Chapter 1: NAMI-A. Introduction
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Introduction Chapter 1 Chapter 1: NAMI-A. Introduction The success of cisplatin [cis-diamminedichloroplatinum (II)] as an anticancer agent has stimulated the search for cytotoxic compounds with more acceptable toxicity profiles, but retention, and if possible expansion, of activity. This has generated interest in molecules containing other heavy metals of Groups 8, 9, and 10 (formerly known as Group VIII) of the periodic table, which have similar properties to platinum. These metals may differ in oxidation state, ligand affinity, and substitution kinetics. Because of their variation in chemical characteristics, the mode of action and spectrum of activity of these compounds can differ significantly from cisplatin [1-3]. Although some elements have proven to be very useful as drugs to cure or diagnose diseases (reviewed in [4]), in general heavy metals and their complexes are well renowned for their toxic effects. They bind to sulfur and nitrogen sites on proteins and thereby interfere with many biochemical pathways [3]. Acute heavy metal poisoning results in severe gastrointestinal symptoms, particularly nausea, vomiting, diarrhea and abdominal pain. The kidney is frequently affected by heavy metals, as they accumulate in renal tubular fluid and are capable of disturbing renal metabolic processes. Chronic low level exposure to heavy metals causes neuromuscular injury, particularly peripheral neurotoxicity, cerebellar disturbance, myalgia, and lassitude [2]. This type of toxicity is observed with the use of platinum anticancer agents and, most likely, other heavy metals investigated for their antitumor properties will not differ in this respect. Group 8, 9 and 10 heavy metals The transition elements, to which the Group 8, 9 and 10 metals belong, show typical chemical behavior that is not shared by the main-group elements. All are metals with partly filled d or f subshells that conduct heat and electricity well, with very few exceptions they exhibit variable valence, and their ions and compounds are colored in most oxidation states. Because of their partly filled subshells, they form complexes easily, and bonding is usually of a more ionic than covalent nature [5]. Groups 8, 9 and 10 are composed of iron, cobalt and nickel in the first transition series, in which the 3d subshell is partly filled. Ruthenium, rhodium and palladium make up the second 19 Introduction Chapter 1 transition series, in which the 4d subshell is partly filled, and osmium, iridium and platinum form the third transition series, with a partly filled 5d subshell (Figure 1). Especially the extended 4d and 5d orbitals give rise to good complex-forming abilities, often strengthened by π-bond formation (back-donation). Therefore, Groups 8, 9 and 10 are subdivided into the iron group (first transition series) and the platinum group (second and third transition series) [5]. As the metals of Groups 8, 9 and 10 have many different valences and form complexes easily, a multitude of compounds can be synthesized with a wide variety of ligands. Thus far, several new compounds have been proven active in vitro against different types of tumor cell lines and can thus be marked as potential new anticancer agents. Among them, ruthenium complexes seem very promising. 26 27 28 Fe Co Ni 55.8 58.9 58.7 44 45 46 Ru Rh Pd 101.1 102.9 106.4 76 77 78 Os Ir Pt 190.2 192.2 195.1 Figure 1. Groups 8, 9 and 10 of the periodic table of elements. Ruthenium A wide range of ruthenium agents has been synthesized and tested for their antitumor properties in the past 30 years. Most of these agents, independent of the ligands attached to the ruthenium ion, have shown relatively low cytotoxicity and are less toxic than cisplatin, correspondingly requiring a higher therapeutic dose [6,7]. Extensive binding to many cellular and extracellular components may account for this fact [7]. Despite their low cytotoxic potential, many ruthenium complexes increase the lifetime expectancy in tumor-bearing hosts [7]. Ruthenium(III) complexes likely remain in their (relatively inactive and unreactive) Ru(III) oxidation state until they reach the tumor site. In this environment, with its lower oxygen 20 Introduction Chapter 1 content and pH than healthy tissue, reduction to the more reactive Ru(II) oxidation state takes place. In this manner (termed “activation by reduction”), ruthenium(III) compounds may provide selective toxicity [3,6,7]. However, to be active in vivo, the complexes must have a biologically accessible reduction potential, which can vary considerably with the ligands present [6]. A second mechanism that could explain the observed antitumor activity is the high affinity of ruthenium(III) for the transferrin iron-binding sites. This binding capacity provides a possibility to target ruthenium(III) complexes to tumors with high transferrin receptor densities [3,6,7]. A large number of ruthenium complexes (both in the II and III oxidation states) with in vitro antitumor activity have been synthesized. The interested reader is referred to references 1, 3, 7, and 8 for reviews on the different cytotoxic ruthenium compounds. The only ruthenium anticancer agent that has entered clinical trials thus far is imidazolium trans-tetrachloro (dimethylsulfoxide)imidazoleruthenium(III), or NAMI-A. This chapter describes its pharmaceutical development. References 1. Pieper T, Borsky K, Keppler BK. Non-platinum antitumor compounds. In: Clarke MJ, Sadler PJ (Eds), Biological Inorganic Chemistry, Vol 1, 1999. Springer-Verlag, Berlin, Germany. 2. McKeage MJ. Comparative adverse effect profiles of platinum drugs. Drug Safety 1995; 13: 228-244. 3. Clarke MJ, Zhu F, Frasca DR. Non-platinum chemotherapeutic metallopharmaceuticals. Chem. Rev. 1999; 99: 2511-2533. 4. Reedijk J. Medicinal applications of heavy-metal compounds. Curr.Opin.Chem.Biol. 1999; 3: 236-240. 5. Cotton FA, Wilkinson G, Murillo CA, Bochman M. Advanced Inorganic Chemistry, 6th edition, 1999. John Wiley & Sons, Inc., New York. 6. Clarke MJ, Galang RD, Rodriguez VM, Kumer R, Pev S, Bryan DM. Chemical considerations in the design of ruthenium anticancer agents, in Metal complexes in cancer chemotherapy. Keppler BK (Ed), VCH, Weinheim, Germany, 1993. p. 582-600. 7. Sava G, Bergamo A. Ruthenium-based compounds and tumour growth control (review). Int. J. Oncol. 2000; 17: 353-365. 8. Köpf-Maier P. Complexes of metals other than platinum as antitumour agents. Eur. J. Clin. Pharm. 1994; 47: 1-13. 21.