical shifts. J. Am. Chem. Soc. 110, 3820–3829 (1988)CrossRefGoogle Scholar
  28. 28.
    Heycs, S.J., Clayden, C.M., Dobson, C.M.: 13C-CP/MAS NMR studies of the cyclomalto-oligosaccharide (cyclodextrin) hydrates. Carbohydr. Res. 233, 1–14 (1992)CrossRefGoogle Scholar
  29. 29.
    Veregin, R.P., Fyfe, C.A., Marccsault, R.H., Tayler, M.G.: Investigation of the crystalline “V” amylase complexes by high resolution carbon-13 CP/MAS NMR. Carbohydr. Res. 160, 41–56 (1987)CrossRefGoogle Scholar
  30. 30.
    (a) Matsui, Y., Suemitsu, D.: The stereoselective retardation of alkaline hydrolysis of organic esters by dinuclear Cu(II) Complexes with cyclodextrins. Bull. Chem. Soc. Jpn. 58, 1658–1662 (1985); (b) Matsui, Y., Kurita, T., Yagi, M., Okayama, T., Mochida, K., Date, Y.: Complexes of Cu (II) with cyclodextrins. Bull. Chem. Soc. Jpn. 48, 2187–2191 (1975)Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2007

Authors and Affiliations

  • Alexis Morales
    • 1
  • Jochem Struppe
    • 2
  • Enrique Meléndez
    • 1
    Email author
  1. 1.Department of ChemistryUniversity of Puerto RicoMayaguezUSA
  2. 2.Brucker Biospin CorporationBillericaUSA

Personalised recommendations