Citation
Zutphen, Svan. (2005, October 17). Targeting Platinum Compounds: synthesis and
biological activity. Retrieved from https://hdl.handle.net/1887/3495
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in theInstitutional Repository of the University of Leiden Downloaded from: https://hdl.handle.net/1887/3495
1
General introduction
Abstract - A general introduction to the use of platinum drugs in medicinal chemistry is
1.1 CANCER
During the life of a healthy species tissue is constantly regenerated through cell death and cell division. It is essential for survival that a delicate balance between the two is kept. Damage of the genetic material can disrupt this balance which may give rise to abnormal growths [1]. The occurrence of such tissue with damaged DNA is very common and normally poses no threat to the species. In very few cases, however, the tissue develops into a lethal tumour or cancer [2]. Nowadays cancer is the second-leading cause of death in the Western world. Efficient treatment of the disease is therefore of major importance. Unfortunately cancer is a very heterogeneous and complex disease. While use of surgery and radiotherapy can result in a cure in 40% of all cancer patients, the remaining 60% of patients may still die as a result of metastasis [3]. At this stage the disease is of systemic nature, requiring a systemic treatment, such as chemotherapy. For a number of diseases chemotherapy has a huge curative potential, in spite of extensive metastatic spreading [4,5]. Furthermore, chemotherapy can relieve patients whose disease has developed to a stage at which it can no longer be cured. Today, improving on existing chemotherapy is essential to both increase the spectrum of tumours that can be cured and to increase the quality of life of patients undergoing treatment.
1.2 THE DISCOVERY OF CISPLATIN
During an experiment to investigate the effect of electric fields on the growth of E. coli bacteria Barnett Rosenberg observed strong filamentous growth, and arrest of cell division [6,7]. After rigorous equipment checks and further testing, the effect was ascribed to traces of platinum compounds formed by slow reaction of the platinum electrodes with the NH4Cl
discovery, a number of platinum complexes were synthesised and their antitumour activity was evaluated. It was then found that in particular cis-[Pt(NH3)2Cl2] or cisplatin
(1, Figure 1.1), possesses antitumour activity.
H3N Pt Cl
Cl NH3
Figure 1.1: Structural formula of cisplatin (1).
This discovery spurred the development of a whole new class of cytotoxic agents. Cisplatin entered clinical trials in 1971 and was approved by the FDA in 1978 [8]. It has since developed to be one of the most widely used drugs in cancer chemotherapy. The platinum drugs (cisplatin, carboplatin and oxaliplatin, section 1.4) are frequently used in combination therapy for numerous solid tumours, including ovarian, head and neck, testicular, bladder, colorectal, gastric, melanoma and small-cell lung cancer [9]. For testicular cancer, curing rates exceeding 95% are attained with cisplatin. Annual sales of the platinum drugs are in excess of €1 billion [10].
Systemic toxicity of cisplatin gives rise to a number of limitations. Dose-limiting side-effects include nausea, vomiting, as well as oto-, neuro- and nephrotoxicity [11]. Furthermore drug resistance, both intrinsic and acquired, obstructs the treatment of a great number of malignancies and makes second-line treatment problematic [9]. Research has therefore focussed on finding alternative platinum complexes that overcome these limitations.
1.3 MECHANISM OF ACTION OF PLATINUM ANTICANCER DRUGS
with other nucleophiles present inside the cell, leading to the many side-effects of the drug and the development of drug resistance [16]. Ultimately, all the platinum re-enters the blood stream and is filtered out by the kidneys and the bile.
1.4 DEVELOPMENT OF CISPLATIN ANALOGUES
Drug discovery based on the optimisation of a lead compound can be approached in two distinct ways. Using available knowledge concerning the mode of action of a drug, modifications can be made that should theoretically improve the effectiveness of the drug. Such a rational approach is most effective when detailed knowledge about drug/target interaction is available [17]. Alternatively modifications can be made randomly yielding rather different compounds with a large variability of properties [18]. In this kind of approach large numbers of compounds may need to be synthesised and combinatorial chemistry involving parallel synthesis and high throughput screening can be employed. In platinum anticancer research both the rational and the random approach have led to a number of clinically useful drugs.
When the search for derivatives of cisplatin with improved selectivity started, a large number of cisplatin analogues were synthesised and studied, leading to the identification of several structure-activity relationships (SAR). These state that, firstly, antibacterial activity and antitumour activity are not directly related, ruling out the use of a simple bacteriocidal assay for the evaluation of this class of compounds. Secondly, to allow for entry into the cell, it was found that complexes need to be neutral. Thirdly, it was deduced that the complexes must possess two leaving groups in cis geometry. At first the optimum lability was sought after, however, although complexes with Cl- or Br- mostly gave good activity, active compounds having both more stable or more labile leaving groups were soon discovered. The geometry of the leaving groups was postulated to be more essential. Although complexes with ligands in
trans position may exhibit comparable toxicity to their cis isomers, they were invariably
found to be without antitumour activity. The opposing two ligands were also found to play an important role. Amines with at least one N-H functionality as opposed to oxygen or sulfur were found to yield the more active compounds. Lastly, platinum was found to be the most active metal compared to the corresponding complexes of other metals such as palladium [19,20].
side-effects [21]. This behaviour is attained by replacement of the chloride leaving groups by a more inert didentate carboxylate leaving group. Nedaplatin (Shionogi & Co. Ltd., 3, Figure 1.2) is similar to carboplatin and has been used in Japan since 1994 [22]. Both drugs, however, display cross-resistance with cisplatin. Oxaliplatin (Eloxatin - Sanofi-Synthelabo, 4, Figure 1.2) with both the leaving groups and the amine ligands changed compared to cisplatin, has a different activity spectrum and circumvents cisplatin resistance [23]. As a result it has been approved for secondary treatment of metastatic colorectal cancers [24].
2 3 4 H3N Pt O NH3 O O O H3N Pt O NH3 O O H2N Pt O NH2 O O O
Figure 1.2: Cisplatin analogues used in the clinic: carboplatin (2), nedaplatin (3) and oxaliplatin (4).
ZD0473 (5, Figure 1.3) is another classical cisplatin analogue. The sterically demanding pyridine ligand acts to decrease the compound’s reactivity towards thiol-containing nucleophiles, hence reducing toxic side effects [25,26]. Compounds with a very different appearance are the polynuclear platinum complexes with an azole and a hydroxo-bridging ligand (6, Figure 1.3) [27]. These rationally designed compounds mimic the platinum-GdG DNA crosslink that is most commonly formed by cisplatin, without introducing the DNA ‘kink’ typical for cisplatin [28]. As a result the complexes trigger apoptosis, whilst evading cisplatin resistance mechanisms based on DNA repair.
N N Pt Pt H3N H3N NH3 NH3 O H N Pt Cl NH3 Cl 5 6 2+
Figure 1.3: Rationally designed cisplatin analogues: sterically hindered platinum(II) complex ZD0473
(5), and pyrazolato-bridged dinuclear platinum(II) complex (6).
charged. Both classes of compounds do, however, display high cytotoxicity, both in cisplatin sensitive and cisplatin resistant cell-lines. This may be because the interaction of these compounds with cellular DNA cannot be the same as cisplatin and direct structural analogues. Resistance mechanisms based on DNA-damage recognition and repair can therefore be evaded. In addition the positive charge carried by the polynuclear compounds, and their structural resemblance to polyamines, such as spermidine and spermine, may result in different uptake mechanisms. This behaviour can contribute to the overcoming of numerous other resistance mechanisms as discussed in section 1.5. Although none of these compounds have as yet been approved for clinical use, several are undergoing clinical trials [29-31].
N Pt Cl Cl N 8 Cl Pt NH3 NH3 NH2 H2N Pt NH3 NH3 NH2 Pt Cl NH3 NH3 H2N (CH2)6 4+ 7 (CH2)6
Figure 1.4: Trinuclear platinum(II) complex BBR-3464 (7) and active trans complex trans-[PtCl2(py)2] (8).
1.5 UPTAKE AND TARGETING OF PLATINUM DRUGS
Until recently, relatively little was known about cisplatin uptake. This has led to the general consensus that cisplatin enters the cell through passive diffusion as a neutral molecule, although the involvement of an active uptake mechanism was suspected [35]. More recent studies towards the resistance against cisplatin have shed new light on the uptake and efflux of cisplatin [36]. Using gene-knockout techniques in yeast, several genes involved in cisplatin resistance were elucidated, one of which is the yeast MAC1 gene, the human homologue of which is CTR1, encoding for a high-affinity copper transporter. Although resistance can be dependent on many other factors, the impaired accumulation of drug is the single most commonly observed alteration in cisplatin resistant cells compared to the sensitive cells from which they are derived. Additionally cells with acquired cisplatin resistance exhibit cross-resistance to a wide variety of metals including copper [37-39]. Regulation of the copper transport mechanism may therefore lead to an improved response to platinum chemotherapy. Alternatively cisplatin analogues targeted towards other active transport mechanisms may give rise to improved therapies that overcome cisplatin resistance.
Targeting of platinum drugs is commonly considered as an effective means of reducing toxic side-effects and increasing drug response. It can be achieved by appending low-molecular weight functional ligands to the drugs, through liposomal-drug formulation, or through the formation of platinum containing polymer-like compounds. These different strategies will be discussed in full detail in Chapter 2.
1.6 ALTERNATIVE TARGETS FOR PLATINUM COMPOUNDS
as ribonucleotide reductase and adenylate cyclase [45]. For cancer therapy these may therefore present attractive (secondary) targets. A different approach is considered in Chapter 6, where the ability of several platinum complexes to inhibit thiol-containing proteases is investigated. Here the aim is to develop a new class of inhibitors, using platinum as an electrophilic unit capable of binding the active site of the target enzymes. Such compounds may ultimately be used to treat a variety of pathological conditions, including rheumatoid arthritis, neurological disorders and even cancer [46]. For these compounds nuclear DNA clearly is no longer a target.
1.7 AIM AND SCOPE OF THIS THESIS
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