Novel benzyl substituted titanocene anti-cancer drugs

From the novel reaction of Super Hydride (LiB(Et)3H) 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 TiCl4, 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 (IC50) of 1.2 × 10−4 M, 2.1 × 10−5 M and 9.0 × 10−5 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.

Bis-[(p-methoxybenzyl)cyclopentadienyl]titanium (IV) dichloride is a promising candidate for an anti-cancer drug and was synthesised starting from 6-(p-methoxyphenyl)fulvene and Super Hydride. Herein, we present the synthesis and X-ray structure of the titanocene followed by MTT-based cytotoxicity tests on pig kidney carcinoma (LLC-PK) cells.Figure optionsDownload as PowerPoint slide