Novel titanocene anti-cancer drugs derived from fulvenes and titanium dichloride Matthias Tacke a, * , Lorcan T. Allen b , Laurence Cuffe a , William M. Gallagher b , Ying Lou a , Oscar Mendoza a , Helge M€ uller-Bunz a , Franz-Josef K. Rehmann a , Nigel Sweeney a a Chemistry Department, Conway Institute of Biomolecular and Biomedical Research, Centre for Synthesis and Chemical Biology (CSCB), University College Dublin, Belfield, Dublin 4, Ireland b Pharmacology Department, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland Received 9 March 2004; accepted 8 April 2004 Abstract Starting from 6-(p  N ; N -dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2- di(p  N ; N -dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphe- nyl)ethanediyl] titanium dichloride (2b) 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  10 4 and 1.9  10 4 M, respectively, were observed. Ó 2004 Elsevier B.V. All rights reserved. Keywords: Anti-cancer drug; cis-Platinum; Titanocene; Fulvene; LLC-PK; A2780/cp70 1. Introduction Despite the resounding success of cis-platinum and closely related platinum anti-tumor agents, the move- ment of other transition-metal anti-cancer drugs to- wards the clinic has been exceptionally slow [1–3]. Metallocene dichlorides (Cp 2 MCl 2 ) with M ¼ Ti, V, Nb and Mo show remarkable anti-tumor activity [4,5]. However, only titanocene dichloride has reached Phase I clinical trials so far, with a maximum tolerable dose of 315 mg/m 2 per week. The dose limiting effects of ti- tanocene dichloride include nephrotoxicity and eleva- tion of creatine and bilirubin levels [6,7]. Unfortunately, the efficacy of Cp 2 TiCl 2 in Phase II clinical trials in patients with metastatic renal-cell carcinoma [8] or metastatic breast cancer [9] was too low to be pursued. Nevertheless, little synthetic effort has been employed to increase the cytotoxicity of any titanocene dichloride derivative [10–12], despite the existence of a novel method starting from titanium dichloride and fulvenes [13–16], which allows direct access to highly substituted ansa-titanocenes [17,18]. This paper reports the synthesis of novel [(1,2-diaryl-1,2-dicyclopentadienyl)-ethanediyl] titanium dichlorides [19,20], which combine the reac- tivity of the titanium dichloride moiety with the ability of hydrogen bonding towards DNA of the ammine li- gand of cis-platinum, if the aryl group is substituted accordingly. 2. Experimental Titanium tetrachloride and n-butyl lithium (2 mol solution in hexane) were obtained commercially from Aldrich Chemical Co. Potassium thiocyanate (KNCS) was obtained commercially from Aldrich Chemical Co; it was well ground before the reaction and dried un- der vacuum. Acetone was dried over magnesium sul- fate. THF and toluene were dried over and distilled from Na/benzophenone prior to use. p-(N ; N -dimethyl- * Corresponding author. Tel.: +35-317-168-428; fax: +35-317-162- 127. E-mail address: matthias.tacke@ucd.ie (M. Tacke). 0022-328X/$ - see front matter Ó 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jorganchem.2004.04.015 Journal of Organometallic Chemistry 689 (2004) 2242–2249 www.elsevier.com/locate/jorganchem