Metallocenes titanocene dichloride

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. 

Titanocene dichloride was the first metallocene derivative to be converted53 into dithiolato complexes, for example compound (38). Some other examples of this structural type exist, and their structural features are described in Section 16.5.3.1. 

Kopf H, Kdpf-Maier P (1979) Titanocene dichloride - the first metallocene with cancero-static activity. Angew Chem IntEd 18 477 -78... 

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... 

Petra Kopf-Maier Metallocene dihalides, especially titanocene dichloride, as antitumor drugs... 

A small number of alkene-linked ani a-metallocenes are known for titanium. Thus reaction of Na2(C5H4)C(R)=C(R) (C5H4) with TiCLi or TiCl3THF3 affords the corresponding alkene-bridged ani a-titanocene dichlorides. There is no indication of interaction between the aUcene r-system and the titanium center. 

Arylations. A rather unusual reaction for the synthesis of triarylmethanes is that which involves benzylic arylation of 4-nitrotoluene and homologs catalyzed by Pd(OAc)2-PhjP in the presence of CS2CO3. One or two aryl groups can be introduced by this method. Arylation of amines by ArX employs the Pd(OAc)2-f-BuONa and a phosphine as catalyst. Pentaarylcyclopentadienes are readily formed in a reaction of metallocenes (nickelocene, titanocene dichloride, zirconocene dichloride) with ArBr in... 

Modification of the Cyclopentadienyl Ligands, The results described so far suggest that the MX2 moiety within the metallocene dihalides represents the active center of the molecules. However, modification of the cyclopentadienyl rings in (C5H5)2TiCl2 as the model system also has a significant influence on the tumor-inhibiting potency of titanocene dichloride. 

The investigations concerning the mode of action of the metallocene dihalides represented by titanocene dichloride and vanadocene dichloride are based on four experimental pillars ... 

As mentioned in the introduction, metallocene-type complexes based on the early transition metals were evaluated as anticancer compounds shortly after the discovery of cisplatin. While the biological activity of each of the metallocene dihalides is unique, titanocene dichloride 7 has been the subject of a number of studies and even entered clinical evaluation, although evaluation was discontinued (not due to its anti-proliferative properties), principally due to formulation problems, despite showing superior activity to certain cancers than other established drugs. This class of compound continues to be modified and studied for anticancer activity, for example, the titanocene-type derivative of tamoxifen 1, described above, and other developments described below. 

For the bent metallocene dihalides, structure-activity relationships were established for the halides and substitution of the Gp rings. Also, hydrolysis reactions were studied in detail with a view on aqueous stability. Model studies with amino acids, nucleic acids, proteins, and blood plasma provided more insight into the mechanism of action. Titanium compounds were most active, and titanocene dichloride has entered clinical trials. Although very promising... 

Fig. 5 Selected examples of anticancer compounds with metallocene fragments a titanocene dichloride b ferrocenyl oestrogen mimic complexes - see Chapter by Jaouen (this volume), for more examples c a ferrocenyl gold complex...

These materials are potent antivirial agents [37,38]. More recently we reported the synthesis of Group IVB metallocene products and the synthesis of Group IVB acyclovir polymers of the following structure from reactions with titanocene dichloride shown in (10) [39],... 

Carraher, Naoshima, and coworkers " have produced a number of products derived from the condensation reaction of natural products using Group IVB metallocene dichlorides. These natural materials include dextran and cotton. Much of this work employed the titanocene dichloride. 

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