Tuning Reactivity of Platinum(II) Complexes

interstrand and intrastrand DNA adducts that are more difficult to repair by the cellular
proteins, and could lead to enhanced cytotoxicity. 23-25
Nonetheless, the actual contribution of the bridge, i.e. its steric and electronic properties,
to the mechanism of the substitution of the leaving group remains unclear, especially in
dinuclear Pt(II) complexes in which the carbon chain length of α,ω-alkanediamine linker
is varied. Results from recent studies by Jaganyi et al., 26 Hoffmann et al. 27 and Farrell et
al., 28 have shown that the reactivity of dinuclear Pt(II) complexes bridged by flexible α,ω-
alkanediamines is dependent on the average distance separating the Pt(II) centres, and
decreases as the length of the aliphatic chain is increased. More importantly, the
molecular geometry and symmetry adopted by these type of complexes is another
critical factor controlling the reactivity of the Pt(II) centres. 27,29,30 In particular, studies
indicate that BBR3464 and its analogues, which have monodentate amine ligands
around the platinum(II) centres and leaving groups in trans geometry to the
alkanediamine linker, are degraded in vitro through liberation of the alkanediamine
bridge under the strong trans-influence of coordinated sulphur and nitrito
nucleophiles, 2,31 leading to substitution of the Pt–Cl bond. 32 In contrast, the cis geometry
as in 1,1/c,c dinuclear structure [cis-{Pt(NH3)2Cl}2-μ-Y] +n, exhibits enhanced stability to
metabolic deactivation; the reactions are slower than their trans-counterparts, but
eventually the NH3 group trans- to the sulphur atom is lost because of the strong
labilising Pt–S bond. 33 However, 1,1/c,c compounds based on 1,2-diaminecyclohexane
(dach) as the carrier ligand show enhanced robustness attributable to the chelate effect
of the dach ring. 34,35
A great attention has been so far paid mostly to multinuclear trans Pt(II) complexes
whose clinical application is limited due to their lowered stability to metabolic
deactivation. In an effort to gain more insight into the role of the flexible α,ω-
diaminealkane linker on reactivity of each of the two platinum(II) centres of the
dinuclear cis-Pt(II) complexes, this study was undertaken using the complexes
presented in Scheme 7.1, by measurement of the pKa values of the coordinated water
ligands in their aquated derivatives, and also substitution reactions using sulphur
nucleophiles thiourea (TU), N,N-dimethylthiourea (DMTU), and N,N,N,N-
tetramethylthiourea (TMTU). Deprotonation of the aquated complexes to give hydroxo
complexes is of interest because the latter complexes are less reactive than the aqua
3