Metal-Ligand Exchange Kinetics in Platinum and Ruthenium Complexes SIGNIFICANCE for EFFECTIVENESS AS ANTICANCER DRUGS

DOI: 10.1595/147106708X255987 Metal-Ligand Exchange Kinetics in Platinum and Ruthenium Complexes SIGNIFICANCE FOR EFFECTIVENESS AS ANTICANCER DRUGS By Jan Reedijk Leiden Institute of Chemistry, PO Box 9502, 2300 RA, Leiden, The Netherlands; E-mail: [email protected] Metal coordination compounds with ‘slow’metal-ligand exchange rates, comparable to those of cell division processes, often appear to be highly active in killing cancer cell lines. This is particularly marked in platinum and ruthenium complexes. Classical examples such as cisplatin, as well as very recent examples from the author’s and other work, will be discussed in detail, and in the context of the current knowledge of the mechanism of antitumour action. It is shown that even though much is known about the molecular mechanism of action of cisplatin, many challenging questions are left for future research. For the ruthenium anticancer drugs molecular mechanistic studies are only at the beginning. Mechanistic studies on both platinum and ruthenium compounds have, however, opened many new avenues of research that may lead to the design of completely new drugs. Since the appearance of the early review on cis- O O diamminedichloridoplatinum(II), commonly known NH2 Pt as cisplatin, 1, in this Journal (1), and its early success- NH2 es in the treatment of a variety of tumours, the topics O O of metal-DNA binding and platinum antitumour 3 Oxaliplatin chemistry have attracted considerable interest from chemists, pharmacologists, biochemists, biologists action of cisplatin and related drugs. This knowledge and medical researchers (2). In fact cisplatin and the has clearly resulted in much improved clinical later compounds carboplatin, 2, and oxaliplatin, 3, administration protocols, as well as motivated enjoy the status of the world’s best-selling anticancer research on other, related drugs containing transition drugs. This interest has stimulated much interdis- metals, and their applications. ciplinary scientific activity, which has already yielded All chemotherapeutic drugs have drawbacks, quite detailed understanding of the mechanism of including intrinsic or acquired resistance, toxicity, and consequent side effects. Cisplatin is no excep- tion. Efforts to mitigate the drawbacks have Cl prompted chemists to synthesise a variety of ana- Cl Pt NH3 logues, but only a handful of new drugs have NH3 resulted that have been shown to be suitable for 1 Cisplatin clinical application. Improved understanding of the mechanism of action of cisplatin, resulting from the efforts of many research groups during the last two O decades, has rationalised the design of new platinum drugs, and drugs based on other metals such as O O O Pt NH3 ruthenium (3–7). Nevertheless, many mechanistic NH3 questions remain, especially for the drugs containing 2 Carboplatin metals other than platinum, and for the most recent derivatives of cisplatin (2, 8, 9). Platinum Metals Rev., 2008, 52, (1), 2–11 2 This overview will begin with a brief introduction (a) Coordination bonds (50 to 150 kJ mol–1) to the molecular, kinetic and thermodynamic details (b) Hydrogen bonds (20 to 60 kJ mol–1) of the coordination chemistry of medicinally relevant (c) Stacking of aromatic ring systems (10 to 40 metals, focusing on platinum, ruthenium and other kJ mol–1) noble metals that have been shown to possess (d) Metal–metal bonds (50 to 150 kJ mol–1) important biological properties. The metal–ligand (e) Other hydrophobic interactions (below 50 coordination bond appears to be particularly signifi- kJ mol–1) cant here. The bond is usually four to eight times (f) Ionic bonds, as in lattices such as NaCl, where weaker than a covalent bond, and there are large each Na+ ion is surrounded by six chloride ions; variations in ligand exchange kinetics for different these bonds dissociate upon dissolution in water metal-ligand pairs. This aspect will be introduced and may be compared in strength with coord- first, and will recur in later parts of the overview. ination bonds. The central part of the overview will briefly sum- Even though the bond strength values above are marise the state of the art in metal anticancer drugs merely indicative of an order of magnitude, they and the current mechanistic insights, not only for cis- clearly indicate that such bonds are weaker than clas- platin and related platinum drugs, but also for sical covalent bonds. These weak interactions play an non-platinum drugs and candidate drugs. important role, for instance in protein structures Finally, an account will be given of the design, (whether secondary, tertiary or quaternary), and in synthesis, structure and biological activities of new DNA structures (stacks within the helix, double bifunctional and multifunctional platinum, rutheni- helices). Many such bonds acting in concert, as in um and mixed-platinum group metal (pgm) Watson-Crick base pairing, or over the range of sev- compounds with bridging ligands, and their possible eral stacks along the DNA helix, may generate a development as anticancer drugs, or for other appli- rather strong interaction and hence a high thermo- cations. dynamic stability. In addition to the thermodynamic stability of Ligand Exchange Kinetics in molecules and aggregates, their kinetic stability must Coordination Compounds be considered. This parameter is far less discussed in To address such issues as structure, reactivity and the literature, and it was the late Professor Henry (in)stability in the chemistry of metal coordination Taube (Nobel Prize in Chemistry, 1983), who devel- compounds, detailed knowledge of their thermo- oped this field (11). He explained why some metal dynamics and kinetics is important, in addition to ions exchange their water ligands as much as four- proper knowledge of the geometric and electronic teen orders of magnitude faster than other metals, structures of the compounds. even when the M–OH2 bonds have the same ther- Most chemists and many other scientists are fully modynamic strength (e.g. 150 kJ mol–1). The conversant with classical covalent chemical bonds, explanation for these differences is related to the such as C–H, C–C, O–H and N–H. These single electronic and geometrical structures, and their bonds usually have a strength of some 250 to importance in the mechanism of action of cisplatin 500 kJ mol–1 (in older units: 60 to 120 kcal mol–1) and other metal compounds that interfere with cell- (10). Double bonds as in C=O and C=N, and triple division processes will be outlined. It has been bonds as in dinitrogen (N≡N), have strengths up to known for several decades that the ligand-exchange 500 and 800 kJ mol–1 respectively. processes of ions such as Mg(II), Ni(II), Ca(II), In addition to these covalent bonds, a large class Na(I), are very fast indeed (up to 109 sec–1), whereas of so-called non-covalent bonds is known. Here, the ligand-exchange processes of Pt(II), Pt(IV), much weaker interactions are found, the bonds are Ru(II), Os(II), Ir(III), Cr(III) are very slow; they may usually easily formed and broken, and so-called take hours (platinum, ruthenium) or even days supramolecular structures may be generated. (osmium, iridium) at ambient temperatures. Examples of such bonds are: In the early literature, the metal–ligand bond in Platinum Metals Rev., 2008, 52, (1) 3 cases of slow metal-ligand exchange was incorrectly anticancer activity (16), up to the most recent papers termed ‘covalent’, or ‘covalent-like’. A better classifi- on the discovery of new platinum compounds in the cation for such bonds is in fact ‘kinetically inert’. last decade. The focus will be on only the last few Most importantly, the ‘slow’ metal ions such as plat- years and on some of the results from the author’s inum and ruthenium, that exchange some of their laboratory, with appropriate references to excellent ligands within the range of one to two hours, show earlier published reviews in this field. After the early high anticancer activity; these ligand exchange rates review in this Journal by Eve Wiltshaw (1), many appear comparable to those of many cellular divi- highly informative reviews followed; those pub- sion processes (2). lished before 1999 are referenced in Lippert’s The mechanism of ligand exchange reactions excellent monograph (17). References (2), (8) and varies, depending on both the metal and the coordi- (18–22) are post-1998 reviews on platinum anti- nated ligand. Square-planar Pt(II) compounds cancer drugs, and deal mainly with cisplatin. They usually exchange their ligands via a so-called associ- are recommended for further reading. ative process, where the incoming ligand coordi- The basic three compounds in worldwide clinical nates as a fifth ligand, after which one of the original use at the time of writing (2007) are cisplatin, 1, car- ligands dissociates. Octahedral Ru(II) coordination boplatin, 2, and oxaliplatin, 3. The orally compounds, on the other hand, tend to lose a ligand administered drug, JM-216/satraplatin, 4, a Pt(IV) first (to generate a five-coordinate intermediate), compound which is reduced in vivo, is promising in after which the new ligand comes in. Details of terms of treatment regime, since it can be admin- ligand-exchange mechanism studies may be found in istered without hospitalisation. However, careful excellent overviews by Taube and Van Eldik control of the side effects requires frequent out- (12–14). patient visits (23–24). A recent overview of the A schematic presentation of ligand exchange commonly used drugs from a patent point of view is rates for a variety of metal-aqua complexes is depic- available (25). ted in Figure 1; the figure is based on early results published by Taube (11). OAc NH Cl History of Platinum Anticancer 3 Pt Drugs Cl C6H11NH2 The development of cisplatin will be discussed OAc briefly, from its serendipitous discovery by 4 Satraplatin Professor Barnett Rosenberg (15) and its reported Fig.

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