Tuning Reactivity of Platinum(II) Complexes
Tuning Reactivity of Platinum(II) Complexes Tuning Reactivity of Platinum(II) Complexes
toxic potential. The most well-known chemistry of platinum is in the oxidation states of 0, +2 and +4. 15 The higher oxidation states, +5 and +6 exist as fluorides and fluoro- complexes, but are quite rare due to their lower stability. 15,16 The Pt(II) and Pt(IV) metal centres are positively charged and therefore , more favoured to bind negatively charged biomolecules such as proteins, nucleic acids and enzymes. The major boost into the Pt(II) chemistry occurred in the 1950s when chemists started to systematically investigate inorganic reaction mechanisms. Substitutions reactions at the square-planar sites were dominated by Pt(II) complexes due to their higher redox stability and moderately slower reactivity. 15,17–20 Also, studies in the early 1960’s by Rosenberg et al. indicated that both bivalent Pt(II) and tetravalent Pt(IV) complexes exhibited antitumor activity. 21 The most well-known of the Pt(II) compounds is [cis- PtCl2(NH3)2] (cisplatin in Figure 1.2). In addition, Pt(II) prefers amine ligands, halogens, sulphides (e.g. R2S) and π-acceptor ligands such as CN¯, C2H4, CO and tertiary phosphines. It has modest affinity for hard bases like F¯ and oxygen ligands since the Pt(II) centre is a soft acid. It can react with bidentate ligands N–N, P–P, S–S, N–O, N–S and N–P to form mononuclear as well as bridged-dinuclear chelate complexes. 22 Its reaction with tridentate ligands such as N– N–N, N–P–N, N–C–N and N–S–N gives mononuclear four-coordinate square-planar complexes. The tetradentate ligands like As–As–As–As and P–P–P–P yield mainly five- coordinate complexes because the higher π-acceptor ability of the As- and P-based ligands stabilises the 18e trigonal–bipyramidal geometry. 1.3.1 Platinum-Based Anticancer Drugs Cisplatin and oxaliplatin [oxalato-1,2-diaminocyclohexaneplatinum(II)]; and satraplatin [(OC-6-43)-bis(acetato(aminedichloro)cyclohexylamine)platinum(IV)] and LA-12 [(OC- 6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)] (Figure 1.2) respectively are, some examples of Pt(II) and Pt(IV) complexes that are in use as anticancer drugs. In particular, Pt(II) complexes are suitable as antitumour agents because these compounds exhibit metal-ligand exchange kinetics in the same order of magnitude as the division of the cancerous cells, which makes them fit to suppress mitosis processes. 23 In addition, Pt(II) has the potential to form thermodynamically 3
stable bonds with N-donor ligands in the DNA helix, thus preventing DNA replication and promoting cell death. Figure 1.2: Chemical structures of selected platinum compounds 1.3.2 Cisplatin Cisplatin is a very effective, but highly toxic antitumor drug. Its clinical use was initiated in the early 1970s, and is one of the most widely employed anticancer agents, useful in ovarian, testicular, small cell lung, and other cancers. 24 It is a square-planar complex, containing two labile chlorines and two relatively inert ammonia molecules coordinated to the central Pt(II) atom in a cis configuration (Figure 1.1). 1.3.2.1 Mechanism of Action The mode of action of cisplatin and other Pt(II) complexes includes hydrolysis in the first step (Scheme 1.1) followed by preferential binding to the guanine N7 atom of DNA. 25 But the exact mechanism is not yet fully understood. The first two reactions to consider are sequential hydrolysis of the two chloro ligands to yield the chloro–aqua and diaqua complexes as illustrated in Scheme 1.1. H 3 N H 3 N Pt Cisplatin Cl Cl Cl - H 2 O H 3 N H 3 N Pt OH 2 Cl Pt(NH 3 ) 2 Cl(H 2 O) + 4 Cl - + H3N Pt OH2 2+ H2O H3N OH2 Scheme 1.1: Sequential hydrolysis of the cisplatin in the cytoplasm. 2+ Pt(NH3 ) 2 (H2O) 2
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stable bonds with N-donor ligands in the DNA helix, thus preventing DNA replication<br />
and promoting cell death.<br />
Figure 1.2: Chemical structures <strong>of</strong> selected platinum compounds<br />
1.3.2 Cisplatin<br />
Cisplatin is a very effective, but highly toxic antitumor drug. Its clinical use was initiated<br />
in the early 1970s, and is one <strong>of</strong> the most widely employed anticancer agents, useful in<br />
ovarian, testicular, small cell lung, and other cancers. 24 It is a square-planar complex,<br />
containing two labile chlorines and two relatively inert ammonia molecules coordinated<br />
to the central Pt(<strong>II</strong>) atom in a cis configuration (Figure 1.1).<br />
1.3.2.1 Mechanism <strong>of</strong> Action<br />
The mode <strong>of</strong> action <strong>of</strong> cisplatin and other Pt(<strong>II</strong>) complexes includes hydrolysis in the<br />
first step (Scheme 1.1) followed by preferential binding to the guanine N7 atom <strong>of</strong><br />
DNA. 25 But the exact mechanism is not yet fully understood. The first two reactions to<br />
consider are sequential hydrolysis <strong>of</strong> the two chloro ligands to yield the chloro–aqua<br />
and diaqua complexes as illustrated in Scheme 1.1.<br />
H 3 N<br />
H 3 N<br />
Pt<br />
Cisplatin<br />
Cl<br />
Cl<br />
Cl -<br />
H 2 O<br />
H 3 N<br />
H 3 N<br />
Pt<br />
OH 2<br />
Cl<br />
Pt(NH 3 ) 2 Cl(H 2 O) +<br />
4<br />
Cl -<br />
+<br />
H3N Pt<br />
OH2 2+<br />
H2O H3N OH2 Scheme 1.1: Sequential hydrolysis <strong>of</strong> the cisplatin in the cytoplasm.<br />
2+<br />
Pt(NH3 ) 2 (H2O) 2
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