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