Tuning Reactivity of Platinum(II) Complexes

comparison of the reactions between 1,1/cis,cis (alkanediamine, n = 6) and 1,1/cis,cis
(4,4’-dipyridylsulfide) (4) with glutathione suggests that steric hindrance of the phenyl
rings of the latter complex is likely to impede deactivation by strong sulphur containing
molecules. 85 However, their cytotoxic activity in tumour cell lines exhibits an increasing
trend with the increase of the carbon chain length when comparing complexes having 6,
8, 10 and 12 carbons in the alkyl moiety. 84,86 In contrast, complexes possessing rigid
bridging ligands, such as hydrazine and azoles (3) are developed to minimize distortion
of the DNA double helix in a 1,2-intrastrand cross-link. 87
1.3.5.2 Aromatic Linkers
A new class of dinuclear Pt(II) complexes with azines as bridging ligands has been
described in a study by Kalayda, 77,88 which exhibited considerable activity in vitro
against several human tumour cell lines. In particular, the pyrazine-linked complex (5)
displays the highest antitumour activity against cisplatin-resistant L1210 murine
leukaemia cell lines. Unlike the dinuclear platinum complexes bridged by the 4,4’-
dipyrazolymethane (dpzm) ligand(6) 89 where it was reported that the rigidity of the
bridge would lead to their poor cytotoxicities, the isomeric azine-bridged complexes
were found to exhibit good antitumour activity, more so in cisplatin resistance cells. 77,88
These complexes (diazines), unlike the trinuclear Pt complex BBR3464 (see Figure 1.9)
that was invented jointly by Novuspharma and Farrell 90,91 and other 1,1-trans,trans
analogues, are expected due to their 1,1-cis,cis geometry to be resistant to
decomposition by S-donor nucleophiles that hampers the clinical use of the trans Pt(II)
complexes hitherto tested. BBR3464 has entered phase II clinical trials, and shows
activity against pancreatic, lung and melanoma cancers. 92 The diazine complexes form
part of the research objectives and are further discussed in chapter 5.
Several dinuclear Pt(II) complexes based on EDTA-like ligands have been synthesised
(7). 37 These complexes are anionic and have a decreasing affinity towards DNA due to
the negative charge. Another reason for lack of anti-tumour activity of these compounds
is the impossibility of the anionic complexes to penetrate through the cell system and
the cytoplasmatic membranes as well as their rapid elimination from the system. 93
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