Tuning Reactivity of Platinum(II) Complexes
Tuning Reactivity of Platinum(II) Complexes Tuning Reactivity of Platinum(II) Complexes
H 3N OH 2 Pt H 3N OH 2 Active Pt(II) species Figure 1.4: DNA-adduct formation with cisplatin leaving two amino groups coordinated on the platinum atom. The main adducts formed in the interaction cisplatin with DNA: (a) interstrand cross-link; (b) 1,2-intrastrand cross-link; (c) 1,3-intrastrand cross-link and; (d) protein-DNA cross-link. 35 Approximately 90% of cisplatin-DNA adducts are 1,2 intrastrand cross-links, 65% of which are two adjacent N7 guanine-N7 guanine sites, while 25% are two adjacent N7 guanine-N7 adenine sites. 36 The N7 atoms of guanine and adenine are the most accessible and reactive nucleophilic sites of platinum to the DNA, and are located in the major groove of the double helix. 37 The larger amount of 1,2-intrastrand adducts are attributed to: • The shortest distance existing between the two N7 atoms of guanine and the ability of the NH groups of cisplatin being involved in intramolecular hydrogen bonding interactions with guanine–O6 atom. 38 • Guanine is the most nucleophilic base with a decreasing order of reactivity: guanine–N7 >> adenine–N7 > cytosine–N3. 39 • The N7 atom of the guanine base is the most electronegative (more electron dense) and more “exposed site” than the corresponding N7 atom of the adenine, which results in the former acting as a stronger ligand towards Pt(II) than the latter. N Minor groove C H N O N Major groove H H O H As a consequence, the guanine N7 atom can replace a thioethereal sulphur atom bonded to platinum, whereas that of adenine cannot. 40 The remaining adducts comprise of interstrand cross-links and monofunctional cisplatin adducts. 7 41 N N Guanine N7 position G H N N N
Coordination of the platinum complex to DNA distorts the normal double helix structure resulting in a significant bending of about 40° away from the site of attachment. 42 This propagates steric constraints that lead to a loss in helix stability. The kink in the DNA structure is recognized by repair cellular proteins like the high mobility group (HMG) proteins (i.e. an 80 amino acid sequence found in many proteins that bend DNA significantly) 43 These may successfully repair the damaged DNA by cutting out platinum–adducts and re-synthesise at the open sites, or fail to repair and thereby block DNA replication and transcription, ultimately inducing cell death by apoptosis (“programmed cell death”). 44 This results in high rate of DNA repairs or higher tolerance to Pt-DNA adducts which can be one of the factors of drug resistance arising in the cause of treatment. 1.3.2.5 Cisplatin Resistance Experimental evidence indicates that resistance may occur at any of the following three levels (Figure 1.5): 45,46 (a) decreased accumulation of platinum compounds due to either reduced influx or enhanced efflux at the plasma membrane; This reduced intake of the drug decreases the amount reaching the intracellular target, the DNA, due to changes in membrane properties and may result in intrinsic resistance; (b) detoxification of platinum compounds by S-donor reductants such as glutathione and methallothioneins; and (c) removal from DNA by evasion of apoptosis or high rate of DNA repairs. 47,48 1.3.2.6 Competition between N– and S–Donor Nucleophiles Pt is a 5d transition metal, which forms strong covalent bonds with N and S donor ligands. From the hard-soft acid-base theory (HSAB), S-donor biomolecules would readily bind to the soft Pt(II) centre 25,49 and generate stable platinum complexes. The formation of the Pt-S adducts is more preferred pathway kinetically since the reactions with S-donors are fast, while binding to the nucleobases (N-donors) occurs very slowly and is thermodynamically more stable under physiological conditions. 50 The interaction of cisplatin with sulphur-containing enzymes is thought to be involved in the resistance of cells to cisplatin. This is closely related to the drug’s bio- 8
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Coordination <strong>of</strong> the platinum complex to DNA distorts the normal double helix structure<br />
resulting in a significant bending <strong>of</strong> about 40° away from the site <strong>of</strong> attachment. 42 This<br />
propagates steric constraints that lead to a loss in helix stability. The kink in the DNA<br />
structure is recognized by repair cellular proteins like the high mobility group (HMG)<br />
proteins (i.e. an 80 amino acid sequence found in many proteins that bend DNA<br />
significantly) 43 These may successfully repair the damaged DNA by cutting out<br />
platinum–adducts and re-synthesise at the open sites, or fail to repair and thereby block<br />
DNA replication and transcription, ultimately inducing cell death by apoptosis<br />
(“programmed cell death”). 44 This results in high rate <strong>of</strong> DNA repairs or higher<br />
tolerance to Pt-DNA adducts which can be one <strong>of</strong> the factors <strong>of</strong> drug resistance arising in<br />
the cause <strong>of</strong> treatment.<br />
1.3.2.5 Cisplatin Resistance<br />
Experimental evidence indicates that resistance may occur at any <strong>of</strong> the following three<br />
levels (Figure 1.5): 45,46 (a) decreased accumulation <strong>of</strong> platinum compounds due to<br />
either reduced influx or enhanced efflux at the plasma membrane; This reduced intake<br />
<strong>of</strong> the drug decreases the amount reaching the intracellular target, the DNA, due to<br />
changes in membrane properties and may result in intrinsic resistance; (b)<br />
detoxification <strong>of</strong> platinum compounds by S-donor reductants such as glutathione and<br />
methallothioneins; and (c) removal from DNA by evasion <strong>of</strong> apoptosis or high rate <strong>of</strong><br />
DNA repairs. 47,48<br />
1.3.2.6 Competition between N– and S–Donor Nucleophiles<br />
Pt is a 5d transition metal, which forms strong covalent bonds with N and S donor<br />
ligands. From the hard-s<strong>of</strong>t acid-base theory (HSAB), S-donor biomolecules would<br />
readily bind to the s<strong>of</strong>t Pt(<strong>II</strong>) centre 25,49 and generate stable platinum complexes. The<br />
formation <strong>of</strong> the Pt-S adducts is more preferred pathway kinetically since the reactions<br />
with S-donors are fast, while binding to the nucleobases (N-donors) occurs very slowly<br />
and is thermodynamically more stable under physiological conditions. 50<br />
The interaction <strong>of</strong> cisplatin with sulphur-containing enzymes is thought to be involved<br />
in the resistance <strong>of</strong> cells to cisplatin. This is closely related to the drug’s bio-<br />
8
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