New titanocene derivatives with high antiproliferative activity against breast cancer cells (original) (raw)
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Novel benzyl substituted titanocene anti-cancer drugs
Journal of Organometallic Chemistry, 2005
From the novel reaction of Super Hydride (LiB(Et) 3 H) with 6-(p-N,N-dimethylanilinyl)fulvene (1a) or 6-(p-methoxyphenyl)fulvene (1b) the corresponding lithium cyclopentadienide intermediates (2a, 2b) were obtained. When reacted with TiCl 4 , bis-[(p-dimethylaminobenzyl)cyclopentadienyl]titanium (IV) dichloride (3a) and bis-[(p-methoxybenzyl)cyclopentadienyl]titanium (IV) dichloride (3b) were obtained. Titanocene 3a was reacted with an ethereal solution of HCl, by which its dihydrochloride derivative (3c) was formed and isolated. Titanocenes 3b and 3c were characterised by X-ray crystallography. When the titanocenes 3a-c were tested against pig kidney carcinoma (LLC-PK) cells inhibitory concentrations (IC 50 ) of 1.2 · 10 À4 M, 2.1 · 10 À5 M and 9.0 · 10 À5 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, most notably for 3b (Titanocene Y), which is a hundred times more cytotoxic than titanocene dichloride itself.
Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride
Journal of Organometallic Chemistry, 2004
Starting from 6-(p À N; N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC 50 ) of 2.7 Â 10 À4 and 1.9 Â 10 À4 M, respectively, were observed.
Structural features of antitumor titanium agents and related compounds
Bioinorganic Chemistry and …, 2005
Previous studies established some Ti compounds as having marked activity against tumors of the gastrointestinal tract and lack of side effects common to widely used cytostatic agents. We describe pertinent structural features of known antitumor Ti agents and other potentially active compounds. Particularly noteworthy features are that Ti-O bonds are short and Ti-O-Ti bond angles are large, demonstrating that in these compounds the O binding has high s-character approaching sp hybridization. /'he successful drug development/1/of the antitumor agent cis-diaminodichloroplatinum(II) (cisplatin) 1, generated a search for other active metal compounds and cis-diethoxy-bis(1-phenylbutane-l,3dionato)titanium(IV), [(bzac)2Ti(OEt)2] (budotitane) 2, was the first non-Pt metal antitumor compound that reached clinical trials /2/. The ligand 1-phenylbutane-l,3-dionato bzac benzoylacetonato, is an asymmetric [3-diketone chelator useful tbr establishing one key structural feature tbr activity in budotitane, namely, the existence of two OEt cis leaving groups, which arc analogous to the 2 CI in cisplatin. Another Ti antitumor agent is titanocene dichloride, (Cp)2TiCI2 3, Cp cyclopentadienyl, which possesses 2 CI leaving groups/5/. Among the differences between Ti antitumor drugs and cisplatin is the spectrum of activity, as Ti drugs operate against gastrointestinal tumors whereas Pt drugs do not. On the other hand, P338 and LI210 leukemia are sensitive targets for Pt drugs but not for budotitane/4/. Other differences include a much faster hydrolysis rate of the leaving groups in the former, and the environment where the metal-leaving group bonds cleave: outside the cell for Ti drugs and inside the cell tbr Pt drugs/1/. Titanocenc dichloride shows a larger spectrum of activity compared to budotitane. This is likely due to better solubility in physiological medium and it is currently in phase II clinical tests /5/, whereas the Structural Features of Antitumor Titanium. Agents and Related Compounds development of budotitane is limited by formulation problems /6/. Titanocene dichloride interacts with transferrin, a protein associated with iron transport, and suggests a possible mode of entry into the tumor cell. That is, the protein, with a Ti atom bound to one of its 2 domains/7,8/, could cross the tumor cell wall, which is characterized by greater amount of transferrin receptors than present in normal cells, and allow metal interaction with unknown targets.
Applied Organometallic Chemistry, 2005
Starting from 2-furylfulvene (1a), 2-thiophenylfulvene (1b), and 1-methyl-2-pyrrolylfulvene (1c), [1,2-di(cyclopentadienyl)-1,2-di-(2-furyl)ethanediyl] titanium dichloride (2a), [1,2-di(cyclopentadienyl)-1,2-di-(2-thiophenyl)ethanediyl] titanium dichloride (2b), and [1,2-di(cyclopentadienyl)-1,2-bis-(1-methyl-2-pyrrolyl)ethanediyl] titanium dichloride (2c) were synthesized. When titanocenes (2a–c) were tested against pig kidney carcinoma cells (LLC-PK), inhibitory concentrations (50%) of 4.5 × 10−4M, 2.9 × 10−4M and 2.0 × 10−4M respectively were observed. Copyright © 2005 John Wiley & Sons, Ltd.
Diarylmethyl substituted titanocenes: Promising anti-cancer drugs
Polyhedron, 2006
From the reaction of tert-butyl lithium with p-bromo-N,N-dimethylaniline (1a), p-bromoanisole (1b) or 1-bromo-3,5-dimethoxybenzene (1c), p-N,N-dimethylanilyl lithium (2a), p-anisyl lithium (2b) or (3,5-dimethoxyphenyl) lithium (2c), respectively, were obtained. When reacted with 6-(p-N,N-dimethylanilinyl)fulvene (3a), 6-(p-methoxyphenyl)fulvene (3b) or 3,5-(dimethoxyphenyl)fulvene (3c), the corresponding lithiated intermediates were formed (4a-c). Titanium tetrachloride was added ''in situ'', obtaining titanocenes 5a-c, respectively. When these titanocenes were tested against pig kidney carcinoma (LLC-PK) cells, inhibitory concentrations (IC 50 ) of 3.8 · 10 À5 M, 4.5 · 10 À5 M, and 7.8 · 10 À5 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.