Glycol Methyl Ether and Glycol Amine Substituted Titanocenes as Antitumor Agents

Abstract

Abstract6‐[4‐(2‐Methoxyethoxy)phenyl]fulvene (3a) and 6‐{4‐[2‐(dimethylamino)ethoxy]phenyl}fulvene (3b) were prepared as the starting materials for the synthesis of three different classes of titanocenes, which are ansa‐titanocenes, diarylmethyl‐substituted titanocenes and benzyl‐substituted titanocenes. Because the synthetic possibilities seem to be limited, only ansa‐titanocene {1,2‐bis(cyclopentadienyl)‐1,2‐bis[4‐(2‐methoxyethoxy)phenyl]ethanediyl}titanium dichloride (4a) and benzyl‐substituted titanocene bis‐{[4‐(2‐methoxyethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride (6a) were obtained and characterised. The change in the substitution pattern of the phenyl moiety from an oxygen atom to a nitrogen atom had such a big influence on the reaction that not one compound of the three titanocene classes could be synthesised, and it was also not possible to obtain diarylmethyl‐substituted titanocenes with the use of either of the fulvenes. When benzyl‐substituted titanocene 6a was tested against pig kidney cells (LLC‐PK), an antiproliferative effect that results in an IC50 value of 43 μM, was observed. This IC50 value is in the lower range of the cytotoxicities evaluated for titanocenes up to now. ansa‐Titanocene 4a surprisingly showed, when tested on the same cell line, a proliferative effect together with a fast rate of hydrolysis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)