Metallocenes antitumor activity

The antitumor activity of titanocene dichloride 21 was first recognized in 1979 (150), and since then the activity of several other metallocenes (V, Nb, Mo, Fe, Ge, and Sn) has been reported (151). Most interest has centered on titanocene dichloride and on vanadocene dichloride 22, which are active against a diverse range of human carcinomas, including gastrointestinal and breast carcinomas, but not against head and neck cancers. There appears to be a lack of crossresistance between titanocene dichloride and cisplatin. 

Good antitumor activity has also been found among ionic metallocene complexes of Ti(IV), Nb(V), Mo(VI), and Re(V), such as 23-26,... 

McLaughlin ML, Cronan JM Jr, Schaller TR, Snelling RD (1990) DNA-metal binding by antitumor-active metallocene dichlorides from inductively coupled plasma spectroscopy analysis titanocene dichloride forms DNA-Cp2Ti or DNA-CpTi adducts depending on pH. J Am Chem Soc 112 8949-8952... 

Harding MM, Mokdsi G (2000) Antitumor metallocenes structure-activity studies and interactions with biomolecules. Curr Med Chem 7 1289-1303... 

Of the eight existing metallocene dichlorides, the six complexes I-VI with M = Ti Ta exhibited antitumor activity. This was... 

Pilot experiments performed during the past months revealed antitumor activity for a third type of metallocene compounds represented by neutral stannocene and ger-manocene derivatives decasubstituted at the cyclopentadienyl rings. They differ from... 

On the other hand, the tumor inhibition effected by (CsH5)2MX2 compounds was distinctly dependent on the central metal atom M present within the molecules. Whereas the metallocene dichloro complexes I-III and V containing the first-row and second-row transition metals titanium, vanadium, niobium or molybdenum effected pronounced antitumor activity with distinct dose-activity relationships and with cure rates of 100% at optimum doses against Ehrlich ascites tumor the compounds IV and VI with... 

These results clearly underline that the antitumor activity of cyclopentadienyl metal complexes cannot simply be ascribed to the isolated action of free cyclopentadiene molecules released from a decomposing polymer [(C5H5)Ti0]402, as was postulated recently The hypothesis that the cyclopentadienyl ring ligands in metallocene diacido and fenicenium complexes may play an important, perhaps crucial, role for the cytostatic action of these compounds would certainly explain why structurally quite different cyclopentadienyl metal complexes like tetrahedral metallocene (Fig. 4) and linear metal-licenium (Fig. 5) complexes are equally effective and characterized by a similar spectrum of activity, especially as cyclopentadiene can be released from the complexes by hydrolytic cleavage of the cyclopentadienyl-metal bond On the other hand, the complexed metal atoms also seem to play an important role whether as a kind of carrier of one or both cyclopentadienyl rings to the site of action, or an anchor capable of... 

Titanium dichloride exhibited excellent antitumor activity, especially against Lewis lung carcinoma and colon carcinoma. Unfortunately, therapeutic doses of this metallocene have an unwanted effect on the liver. The detailed mechanism is unknown. Substitution of chloride by other ligands has an insignificant therapeutic effect. On the other hand, changes on the cyclopen-tadienyl ring yield totally inactive compounds. Of special interest in this field is the review article by I. Haiduc and C. Silvestm, Metal Complexes in Cancer Chemotherapy, containing 400 references. 

These complexes have shown anti-proliferative activity against various experimental tumors, e.g., Erlich ascites tumor, sarcoma 180, B16 melanoma, colon 38 carcinoma, Lewis lung carcinoma, as well as against xenografted human carcinoma. Whereas the antitumor metallocene dihalides (a. Figure 9.6.1.)... 

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