Tuning Reactivity of Platinum(II) Complexes

the hydrolysis of the complex, whereas the non-hydrolysable and sterically demanding
lipophilic chelating amine (dach) ligand makes the complex less polar. This has been
proposed to contribute to a better cellular uptake. 60 In addition, the dach ligand
prevents the binding of the DNA repair proteins by pointing into the major DNA groove
(Figure 1.6). These adducts shield the inhibition of DNA replication, resulting in
apoptosis and cell death. Oxaliplatin and carboplatin both have bidentate leaving groups
that reduce the severity of the side effects by slow ligand exchange reaction with plasma
proteins.
Figure 1.6: DNA adducts formed by oxaliplatin 13 .
Sterically Hindered Platinum(II) Complex (ZD0473)
One of the main mechanisms of cisplatin-resistance is an increase in intracellular thiol-
mediated detoxification by peptides and proteins such as glutathione and
metallothionines (see section 1.3.2.5). Cis-ammninedichlorido(2-methylpyridine)Pt(II),
(ZD0473) (Figure 1.7) is the first drug to be administered orally. It is sterically hindered
platinum(II) complex and is in phase II clinical trials. 61 Crystal structures of the complex
have shown that the pyridine ring is tilted at 102.7° with respect to the PtN2Cl2
coordination square-plane. 62 This introduces steric hindrance directly above the
platinum coordination plane, limiting the axial attack by the incoming nucleophile to
11