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.
^O'Connor K, Gill C, Tacke M, Rehmann FJ, Strohfeldt K, Sweeney N, Fitzpatrick JM, Watson RW (2006). "Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells". Apoptosis. 11 (7): 1205–1214.
doi:
10.1007/s10495-006-6796-1.
PMID16699961.
S2CID31009957.
^Weber H, Claffey J, Hogan M, Pampillón C, Tacke M (2008). "Analyses of Titanocenes in the spheroid-based cellular angiogenesis assay". Toxicol in Vitro. 22 (2): 531–534.
doi:
10.1016/j.tiv.2007.09.014.
PMID17981007.
^Kelter G, Sweeney NJ, Strohfeldt K, Fiebig HH, Tacke M (2005). "In-vitro anti-tumor activity studies of bridged and unbridged benzyl-substituted titanocenes". Anticancer Drugs. 16 (10): 1091–1098.
doi:
10.1097/00001813-200511000-00008.
PMID16222151.
S2CID44409481.
^Oberschmidt O, Hanauske AR, Pampillón C, Sweeney NJ, Strohfeldt K, Tacke M (2007). "Antiproliferative activity of Titanocene Y against tumor colony-forming units". Anticancer Drugs. 18 (3): 317–321.
doi:
10.1097/CAD.0b013e3280115f86.
PMID17264765.
S2CID22670179.
^Vessières A, Plamont MA, Cabestaing C, Claffey J, Dieckmann S, Hogan M, Müller-Bunz H, Strohfeldt K, Tacke M (2009). "Proliferative and anti-proliferative effects of titanium- and iron-based metallocene anti-cancer drugs". Journal of Organometallic Chemistry. 694 (6): 874–879.
doi:
10.1016/j.jorganchem.2008.11.071.
^Lally G, Deally A, Hackenberg F, Quinn SJ, Tacke M (2013). "Titanocene Y – Transport and Targeting of an Anticancer Drug Candidate". Letters in Drug Design & Discovery. 10 (8): 675–682.
doi:
10.2174/15701808113100890027.
^Tacke M (2008). "The Interaction of Titanocene Y with Double-Stranded DNA: A Computational Study". Letters in Drug Design & Discovery. 5 (5): 332–335.
doi:
10.2174/157018008784912036.
^Erxleben A, Claffey J, Tacke M (2010). "Binding and hydrolysis studies of antitumoural titanocene dichloride and Titanocene Y with phosphate diesters". J. Inorg. Biochem. 104 (4): 390–396.
doi:
10.1016/j.jinorgbio.2009.11.010.
PMID20036426.
^Kater L, Claffey J, Hogan M, Jesse P, Kater B, Strauss S, Tacke M, Prokop A (2012). "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.
doi:
10.1016/j.tiv.2011.09.010.
PMID21986259.
^Hilger A, Alex D, Deally A, Gleeson B, Tacke M, Ralf (2011). "Titanocene Y and Vanadocene Y: Platinum Resistance-Breaking Cytotoxic and DNA-Targeting Anticancer Drug Candidates". Letters in Drug Design & Discovery. 8 (10): 904–910.
doi:
10.2174/157018011797655241.{{
cite journal}}: CS1 maint: multiple names: authors list (
link)
^Dowling CM, Claffey J, Cuffe S, Fichtner I, Pampillón C, Sweeney NJ, Strohfeldt K, Watson RW, Tacke M (2008). "Antitumor activity of Titanocene Y in xenografted PC3 tumors in mice". Letters in Drug Design & Discovery. 5 (2): 141–144.
doi:
10.2174/157018008783928463.
^Beckhove P, Oberschmidt O, Hanauske AR, Pampillón C, Schirrmacher V, Sweeney NJ, Strohfeldt K, Tacke M (2007). "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.
doi:
10.1097/CAD.0b013e328010a6f7.
PMID17264764.
S2CID42898975.
^Fichtner I, Pampillón C, Sweeney NJ, Strohfeldt K, Tacke M (2006). "Antitumor activity of Titanocene Y in xenografted CAKI-1 tumors in mice". Anticancer Drugs. 17 (3): 333–336.
doi:
10.1097/00001813-200603000-00012.
PMID16520662.
S2CID45195878.