Platinum anticancer agents

Platinum anticancer agents

Despite the success of cisplatin, there is a need to develop new platinum anticancer drugs. Cisplatin is a very toxic compound and can have severe side effects such as nephrotoxicity (kidney poisoning), ototoxicity (loss of high-frequency hearing) and peripheral neuropathy (damage to nerves of the peripheral nervous system), although it is possible to control some of these effects. Very typically, cancer cells can become resistant to cisplatin after repeated administration. 

This is a fairly common problem experienced at the repeat treatment with cisplatin. Furthermore, compounds active against a variety of cancer types are required to combat cancer.

Two second-generation platinum drugs are so far successfully registered worldwide – carboplatin and oxaliplatin. There are others such as nedaplatin, which is registered in Japan for the treatment of head and neck, testicular, lung, cervical, ovarian and nonsmall-cell lung cancer. In South Korea, heptaplatin is used against gastric cancer, whereas lobaplatin is licensed in China for the treatment of cancers including metastatic breast cancer, small-cell lung cancer and myelogenous leukaemia .

Nevertheless, the development of new platinum-based drugs has been less successful than expected. The majority of compounds are not used in a clinical setting because their efficacy is too low, toxicity is too high or the compounds showed a poor aqueous solubility, a fairly common problem for transition-metal-based compounds.

1. Carboplatin

Carboplatin, cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II), is a second-generation platinum drug. Its structure is based on cisplatin with the difference that the chloride ligands are exchanged for a bidentate chelating ligand. A consequence is that carboplatin is less reactive than cisplatin and therefore is less nephro-toxic and orthotoxic than the parent compound. Unfortunately, it is more myelosuppressive than cisplatin, which reduces the patients’ white blood cell count and makes them susceptible to infections . Carboplatin was licensed by the FDA in 1989 under the brand name Paraplatin and has since then gained worldwide recognition. Carboplatin on its own or in combination with other anticancer agents is used in the treatment of a variety of cancer types including head and neck, ovarian, small-cell lung, testicular cancer and others  (Figure 7.29).

Carboplatin is a pale-white solid showing good aqueous solubility. The synthesis starts with potassium tetrachloroplatinate, which is reacted to the orange [PtI₄]²⁻ anion. Analogous to the synthesis of cisplatin, in the following steps the anion is reacted with ammonia (due to the translabellizing effect of iodide, the ammonia ligands are directed into the cis position) and converted to cis-[Pt(NH₃)(H₂O)₂]SO₄. In the final step, the complex is reacted with the chelating agent Ba(cbda) (cbdca, cyclobutane-1,1-dicarboxylate) and carboplatin is formed  (Figure 7.30).

Carboplatin is administered by intravenous (IV) injection. A typical solution contains the drug in a high concentration in water or in a mannitol or dextrose solution. The dose is determined either on the basis of the body surface area of the patient or according to their renal function. The doses are typically three to six times higher than cisplatin, which reflects the lower chemical reactivity and toxicity of this drug. Carboplatin can be given on an outpatient basis, as it is better tolerated than cisplatin.

The mode of action relies on the ring-opening of the cbdca chelate ring and interaction of the platinum centre with DNA. Carboplatin is seen as a prodrug, which itself is not very reactive within the human body but once activated shows its full potential. Hydrolysis of carboplatin and removal of the chelate ligand or at least the opening of the ring makes this compound much more cytotoxic than the parent compound itself (Figure 7.31).

In vitro studies have shown that the drug binds to DNA and forms initially a mono-functional adduct, which over time is converted into the di-functional platinum–DNA adduct. There are indications that carboplatin forms DNA intrastrand cross-links analogous to cisplatin, but its reactivity towards DNA is reduced .

2. Oxaliplatin

Oxaliplatin (cis-[oxalato] trans-1,2-diaminocyclohexane platinum(II)), for example, marketed under the trade name Eloxatin, is considered as a third-generation platinum-based anticancer drug. Its structure differs from previously synthesised platinum compounds by the configuration of its amino substituents. Its platinum centre is coordinated by two chelating ligands, namely an oxalate ligand and a so-called DACH (1,2-diaminocyclohexane) ligand. In comparison to cisplatin, the two chlorine leaving groups are replaced by an oxalato leaving group. The simple amino groups are replaced by the DACH ligand, which is the nonleaving group (Figure 7.32).

Cisplatin and carboplatin are hydrolysed to a common diamino-platinum species, whereas the hydrolysis product of oxaliplatin contains the bulky DACH group, which sterically hinders the DNA repair mechanism. These mismatch repair enzymes are particularly active in colon cancer and, not surprisingly, oxaliplatin shows excellent activity in the treatment of colon and rectal cancers  (Figure 7.33).

The clinical use of oxaliplatin was approved by the European Union in 1999 and by the FDA in 2002. It is most effective in combination with 5-fluorouracil and leucovorin (5-FU/LV) in the treatment of metastatic carcinomas of the colon or rectum . Oxaliplatin induces less side effects than cisplatin; for example, it is less nephrotoxic and ototoxic and leads to less myelosuppression. Unfortunately, treatment with oxaliplatin can lead to nerve damage, which may not be reversible in the case of chronic exposure of the patient to the drug. Oxaliplatin is usually administered intravenously as infusion over a period of 2–6 h in doses similar to cisplatin. The neurotoxic side effects are dose-limiting .

The synthesis of oxaliplatin starts with K₂[PtCl₄], the same starting material used for the synthesis of carboplatin. This is reacted with water and 1 equiv of the nonleaving ligand, 1R,2R-DACH ligand. 

Note that there are different stereoisomers of the DACH ligand, and cytotoxicity studies have shown that the use of this specific stereoisomer 1R,2R-DACH leads to the most potent compound. Upon treatment with silver nitrate, the diaqua complex is formed. Any excess of silver ions can be removed by adding potassium iodide. This leads to the formation of the insoluble silver iodide, which can be filtered off. The diaquo platinum complex is subsequently treated with 1 equiv of oxalic acid, and oxaliplatin is formed as a solid (Figure 7.34).

It is believed that DNA is the major cellular target of oxaliplatin, as researchers have shown that it forms intrastrand cross-links similar to cisplatin. The oxaliplatin–DNA adduct also leads to a bending of the DNA similar to the cisplatin–DNA adduct. Nevertheless, there are significant differences to the cisplatin–DNA adduct. The oxaliplatin–DNA adduct forces a narrow minor groove bend (helix bend of 31^∘), whereas the equivalent cisplatin–DNA adduct leads to a wide minor groove (60–80^∘). Also, it has been observed in the solid state structure of the oxaliplatin–DNA adduct that there is a hydrogen bond formed between the NH of the DACH group and the oxygen atom of guanine base, which interacts with the platinum centre .

3. Other platinum drug candidates

There are numerous platinum compounds under research for their potential use as anticancer agents. Only a few of them have found their way into the clinic so far, with cisplatin, carboplatin and oxaliplatin being the most successful ones.

One example is nedaplatin, cis-diammineglycolatoplatinum(II), which is structurally similar to carboplatin. The chemical structure consists of a central platinum(II) atom with two cis-ammonia groups as nonleaving groups and – in contrast to carboplatin – the dianionic form of glycolic acid as the leaving group. Nedaplatin has been approved for the clinical use in the Japanese market for the treatment of head and neck, testicular, ovarian, lung and cervical cancer. It is typically administered by IV injection and its dose-limiting side effect is myelosuppression (Figure 7.35).

Lobaplatin and heptaplatin are further examples of platinum-based agents being used in China and South Korea, respectively. Lobaplatin is used in the treatment of nonsmall-cell lung cancer and breast cancer. Hep-taplatin is used in South Korea to treat gastric cancer. Both drugs show the typical side effects such as myelosuppression and mild hepatotoxicity. Their success is limited and has not led to approval in the EU or by the FDA (Figure 7.36).

Satraplatin (JM216, cis,trans,cis-[PtCl₂(OAc)₂(NH₃)(C₆H₅NH₂)]) is a Pt(IV) or Pt⁴⁺ complex, which is active by oral administration, as it is more hydrophobic than cisplatin. This form of administration is very attractive because of the convenience and freedom it provides to the patient. Satraplatin also has a milder tox-icity profile and is shows no cross-resistance with cisplatin. Satraplatin in combination with prednisone has completed phase III clinical trials against hormone-refractory prostate cancer. The results were very encour-aging, but the overall survival rate did not improve significantly enough. As a result, the fast-track approval of the FDA was not granted  (Figure 7.37).

Structurally, satraplatin consists of a Pt(IV) centre, which is coordinated by six ligands forming a close to octahedral geometry. In general, octahedral Pt(IV) complexes (low-spin d⁶) are much more kinetically inert than square planar Pt(II) complexes. Pt(IV) complexes can be readily reduced in vivo to Pt(II) by reductants such as ascorbate or thiols (e.g. cysteine, GSH).

The synthesis of satraplatin starts with cisplatin, which is reacted with tetraethylammonium chloride (Et₄NCl) – a source of Cl⁻. As a result of the trans-directing effect, the iodide ligand is introduced in a second step adjacent to the ammonia group. Subsequently, 1 equiv of cyclohexylamine is added, which coordinates to the platinum centre trans to the iodide. Silver nitrate is used to remove the iodide ligand, as no further ‘trans-directing’ action is required. The Pt²⁺ is finally oxidised to Pt⁴⁺, which expands the coordination sphere from 4 to 6 – octahedral geometry. In the last step, the acetate ligands are introduced (Figure 7.38).

Satraplatin is the only orally administered platinum-based drug that has entered clinical trials so far. The difficulty for this administration route lies in the aggressive conditions that are present in the stomach. In general, metal complexes do not survive the acidic conditions in the stomach and therefore will not reach the gastrointestinal (GI) tract unchanged. The advantage of satraplatin is that the complex is relatively inert to any exchange reactions and therefore has an increased chance of reaching the pH-neutral GI tract unchanged. From here, the drug enters the blood stream. In vitro studies with fresh human blood have shown that within minutes the reduction of the platinum centre to Pt²⁺ takes place in the red blood cells. This may be facilitated by haemoglobin, cytochrome c and NADH, and leads to a square planar Pt²⁺ complex containing the chloride and ammonia ligands .

Further research has led to the development of multi-platinum complexes. This is against the ‘rules’ set out for platinum-based anticancer drugs, which state that a successful drug candidate should consist of only one platinum centre with amine-based nonleaving groups in cis position and two leaving groups, also in cis position. Clearly, polynuclear platinum compounds fall outside these rules, but researchers have synthesised the unusual trinuclear complex BBR3464, which was very successful in in vitro studies and even reached clinical trials against melanoma and metastatic lung and pancreatic cancer  (Figure 7.39).