**1. Introduction**

384 Nitroxides – Theory, Experiment and Applications

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Nitroxyl radicals (NRs), which are sometimes called "organic nitrogen oxides" exhibit a wide range of biological activities, e.g., hemodynamic effect, protection against ionizing radiation, suppression of oxidative stress in different types of pathology (Soule et al., 2007; Wilcox, 2010). Already in early studies of the simplest NRs, their antitumor activity was demonstrated on a model tumor, leukemia La (Konovalova et al., 1964) and their cytotoxicity was shown for HeLa cells (Klimek, 1966). Subsequent studies included: 1) indepth studies of antitumor activity of simple NRs (TEMPOL, TEMPO), 2) trials of therapeutical efficiency of NRs used in combination with the clinically approved anticancer drugs, and 3) synthesis and studies of hybrid compounds with NRs covalently bound to anticancer pharmacophores. Recent studies have shown that simple nitroxyls affect the cell viability through a redox-mediated signaling and induce a multifactor cell death response, including oxidative damage, cell cycle arrest and apoptosis (Gariboldi et al., 1998; 2000; 2003; Suy et al., 2005).

Nitroxide TEMPOL potentiates the cytotoxicity of doxorubicin in the culture of tumor cells with multidrug resistance (Gariboldi et al., 2006), and reduces its cardiotoxicity in rats (Monti et al, 1996). Combinations of low doses of nitroxyl TEMPO and doxorubicin or mitoxantrone exhibit additive or synergistic cytotoxicity, depending on the type of the tumor cells (Suy et al., 2005). In experiments on mice, nitroxyls at low doses (0.25–10 mg/kg) were shown to decrease toxicity of anticancer drugs substantially (Konovalova et al., 1991).

A considerable amount of research has been carried out on hybrid compounds containing NRs linked covalently to an anticancer pharmacophore. Nitroxyl derivatives of (thio)phosphamides (Shapiro et al., 1971; Emanuel et al., 1976; Sosnovsky & Paul, 1984;

© 2012 Sen' et al., licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 Sen' et al., licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Sosnovsky & Li, 1985a), cyclophosphamide (Tsui et al., 1982), actinomycin D (Sinha et al., 1979), ethylenimino triazines (Emanuel & Konovalova, 1992), nitrosoureas (Raikov et al., 1985; Sosnovsky & Li, 1985b; Emanuel et al., 1986; Sen', 1993), 5-fluorouracil (Emanuel et al., 1985; Sen' et al., 1989), daunorubicin (Emanuel et al., 1982) were synthesized and studied. In comparison with the parent compounds, nitroxyl derivatives of the cytostatic drugs possess lower overall toxicity in animal studies and higher values of the *half inhibitory* concentrations IC50 in cell cultures. At the same time, they exhibit higher chemotherapeutic indexes (are effective in a wider range of doses) and, in the cases studied, are characterized by fewer side effects. For example, ruboxyl, a nitroxyl derivative of daunorubicin, is 8-fold less toxic to mice than the parent compound. At optimal doses, ruboxyl is more effective in experimental animal tumors and has no cardiotoxicity (Emanuel et al., 1982, 1992). After a successful phase II clinical trials (1991), its further study was interrupted due to financial problems.

Over the past 30 years, platinum complexes occupy leading positions among drugs for cancer chemotherapy. The antitumor activity of cisplatin (CP) was discovered in 1960s, and in 1978 it was approved for clinical use (Kelland, 2007). The subsequent search for improved cisplatin analogues resulted in introduction of carboplatin (1989) and oxaliplatin (2002) into clinical practice. About 15 other complexes, for various reasons, have been rejected in clinical trials. Currently, JM216 (satraplatin), picoplatin, and nanopolymer ProLindac, bearing the oxaliplatin moiety, are subject to clinical trials (Wheate et al., 2010) (Fig. 1).

**Figure 1.** Platinum anticancer drugs which are in clinical use and undergoing clinical trials.

Cisplatin and other bivalent platinum complexes are effective against a number of human tumors. They are used in almost half of the treatment regimes in combinations with other anticancer drugs (Wheate et al., 2010). Complexes of bivalent platinum are highly reactive and, therefore, they are highly toxic drugs. To avoid acute toxicity, cisplatin is administered by continuous infusion of a very dilute solution (Blokhin & Perevodchikova, 1984). Another disadvantage of cisplatin is a rapid development of tumor resistance to this drug (Koeberle et al., 2010).

Complexes of Pt(IV), being chemically more inert than Pt(II) complexes, are characterized by moderate toxicity, and are suitable for oral administration. Complexes like satraplatin can pass through the digestive tract where they are absorbed into the bloodstream. With the bloodstream they reach organs and tissues, interact with cellular targets, and thus provide an antitumor effect (Kelland, 1999). Complexes of Pt(IV) are prodrugs (drug precursors) that, after entering into the cell or on the way to it, are reduced to corresponding active Pt(II) derivatives causing cytotoxic effect. At the same time, Pt(IV) complexes are potent inhibitors of proliferation of tumor cells including those resistant to cisplatin. Recent advances in the study of anticancer platinum amino complexes are summarized in a number of reviews (Kelland, 2007; Wheate et al., 2010; Klein & Hambley, 2009; Koeberle et al., 2010; Bonetti et al., 2009).

This review focuses mainly on the authors' data on synthesis and studies of new highly active platinum compounds with low toxicity, *viz*, Pt(II) and Pt(IV) complexes with biologically active aminonitroxyl radicals. In addition to biological activity, the advantage of such compounds is their paramagnetism which gives an opportunity to use them as spin labels in the study of the mechanism of antitumor action. The work involved the synthesis of platinum-nitroxyl complexes (PNCs), studies of their structure, physico-chemical properties and interactions with the main target, DNA. Studies of cytotoxic properties of PNCs, their impact on cell cycle and cell death were carried out using *in vitro* cultured tumor cells. Studies of antitumor activity, development of the tumor resistance, and synergistic antitumor effects of combinations of new complexes with cisplatin were performed in animal model tumor leukemia P388.
