Diarylmethyl substituted titanocenes: Promising anti-cancer drugs

• Published in: Polyhedron 2006-07, Vol.25 (10), p.2101-2108
• Main Authors: Pampillón, Clara, Mendoza, Oscar, Sweeney, Nigel J., Strohfeldt, Katja, Tacke, Matthias
• Format: Article
• Language: English
• Subjects: Anti-cancer drug; Cis-platin; Fulvene; LLC-PK; tert-Butyl lithium; Titanocene
• ISSN: 0277-5387
• DOI: 10.1016/j.poly.2006.01.007

Bis-[di-( p- N, N-dimethylaminophenyl)methylcyclopentadienyl] titanium(IV) dichloride is a promising candidate for an anti-cancer drug and was synthesised starting from 6-( p- N, N-dimethylanilinyl)fulvene and 4-lithio- N, N-dimethylaniline. Herein, we present the synthesis and DFT structure of the titanocene and two further derivatives followed by MTT-based cytotoxicity tests on pig kidney carcinoma (LLC-PK) cells. 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 −5 M, 4.5 × 10 −5 M, and 7.8 × 10 −5 M, respectively, were observed. These values represent improved cytotoxicity against LLC-PK, compared to their ansa-analogues.