Tuning Reactivity of Platinum(II) Complexes

The mononuclear Pt(II) complexes 1-3 (Figure 2.1) do not adhere to the Cleare and
Hoeschele structure-activity relationship principle. 9,10 Nevertheless, they exhibit
cytotoxicity against tumour cell lines comparable to cisplatin. 11,12 Variations in their
cytotoxic activity are related to the differences in lipophilicity of these complexes. The
most lipophilic complex (1) is also the most cytotoxic, 11 since its higher lipophilicity can
facilitate improved passive uptake rates of the drug molecules across the lipid cell
membrane and affect the activity of the drug. In addition, the presence of bulky groups
such as pyridine and flexible substituents significantly reduces the rate of deactivation
by S-containing molecules like glutathione (GHS) as discussed for ZD0473 in Chapter 1
(section 1.3.5). 13,14 Complex 3 (Figure 2.1) hardly reacted with GHS as it is sterically
hindered. This steric hindrance reduces in vivo reactions associated with competing S-
nucleophiles like GHS and sulphur containing proteins. In summary, the lability of the
Pt–Cl bond can contribute to the observed cytotoxicity.
1
N
N
H
O N
Pt
Cl
S
O
O
+
N
N
O
Pt
2
Cl
NH 2
N
2 3
Figure 2.1: Structures of some monofunctional platinum(II) complexes active against
human colon carcinoma cell line (HCT-116). 11
Therefore besides controlling antitumor activity, the kinetics of ligand exchange
reactions of the Pt(II) complexes is important in controlling other side reactions that
could mediate toxicity. A brief summary of the relevant theoretical aspects of possible
ligand substitution reaction mechanisms of d 8 square-planar Pt(II) complexes was
undertaken.
+
N
O
Pt
Cl
NH 2
+