Titanocene Y

Short description: Organotitanium compound

Structure of Titanocene Y

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]

## Contents

* 1 Discovery
* 2 Mechanism of action
* 3 Animal testing
* 4 References
* 5 External links

## 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.

## References

1. ↑ 1.0 1.1 "Novel benzyl substituted titanocene anti-cancer drugs". Journal of Organometallic Chemistry 690 (21–22): 4537–4544. 2005. doi:10.1016/j.jorganchem.2005.06.039.
2. ↑ "Titanocene dichloride--the first metallocene with cancerostatic activity". Angew. Chem. Int. Ed. Engl. 18 (6): 477–478. 1979. doi:10.1002/anie.197904771. PMID 111586.
3. ↑ "Phase II Clinical Trial of Titanocene Dichloride in Patients with Metastatic Breast Cancer". Onkologie 23 (1): 60–62. 2000. doi:10.1159/000027075.
4. ↑ "Phase II trial of titanocene dichloride in advanced renal-cell carcinoma". Cancer Chemother. Pharmacol. 42 (5): 415–417. 1998. doi:10.1007/s002800050838. PMID 9771957.
5. ↑ "Functionalized Cyclopentadienyl Titanium Organometallic Compounds as New Antitumor Drugs". Organometallics 23 (2): 288–292. 2004. doi:10.1021/om030403i.
6. ↑ "Bioorganometallic fulvene-derived titanocene anti-cancer drugs". Chem Soc Rev 37 (6): 1174–1187. 2008. doi:10.1039/b707310k. PMID 18497930.
7. ↑ "Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells". Apoptosis 11 (7): 1205–1214. 2006. doi:10.1007/s10495-006-6796-1. PMID 16699961.
8. ↑ "Analyses of Titanocenes in the spheroid-based cellular angiogenesis assay". Toxicol in Vitro 22 (2): 531–534. 2008. doi:10.1016/j.tiv.2007.09.014. PMID 17981007.
9. ↑ "In-vitro anti-tumor activity studies of bridged and unbridged benzyl-substituted titanocenes". Anticancer Drugs 16 (10): 1091–1098. 2005. doi:10.1097/00001813-200511000-00008. PMID 16222151.
10. ↑ "Antiproliferative activity of Titanocene Y against tumor colony-forming units". Anticancer Drugs 18 (3): 317–321. 2007. doi:10.1097/CAD.0b013e3280115f86. PMID 17264765.
11. ↑ "Proliferative and anti-proliferative effects of titanium- and iron-based metallocene anti-cancer drugs". Journal of Organometallic Chemistry 694 (6): 874–879. 2009. doi:10.1016/j.jorganchem.2008.11.071.
12. ↑ "Titanocene Y – Transport and Targeting of an Anticancer Drug Candidate". Letters in Drug Design & Discovery 10 (8): 675–682. 2013. doi:10.2174/15701808113100890027.
13. ↑ 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.
14. ↑ "Binding and hydrolysis studies of antitumoural titanocene dichloride and Titanocene Y with phosphate diesters". J. Inorg. Biochem. 104 (4): 390–396. 2010. doi:10.1016/j.jinorgbio.2009.11.010. PMID 20036426.
15. ↑ "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. doi:10.1016/j.tiv.2011.09.010. PMID 21986259.
16. ↑ 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.
17. ↑ "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. doi:10.1038/sj.bjc.6604021. PMID 17923871.
18. ↑ "Antitumor activity of Titanocene Y in xenografted PC3 tumors in mice". Letters in Drug Design & Discovery 5 (2): 141–144. 2008. doi:10.2174/157018008783928463.
19. ↑ "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. doi:10.1097/CAD.0b013e328010a6f7. PMID 17264764.
20. ↑ "Antitumor activity of Titanocene Y in xenografted CAKI-1 tumors in mice". Anticancer Drugs 17 (3): 333–336. 2006. doi:10.1097/00001813-200603000-00012. PMID 16520662.

## External links

* Titanocene Y at the US National Library of Medicine Medical Subject Headings (MeSH)

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Titanium compounds

Titanium(II)|

* TiCl2
* TiH2
* TiO
* TiS
* TiSi2

| Organotitanium(II) compounds|

[(C5H5)2Ti(CO)2]

|

Titanium(III)|

* TiAl
* TiBr3
* TiCl3
* TiF3
* TiI3
* TiN
* TiP
* Ti2O3
* Ti2S3

| Organotitanium(III) compounds|

[(C5H5)2TiCl]2

|

Titanium(IV)|

* TiB2
* TiBr4
* TiC
* TiCl4
* Ti(ClO4)4
* TiF4
* H2TiF6
* TiH4
* TiI4
* Ti(NMe2)4
* Ti(NO3)4
* TiO2
* H4TiO4
* Ti4(OCH2CH3)16
* Ti(OCH(CH3)2)4
* Ti(OCH2CH2CH2CH3)4
* KTiOPO4
* NiO*Sb2O3*20TiO2
* TiS2
* TiSe2
* TiSi2

| Titanate compounds|

* BaTiO3
* Ba2TiO4
* Bi4Ti3O12
* CaTiO3
* CaCu3Ti4O12
* CaZrTi2O7
* Cs2TiO3
* Dy2Ti2O7
* EuBaTiO4
* FeTiO3
* Ho2Ti2O7
* Li2TiO3
* MnTiO3
* Na2Ti3O7
* Na0.5Bi0.5TiO3
* NiTiO3
* PbTiO3
* Pb(Zr,Ti)O3
* SrTiO3
* ZnTiO3

|

Organotitanium(IV) compounds|

* [(C5H5)2TiCl2]
* [(C5H5)2Ti(CH3)2]
* [(C5H5)2TiS5]
* [(C5H5)2Ti(μ-Cl)(μ-CH2)Al(CH3)2]
* [(η5-C5H4-CH2C6H4OCH3)2TiCl2]

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