%0 Journal Article
%T Synthesis and Biological Evaluation of Achiral Indole-Substituted Titanocene Dichloride Derivatives
%A Anthony Deally
%A Frauke Hackenberg
%A Grainne Lally
%A Matthias Tacke
%J International Journal of Medicinal Chemistry
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/905981
%X Six new titanocene compounds have been isolated and characterised. These compounds were synthesised from their fulvene precursors using Super Hydride (LiBEt3H) followed by transmetallation with titanium tetrachloride to yield the corresponding titanocene dichloride derivatives. These complexes are bis-[((1-methyl-3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5a), bis-[((5-methoxy-1-methyl,3-diethylaminomethyl)indol-2-yl)methylcyclopentadienyl] titanium (IV) dichloride (5b), bis-[((1-methyl,3-diethylaminomethyl)indol-4-yl)methylcyclopentadienyl] titanium (IV) dichloride (5c), bis-[((5-bromo-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5d), bis-[((5-chloro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5e), and bis-[((5-fluoro-1-methyl)indol-3-yl)methylcyclopentadienyl] titanium (IV) dichloride (5f). All six titanocenes 5a¨C5f were tested for their cytotoxicity through MTT-based in vitro tests on CAKI-1 cell lines using DMSO and Soluphor P as solubilising agents in order to determine their IC50 values. Titanocenes 5a¨C5f were found to have IC50 values of 10 (¡À2), 21 (¡À3), 29 (¡À4), 140 (¡À6), and 450 (¡À10)£¿¦ÌM when tested using DMSO. 1. Introduction Titanium-based reagents have been investigated for their use as anticancer agents for more than a decade and have been shown to have significant potential against solid tumours. In fact, budotitane ([cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)]) which was designed by following cisplatin models was the first nonplatinum drug to enter clinical trials in 1993 [1]. Following on from this work was the use of titanocene dichloride as an anticancer compound in the clinic. Pioneering work by K£¿pf and K£¿pf-Maier cannot be overlooked as it was them who first identified the antitumor potential of metallocene dihalides [2]. The compound looked very promising during its preclinical evaluation; studies showed that an Ehrlich ascites cure of 100% and Colon 38 adenocarcinoma inhibition was better than that of cisplatin [3]. However, the use of titanocene dichloride as a single agent in the clinic was not sufficiently promising to warrant further studies, and titanocene dichloride has been discontinued from further clinical trials [4, 5]. One of the main downfalls of titanocene dichloride being used in the clinic was the uncertainty regarding the composition of the biologically active titanium species responsible for the antitumor activity. The hydrolysis products of titanocene dichloride at physiological pH have hampered identification
%U http://www.hindawi.com/journals/ijmc/2012/905981/