Vanadocene 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. 

In THE, CP2VCI2 has two irreversible reductions that each lead to chloride loss Ef" =—1.15 and —2.20 V versus Cp2Ee/THE), which ultimately lead to the observation of the reversible couple for vanadocene at —3.27 V versus Cp2Fe/THE [58], In acetonitrile, a series of substituted vanadocene dichlorides ((C5H4R)2VCl2, R = Me, Pr, Bu)) [59] is... 

Cp2V(OTf)2 (30), which is derived from vanadocene dichloride, forms the d vanadocene complex (31) with 1,10-phenanthrohne or 2,2 -bipyridine (Scheme 17). The two nitrogen atoms and centroids of the two cyclopentadienyl rings occupy a distorted tetrahedral geometry around V(1V) center. Relatively low V(1V)-V(111) reduction potential is observed. 

Vanadocene dichloride-zii Reductive couplings. presence of a chlorotriorga... 

Vanadocene-containing polyesters and polyethers are now under active study.248,249 250 Vanadocene dichloride has known anticancer activity, so polymers, such as 109, will be evaluated. 

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

Precursor Incorporation Studies. Studies of the incorporation of tritiated precursors of the DNA, RNA, or protein synthesis, i.e. of thymidine, uridine, or leucine, into the acid-insoluble fraction of EAT cells were accomplished after in vivo as well as in vitro treatment with (C5H5)2MCl2 (M Ti, V). In all experiments, the nucleic acid metabolism turns out to be much more sensitive to the metallocene dihalide action than the protein metabolism (33, 34). In particular, treatment with vanadocene dichloride induces an extended and persistent suppression of the DNA synthesis without signs of regeneration processes (Figure 2). 

Microanalytical Studies. The EELS investigations after in vivo as well as after in vitro treatment of EAT with the antitumor agents titanocene dichloride and vanadocene dichloride reveal reproducibly the main enrichment of the central metals Ti and V within the nuclear heterochromatin. To a minor extent, the metals are associated with the euchromatin, the nucleolus, and the cytoplasmic ribosomes. In most cases, no metal atoms can be detected in other cellular regions by EELS. This means that the treatment with titanocene or vanadocene dichloride results apparently in an accumulation of the central metals Ti and V within those cellular regions which are rich in nucleic acids. 

Synonyms Dichloro-pi-cyclopentadienylvanadium Dichlorovanadocene Vanadocene dichloride... 

Vanadium (III) tris (acetylacetonate) Vanadium, tris (2,4-pentanedionato) Vanadium, tris (2,4-pentanedionato-0,0 -). See Vanadium tris acetyl acetonate Vanadocene dichloride. See Bis (cyclopentadienyl) vanadium dichloride Vanadous chloride. See Vanadium chloride (ous)... 

The major interest in these metallocenes involves their use as catalysts in the synthesis of a number of stereoregular vinyl polymers such as polyethylene and polypropylene. They are also being investigated for their biological activities. Because one of the major driving forces for the synthesis of polymeric derivatives is their biological activity, we will briefly review some of this effort focusing on vanadocene dichloride, since that is the compound most often studied. 

Both titanocene and vanadocene dichloride inhibit DNA and RNA replication accumulating in nucleic acid rich portions of tumor cells [7,8]. Because of this it is believed that the formation of DNA-metaUocene adducts in vivo is involved in then-ability to inhibit cell growth. Further, it has been found that metallocene-protein interactions are also important and that metal-tranferrin compounds have been included in their mode of action [9]. 

Along with blood plasma proteins, proteins involved in cellular replication have also been implicated in the action of several metallocenes. Vanadocene dichloride inhibits both protein kinase C and bacterial topoisomerase activity [10]. 

Tarasov and coworkers reported on the formation of 1 1 complexes from the reaction of vanadocene dichloride and tartaric acids. The products probably include materials with structure (1) when in basic solution. 

Chelated materials were formed from reaction of vanadocene dichloride with heterocyclic 1,2-dithiolates [26], The product from l,3-dithiolene-2-thione-4,5-ditholate is given in (2). 

Cyclic phosphate compounds are formed when aqueous solutions of vanadocene dichloride and phosphates are brought together. The proposed structure is given as (3) [27],... 

Malik, Duncan, Tomalia, and Esfand [29] reported the use of a variety of amine and acid-containing polymers that chelated platinum forming cisplatin derivatives. They also reported the synthesis of similar dendritic-antineoplastic drugs using vanadocene dichloride. The structure from the poly(propyleneimine) dendrimers contains units are shown in (5) and (6). 

As part of our effort to create anticancer, antibacterial, and antiviral agents we recently synthesized the analogous product except employing vanadocene dichloride giving polymers [40] of the form shown in (11). 

Table 9.2 Most abundant ion fragments generated in the 100 to fOOOamu range for the product of vanadocene dichloride and acyclovir...

Table 9.3 Ion fragments in the mass range of 3,680 to 3,910 daltons for the product of acyclovir and vanadocene dichloride...

Dorer, B. Prosenc, M. -Ft. Rief, U. Brintzinger, H. H. Synthesis and structure of titanocene, zireono-cene, and vanadocene dichloride complexes with two ethanediyl bridges. Organometallics 1994,13,... 

Vanadocene dichloride (II) represented that metallocene compound which showed best activity in vitro. It effected highly significant reduction in cell proliferation at a... 

Vanadocene dichloride (II) was shown to be characterized by marked antiproliferative effects against fluid and solid Ehrlich ascites tumor as well as against other experimental tumor systems such as intraperitoneally growing mouse mammary tumor TA3Ha The growth of the latter tumor was inhibited remarkably to a similar extent as observed after application of optimum doses of cisplatin. In both cases, the life span of the host animals was prolongated by about 180% in relation to untreated controls ... 

Significant antiviral ejfectivity was shown in vitro for titanocene dichloride (I) against numerous DNA and RNA viruses in the extracellular phase Typical examples of viruses, which were inhibited by direct contact with I and lost infectivity up to 100%, were orthopoxvirus (vaccinia) and herpes virus (pseudorabies) as DNA viruses, and rhabdovirus (vesicular stomatitis), paramyxovirus (Newcastle disease) and diverse orthomyxoviruses (e.g. influenza A and B) as RNA viruses. A comparable antiviral effect against herpes viruses was detectable after application of the ferricenium salt whereas, on the other hand, vanadocene dichloride (11) and molybdenocene dichloride (V) failed to show antiviral activity under the same experimental conditions. 

Hie time-dependent organ distributions of titanium and vanadium were analyzed by flameless atomic absorption spectroscopy in dried organ specimens after single intraperitoneal administrations of therapeutic doses of titanocene dichloride (I, 60 mg/ kg) or vanadocene dichloride (II, 80 mg/kg) / at time 0. 

In vitro, cydopentadienyl metal complexes were able to suppress the proliferation of normal or transformed tumor cells. Best activity was found for vanadocene dichloride in this respect. In vivo, numerous of the cydopentadienyl metal complexes inhibited the development of diverse experimental animal tumors (e.g., Ehrlich asdtes tumor, sarcoma 180, B16 melanoma, colon 38 cardnoma and Lewis lung cardnoma) and the growth of human cardnomas xenografted to nude mice. Espedally certain titanocene and ferricenium compoimds were cytostatically effective against human colorectal cardnomas. Moreover, titanocene complexes were shown to be antiviral agents and potent antiinflammatory compounds comparable to phenylbutazone. 

After in vivo and in vitro treatment with titanocene or vanadocene dichloride, precursor incorporation studies showed a pronounced and persistent inhibition of nucleic acid synthesis, especially of DNA synthesis. 

Cytokinetic investigations revealed the appearance of a G2 block and the immigration of inflammatory cells belonging to the host defensive system after in vivo application of titanocene or vanadocene dichloride. After treatment in vitro, cell arrests at the Gi/ S boundary and in G2 were induced. These results correspond to the findings observed after administration of other cytostatic agents interfering with the nucleic add metabolism. 

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