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)

Proliferative and antiproliferative effects in substituted titanocene anticancer drugs

“…Therefore it was not possible to isolate the lithium intermediate and transmetallate it with TiCl 4 . The same effect was observed when the analogue 6-{4-[2-(N,N-dimethylamino)ethoxy]phenyl} fulvene was used for the synthesis of the corresponding benzyl-substituted titanocene [15].…”

“…We recently reported about the proliferative effect of an analogue substituted ansa-titanocene, the {1,2-di(cyclopentadienyl)-1,2-di[4-(2-methoxyethoxy)phenyl] -ethanediyl} titanium dichloride [15]. This ansa-titanocene showed in the in vitro cell tests on the LLC-PK cell line a similar proliferative effect, but in contrast the benzyl-substituted titanocene with the same substitution pattern showed a cytotoxic effect.…”

Synthesis and cytotoxicity studies of new dimethylamino-functionalised and heteroaryl-substituted titanocene anti-cancer drugs

“…Surprisingly, a change in the substitution pattern of titanocenes can also lead to proliferative effects, as seen in the case of some glycol methyl ether and glycol amine substituted titanocenes [23].…”

Synthesis and cytotoxicity studies of methoxy benzyl substituted titanocenes

“…More recently, novel methods starting from fulvenes and other precursors [7,8] allow direct access to antiproliferative titanocenes via reductive dimerisation with titanium dichloride [9][10][11][12][13], hydridolithiation [14][15][16][17] or carbolithiation [18][19][20][21][22][23][24][25][26] of the fulvene followed by transmetallation with titanium tetrachloride in the latter two cases.…”