Tuning Reactivity of Platinum(II) Complexes

linker remained coordinated to the metal centres possibly due to their cis geometry to
the incoming thiourea nucleophiles.
7.1 Introduction
The anticancer properties of cis diamine platinum(II) compounds is now well known
since cis-diamminedichloridoplatinum(II), cis-Pt(NH3)2Cl2, (cisplatin) and its analogues
oxaliplatin and carboplatin 1 are effective anti-tumour agents. They have been used
either singularly or in combination in the treatment of many tumours such as testicular,
ovarian, cervical, head/neck and colorectal cancer. 2-7 However, their clinical use has
been compromised by severe side effects e.g. nausea, ear damage, loss of sensation in
hands, vomiting, kidney toxicity, 8-11 and the emergence of platinum resistance, especially
those caused by the reduction of intracellular accumulation. These limitations have
stimulated great interest in the development of new platinum compounds;
approximately 30,000 new platinum complexes have been synthesised and screened
with the intention of overcoming cisplatin resistance or enlarging the spectrum of
activity. 10-13 Part of the search includes understanding the kinetics and thermodynamic
properties of the platinum complexes for a better understanding of the mechanistic
pathway of these reactions in biological systems.
Multinuclear Pt(II) complexes represent a novel class of compounds that have shown
great potential in cancer chemotherapy. 14 This family includes dinuclear complexes
consisting of two or more platinum(II) centres that are bridged by long and flexible
aliphatic diamine chains, 15,16 rigid aromatic diamines such as azoles, 17 diazines 18 or, a
semi-rigid linker like 4,4′-dipyrazolylmethane 19 and 4,4′-methylenedianiline 14 structural
groups, and the trinuclear [{trans-Pt(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)nNH2}2] +4
(1,0,1/t,t,t, n = 6, or BBR3464), which has entered phase II clinical evaluation. 20,21
Collectively, multinuclear platinum(II) complexes exhibit a significantly different binding
mechanism to DNA that involves electrostatic and hydrogen bonding interactions with
polyanionic DNA, 22 and therefore, display attractive biological properties over classical
drugs cisplatin and its analogues. For instance, the overall high charge coupled to
flexibility and lipophilicity of the linker chains, confers improved water solubility and
enhanced cellular drug uptake. Furthermore, because of the markedly longer distances
between the leaving groups, these complexes are capable of forming long-range (Pt, Pt)
2