Titanocene Y Explained

Titanocene Y also known as bis[(''p''-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride or dichloridobis(η5-(p-methoxybenzyl)cyclopentadienyl)titanium is an organotitanium compound that has been investigated for use as an anticancer drug.[1]

Discovery

Titanocene dichloride is known to be a potential anticancer drug[2] since the late 1970s. After initial clinical trials against breast and renal-cell cancer were performed with this compound,[3] [4] the search for improved derivatives started.[5] Particularly, lipophilic titanocene dichloride derivatives derived from fulvenes[6] were synthesised in structural diversity and this led to the development of bis[(''p''-methoxybenzyl)cyclopentadienyl]titanium(IV) dichloride,[1] which became better known in the literature under its trivial name of Titanocene Y.

Mechanism of action

Titanocene Y is a cytotoxic apoptosis-inducing[7] and anti-angiogenic[8] drug candidate targeting renal-cell cancer and other solid tumors.[9] [10] The compound is transported via serum albumin selectively into cancer cells[11] [12] and targets their DNA by coordinating strongly to phosphate groups.[13] [14] Additionally, Titanocene Y is able to induce apoptosis via the FAS receptor pathway.[15] Very encouraging is the fact that Titanocene Y is breaking platinum-resistance in human colon and human lung cancer cells,[16] which might make it attractive as a cytotoxic component of future 2nd or 3rd line cancer treatments.

Animal testing

Titanocene Y was tested extensively in vivo; it showed promising results against xenografted human epidermoid carcinoma[17] and prostate cancer,[18] while best results are reached against breast[19] and renal-cell cancer.[20] Titanocene Y can be given in the mouse in high dosages and it shows generally mild toxicity in the form of diarrhea. Titanocene Y is not patent protected and would therefore benefit from non-commercial sponsoring to develop it into a cytotoxic drug candidate for the treatment of advanced renal-cell cancer – an area in need of better therapies.

Notes and References

  1. Sweeney NJ, Mendoza O, Müller-Bunz H, Pampillón C, Rehmann FJ, Strohfeldt K, Tacke M . Novel benzyl substituted titanocene anti-cancer drugs . Journal of Organometallic Chemistry . 2005 . 690 . 21–22 . 4537–4544 . 10.1016/j.jorganchem.2005.06.039 .
  2. Köpf H, Köpf-Maier P . Titanocene dichloride--the first metallocene with cancerostatic activity . Angew. Chem. Int. Ed. Engl. . 18 . 6 . 477–478 . 1979 . 111586 . 10.1002/anie.197904771 .
  3. Kröger N, Kleeberg UR, Mross K, Edler L, Hossfeld DK . Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer . Onkologie . 2000 . 23 . 1 . 60–62 . 10.1159/000027075 . 72817279 .
  4. Lümmen G, Sperling H, Luboldt H, Otto T, Rübben H . Phase II trial of titanocene dichloride in advanced renal-cell carcinoma . Cancer Chemother. Pharmacol. . 42 . 5 . 415–417 . 1998 . 9771957 . 10.1007/s002800050838. 2724249 .
  5. Allen OR, Croll L, Gott AL, Knox RJ, McGowan PC . Functionalized Cyclopentadienyl Titanium Organometallic Compounds as New Antitumor Drugs . Organometallics . 2004 . 23 . 2 . 288–292 . 10.1021/om030403i .
  6. Strohfeldt K, Tacke M . Bioorganometallic fulvene-derived titanocene anti-cancer drugs . Chem Soc Rev . 37 . 6 . 1174–1187 . 2008 . 18497930 . 10.1039/b707310k .
  7. O'Connor K, Gill C, Tacke M, Rehmann FJ, Strohfeldt K, Sweeney N, Fitzpatrick JM, Watson RW . Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells . Apoptosis . 11 . 7 . 1205–1214 . 2006 . 16699961 . 10.1007/s10495-006-6796-1 . 31009957 .
  8. Weber H, Claffey J, Hogan M, Pampillón C, Tacke M . Analyses of Titanocenes in the spheroid-based cellular angiogenesis assay . Toxicol in Vitro . 22 . 2 . 531–534 . 2008 . 17981007 . 10.1016/j.tiv.2007.09.014 .
  9. Kelter G, Sweeney NJ, Strohfeldt K, Fiebig HH, Tacke M . In-vitro anti-tumor activity studies of bridged and unbridged benzyl-substituted titanocenes . Anticancer Drugs . 16 . 10 . 1091–1098 . 2005 . 16222151 . 10.1097/00001813-200511000-00008. 44409481 .
  10. Oberschmidt O, Hanauske AR, Pampillón C, Sweeney NJ, Strohfeldt K, Tacke M . Antiproliferative activity of Titanocene Y against tumor colony-forming units . Anticancer Drugs . 18 . 3 . 317–321 . 2007 . 17264765 . 10.1097/CAD.0b013e3280115f86 . 22670179 .
  11. Vessières A, Plamont MA, Cabestaing C, Claffey J, Dieckmann S, Hogan M, Müller-Bunz H, Strohfeldt K, Tacke M . Proliferative and anti-proliferative effects of titanium- and iron-based metallocene anti-cancer drugs . Journal of Organometallic Chemistry . 2009 . 694 . 6 . 874–879 . 10.1016/j.jorganchem.2008.11.071 .
  12. Lally G, Deally A, Hackenberg F, Quinn SJ, Tacke M . Titanocene Y – Transport and Targeting of an Anticancer Drug Candidate . Letters in Drug Design & Discovery . 2013 . 10 . 8 . 675–682 . 10.2174/15701808113100890027.
  13. Tacke M . The Interaction of Titanocene Y with Double-Stranded DNA: A Computational Study . Letters in Drug Design & Discovery . 2008 . 5 . 5 . 332–335 . 10.2174/157018008784912036 .
  14. Erxleben A, Claffey J, Tacke M . Binding and hydrolysis studies of antitumoural titanocene dichloride and Titanocene Y with phosphate diesters . J. Inorg. Biochem. . 104 . 4 . 390–396 . 2010 . 20036426 . 10.1016/j.jinorgbio.2009.11.010 .
  15. Kater L, Claffey J, Hogan M, Jesse P, Kater B, Strauss S, Tacke M, Prokop A . The role of the intrinsic FAS pathway in Titanocene Y apoptosis: The mechanism of overcoming multiple drug resistance in malignant leukemia cells . Toxicol in Vitro . 26 . 1 . 119–124 . 2012 . 21986259 . 10.1016/j.tiv.2011.09.010 .
  16. Hilger A, Alex D, Deally A, Gleeson B, Tacke M. Ralf . Titanocene Y and Vanadocene Y: Platinum Resistance-Breaking Cytotoxic and DNA-Targeting Anticancer Drug Candidates . Letters in Drug Design & Discovery . 2011 . 8 . 10 . 904–910 . 10.2174/157018011797655241 .
  17. Bannon JH, Fichtner I, O'Neill A, Pampillón C, Sweeney NJ, Strohfeldt K, Watson RW, Tacke M, Mc Gee MM . Substituted titanocenes induce caspase-dependent apoptosis in human epidermoid carcinoma cells in vitro and exhibit antitumour activity in vivo . Br. J. Cancer . 97 . 9 . 1234–1241 . 2007 . 17923871 . 2360460 . 10.1038/sj.bjc.6604021 .
  18. Dowling CM, Claffey J, Cuffe S, Fichtner I, Pampillón C, Sweeney NJ, Strohfeldt K, Watson RW, Tacke M . Antitumor activity of Titanocene Y in xenografted PC3 tumors in mice . Letters in Drug Design & Discovery . 5 . 2 . 141–144 . 2008 . 10.2174/157018008783928463 .
  19. Beckhove P, Oberschmidt O, Hanauske AR, Pampillón C, Schirrmacher V, Sweeney NJ, Strohfeldt K, Tacke M . Antitumor activity of Titanocene Y against freshly explanted human breast tumor cells and in xenografted MCF-7 tumors in mice . Anticancer Drugs . 18 . 3 . 311–315 . 2007 . 17264764 . 10.1097/CAD.0b013e328010a6f7 . 42898975 .
  20. Fichtner I, Pampillón C, Sweeney NJ, Strohfeldt K, Tacke M . Antitumor activity of Titanocene Y in xenografted CAKI-1 tumors in mice . Anticancer Drugs . 17 . 3 . 333–336 . 2006 . 16520662 . 10.1097/00001813-200603000-00012. 45195878 .

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