JBIC Journal of Biological Inorganic Chemistry

, Volume 12, Issue 7, pp 959–967 | Cite as

Synthesis, Ti(IV) intake by apotransferrin and cytotoxic properties of functionalized titanocene dichlorides

  • Li Ming Gao
  • Ramón Hernández
  • Jaime Matta
  • Enrique MeléndezEmail author
Original Paper


Functionalization of cyclopentadienyl (Cp) ligands and incorporation of these into a Ti(IV) center require careful design and selection of the appropriate synthetic routes to obtain the desired product in reasonably good yields. As part of our research efforts in the area of titanocene antitumor agents, we have revisited the synthesis of Cp rings with electron-withdrawing groups and their corresponding titanocene dichlorides, (Cp-R)2TiCl2 and (Cp-R)CpTiCl2, where R is CO2CH3 and CO2CH2CH3. These complexes were characterized by elemental analysis and 1H and 13C NMR and IR spectroscopies. This report presents the first detailed synthetic route for (Cp-CO2CH2CH3)CpTiCl2 and provides an alternate route for synthesis of (Cp-R)2TiCl2 complexes. The ability of these complexes to deliver Ti(IV) to apotransferrin was investigated to elucidate how the functionalized Cp ligands affect the titanium intake by apotransferrin. The subject complexes transfer Ti(IV) to human apotransferrin, loading both N- and C-lobes. The antitumor activity of these complexes against HT-29 cancer colon cells was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Carboethoxy Cp functionalization results in complexes with a toxicity comparable to that of titanocene dichloride. The carbomethoxy-functionalized complexes proved to be nonactive at the time intervals studied here, regardless of their ability to donate the titanium atom to human apotransferrin.


Titanocene dichloride Functionalized cyclopentadienyl Colon cancer Antitumor activity Apotransferrin 



E.M. acknowledges the NIH-MBRS SCORE programs at the University of Puerto Rico at Mayaguez and the Ponce School of Medicine for financial support, the NSF-MRI program for providing funds for the purchase of the 500-MHz NMR instrument and the Sloan Foundation for financial support in the form of a graduate fellowship to R.H.


  1. 1.
    Köpf-Maier P (1994) Eur J Clin Pharmacol 47:1PubMedCrossRefGoogle Scholar
  2. 2.
    Köpf-Maier P, Köpf H (1988) Struct Bonding 70:103Google Scholar
  3. 3.
    Köpf-Maier P, Köpf H (1987) Chem Rev 87:1137CrossRefGoogle Scholar
  4. 4.
    Köpf-Maier P, Köpf H (1994) In: Fricker SP (eds) Metal compounds in cancer therapy, organometallic titanium, vanadium, niobium, molybdenum and rhenium complexes—early transition metal antitumor drugs. Chapman and Hall, London pp 109–146Google Scholar
  5. 5.
    Harding MM, Mokdsi G (2000) Curr Med Chem 7:1289PubMedGoogle Scholar
  6. 6.
    Meléndez E (2002) Crit Rev Oncol Hematol 42:309PubMedCrossRefGoogle Scholar
  7. 7.
    Toney JH, Marks TJ (1985) J Am Chem Soc 107:947CrossRefGoogle Scholar
  8. 8.
    Boyles JR, Baird MC, Campling BG, Jain NJ (2001) Inorg Biochem 84:159CrossRefGoogle Scholar
  9. 9.
    Valadares MC, Klein SL, Guaraldo AMA, Queiroz MLS (2003) Eur J Pharmacol 473:191PubMedCrossRefGoogle Scholar
  10. 10.
    Allen OR, Croll L, Gott AL, Knox RJ, McGowan PC (2004) Organometallics 23:288CrossRefGoogle Scholar
  11. 11.
    Causey PW, Baird MC, Cole SPC (2004) Organometallics 23:4486CrossRefGoogle Scholar
  12. 12.
    Tacke M, Allen LT, Cuffe L, Gallagher WM, Lou Y, Mendoza O, Mueller-Bunz H, Rehmann F-JK, Sweeney NJ (2004) Organometal Chem 689:2242CrossRefGoogle Scholar
  13. 13.
    Rehmann F-JK, Cuffe LP, Mendoza O, Rai DK, Sweeney N, Strohfeldt K, Gallagher WM, Tacke M (2005) App Organometal Chem 19:293CrossRefGoogle Scholar
  14. 14.
    Sweeney NJ, Mendoza O, Müller-Bunz H, Pampillón C, Rehmann F-JK, Strohfeldt K, Tacke MJ (2005) Organometal Chem 690:4537CrossRefGoogle Scholar
  15. 15.
    Gansäuer A, Franke D, Lauterbach T, Nieger M (2005) J Am Chem Soc 127:11622PubMedCrossRefGoogle Scholar
  16. 16.
    Kelter G, Sweeney NJ, Strohfeldt K, Fiebig H-H, Tacke M (2005) Anti-Cancer Drugs 16:1091PubMedCrossRefGoogle Scholar
  17. 17.
    Valadares MC, Ramos AL, Rehmann F-JK, Sweeney NJ, Strohfeldt K, Tacke M, Queiroz MLS (2006) Eur J Pharmacol 534:264PubMedCrossRefGoogle Scholar
  18. 18.
    Fichtner I, Pampillon C, Sweeney NJ, Strohfeldt K, Tacke M (2006) Anti-Cancer Drugs 17:333PubMedCrossRefGoogle Scholar
  19. 19.
    Meléndez E, Marrero M, Rivera C, Hernández E, Segal A (2000) Inorg Chem Acta 298:176CrossRefGoogle Scholar
  20. 20.
    Pérez Y, López V, Rivera-Rivera L, Cardona A, Meléndez E (2004) J Biol Inorg Chem 10:94PubMedCrossRefGoogle Scholar
  21. 21.
    Lamboy JL, Pasquale A, Rheingold AL, Meléndez E (2007) Inorg Chim Acta 360:2115CrossRefGoogle Scholar
  22. 22.
    Rausch M, Lewison JF, Hart WP (1988) J Organometal Chem 358:161CrossRefGoogle Scholar
  23. 23.
    Lang H, Miechel E, Stein T, Back S, Hoverstrydt E (2001) J Organometal Chem 633:71CrossRefGoogle Scholar
  24. 24.
    Jones SS, Rausch M, Bitterwolf TE (1990) J Organometal Chem 396:279CrossRefGoogle Scholar
  25. 25.
    Guo M, Sun H, McArdle HJ, Gambling L, Sadler PJ (2000) Biochemistry 39:10023PubMedCrossRefGoogle Scholar
  26. 26.
    Messori L, Orioli P, Banholer V, Pais I, Zatta P (1999) FEBS Lett 422:157CrossRefGoogle Scholar
  27. 27.
    Harstrick A, Schmoll H-J, Sass G, Poliwoda H, Rustum Y (1993) Eur J Cancer 29A:1000PubMedCrossRefGoogle Scholar
  28. 28.
    Kurbacher CM, Bruckner HW, Andreotti PE, Kurbacher JA, Saβ G, Krebs D (1995) Anti-Cancer Drugs 6:697PubMedCrossRefGoogle Scholar
  29. 29.
    Pampillón C, Sweeney NJ, Strohfeldt K, Tacke M (2007) J Organometal Chem 692:2153CrossRefGoogle Scholar
  30. 30.
    Mossman T (1983) J Immunol Methods 65:55CrossRefGoogle Scholar
  31. 31.
    Denizot F, Lang R (1986) J Immunol Methods 89:271PubMedCrossRefGoogle Scholar

Copyright information

© SBIC 2007

Authors and Affiliations

  • Li Ming Gao
    • 1
  • Ramón Hernández
    • 1
  • Jaime Matta
    • 2
  • Enrique Meléndez
    • 1
    Email author
  1. 1.Department of ChemistryUniversity of Puerto RicoMayaguezPuerto Rico
  2. 2.Department of Pharmacology, Toxicology and PhysiologyPonce School of MedicinePoncePuerto Rico

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