Anticancer compounds cisplatin

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. 

Figure 10.5 Controlled release of anticancer compounds from polymeric matrices, (a) Release of cisplatin (circles) from p(FAD/SA) initially containing 10% drug. Similar results have been obtained for BCNU, MTX, and a variety of other compounds (see [18, 19] for details), (b) Release of BCNU from EVAc (circles), p(CPP/ SA) (squares), and p(FAD/SA) (triangles) matrices initially containing 20% drug.

A few synthetic approaches were reported to obtain sets of new 1,2,4-triazine derivatives. A well-known synthetic protocol was used to prepare a series of the 1,2,4-triazine derivatives 14 bearing a piperazine amide moiety. The synthetic route included the condensation of S-methyl thiosemicarba-zide 15 and benzil derivatives 16 followed by nucleophilic substitution of the methylthio group with piperazine resulting in 1,2,4-triazines 17 and further functionalization of the piperazine moiety. In vitro antitumor activity against breast cancer cells of the 1,2,4-triazines 14 was evaluated using the XTT method, BrdU method, and flow cytometric analysis. A few of the compounds demonstrated antiproliferative effect comparable with an effective anticancer drug, cisplatin (14BMC6313). 

The compound [Pt(NH3)2Cl2] was first prepared In 1845 by two different synthetic routes. The a form of the compound (known as Peyrone s salt) was made by the reaction of [PtC ] " with NH3, while the / form (also called Resiet s second chloride) resulted when [Pt(NH3)4]Cl2 was heated to 250 °C. Many years later, Alfred Werner showed that the two compounds were isomers of each other and suggested that they had square planar molecular geometries. Currently, we know the a form as the anticancer drug cisplatin, c/s-[Pt(NH3)2Cl2], and the form as its geometrical isomer trans-[Pt(NH3)2Cl2]. 

When Werner turned his attention to platinum compounds, he synthesized PtCl2(NH3)2. He was able to prepare two geometric isomers of the compound (see Figure 3.14). Little did he know that the cis isomer, now known familiarly as cisplatin, would turn out to be a potent anticancer compound (see Chapter 6,... 

Pt(TV) Prodrugs. Platinum(IV) complexes have been widely studied as potential prodrugs that avoid the limitations of the cisplatin class of anticancer drugs. Indeed, the Pt(IV) compound satraplatin [Pt(cha)Cl2(OAc)2(NH3)] (cha, cyclohexylamine) is currently in clinical trials for treatment of hormone-refractory prostate cancer (Fig. 1) (22). Satraplatin is the first orally bioavailable platinum derivative under active clinical investigation and is particularly attractive because of the convenience of administration, milder toxicity profile, and lack of cross-resistance with cisplatin. These results are promising and support the idea that platinum(IV) complexes offer the opportunity to overcome some of the problems associated with cisplatin and its analogs. 

The first report on the anticancer properties of ruthenium was published in 1976 when the Ru(III) compound /ac-[RuC13(NH3)3] (Fig. 11) was found to induce filamentous growth of Escherichia coli at concentrations comparable to those at which cisplatin generates similar effects (49). This Ru(III) complex and related compounds such as cis-[RuCl2(NH3)4]Cl illustrated the potential anticancer activity of ruthenium complexes, but insolubility prevented further pharmacological use. Since these initial studies, other Ru(III) complexes have been studied for potential anticancer activity, and two compounds, NAMI-A (50) and KP1019 (51), are currently undergoing clinical trials. Remarkably,... 

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