Four complexes of the type [Pt(N-N-X)Cl](X = N or C) were tailor synthesized for mechanistic studies in methanol. The terdentate ligands included terpy, 4'-Ph-terpy, 4'-(2"-CF(3)-Ph)-terpy, and 4'-(2"'-CF(3)-Ph)-6-Ph-2,2'-bipy. The rate of substitution of the chloro ligand by thiourea, N,N'-dimethylthiourea, and N,N,N',N'-tetramethylthiourea was studied as a function of nucleophile concentration, temperature and pressure by using a stopped-flow technique. The observed pseudo-first-order rate constants for the substitution reactions obeyed the simple rate law k(obs) = k(2)[Nu]. Second-order kinetics and negative activation entropies and volumes support an associative substitution mechanism. At 298 K, the values of the second-order rate constant show a slight dependence on the nature of the moiety attached to the terpy ligand. Changing from a nitrogen sigma-donor to a carbon sigma-donor in the cis position, results in a deceleration of the substitution rate. The results suggest that the Pt-C bond in the cis position activates the metal centre in a different way than in the trans position.

Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by 1 H NMR, 195 Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5 0 -monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.

A series of azine-bridged dinuclear platinum(II) complexes of the type [{trans-Pt(NH 3 ) 2 (OH 2 )} 2 (μ-azn)](ClO 4 ) 4 (where azn = pyrazine (pzn, Pt1), 2,3-dimethylpyrazine (2,3-pzn, Pt2), and 2,5-dimethylpyrazine (2,5-pzn, Pt3)) were synthesized to investigate the influence of the bridging azine ligand on the reactivity of the platinum(II) centers. The pK a values of the complexes were determined via acid-base titration, and the rate of substitution of the aqua moiety by a series of neutral nucleophiles, viz. thiourea (TU), 1,3-dimethyl-2-thiourea (DMTU), and 1,1,3,3-tetramethyl-2-thiourea (TMTU), was determined under pseudo-first-order conditions as a function of concentration and temperature using standard spectrophotometric techniques. The introduction of the methyl groups to the bridging azine linker in Pt2 and Pt3 leads to a moderate increase in the pK a values obtained for the first and second deprotonation steps, respectively, as a result of the increased σ-donor capacity of the bridging azine ligand trans to the aqua moiety. A comparison of the rate constants, k 1 and k 2 , at 298 K, obtained for the substitution of the aqua moieties from Pt1, Pt2, and Pt3 by TU, shows that the introduction of the σ-donating methyl groups on the bridging azine ligand in Pt2 and Pt3 results in a corresponding decrease in the reactivity, by ca. five times for the first substitution step and ca. 10 times for the second substitution step. Density functional theory calculations at the B3LYP/LACVP** level of theory for the complexes demonstrate that the introduction of electron-donating methyl groups results in (i) increased steric hindrance over the metal centers and (ii) decreased the positive charge on the metal center and increases energy separation of the frontier molecular orbitals (E HOMO -E LUMO ) of the ground-state platinum(II) complexes, leading to a less-reactive metal center. C

A series of dinuclear platinum II complexes of the type [{trans-Pt(H 2 O)(NH 3 ) 2 } 2 -NH 2 (CH 2 ) n H 2 N] 4+ (where n = 2, 3, 4, and 6) were synthesized to investigate the influence of the bridging diamine linker on the reactivity of the platinum centers. The pK a values were determined, and the rates of substitution of the aqua moieties by a series of neutral nucleophiles viz. thiourea, 1,3-dimethyl-2-thiourea, and 1,1,3,3-tetramethyl-2-thiourea were studied as a function of concentration and temperature. All reactions studied gave excellent fits to a single exponential and obeyed the simple rate law, k obs = k 2 [Nu]. Negative activation entropies support an associative mode of substitution. The results obtained suggest that the rate of substitution is definitely influenced by the length of the diamine chain, with the rate of substitution decreasing as the length of the diamine chain increases.

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